nutrients

Review
Prebiotics and Probiotics for Gastrointestinal Disorders
Sameeha Rau, Andrew Gregg , Shelby Yaceczko and Berkeley Limketkai *

Vatche & Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of
California Los Angeles, Los Angeles, CA 90095, USA; [email protected] (S.R.);
[email protected] (A.G.); [email protected] (S.Y.)
* Correspondence: [email protected]

Abstract: The complex role of the gut microbiome in the pathogenesis of gastrointestinal (GI) disor-
ders is an emerging area of research, and there is considerable interest in understanding how diet can
alter the composition and function of the microbiome. Prebiotics and probiotics have been shown to
beneficially modulate the gut microbiome, which underlies their potential for benefit in GI conditions.
Formulating specific recommendations for the public regarding these dietary supplements has been
difficult due to the significant heterogeneity between strains, doses, and duration of treatment inves-
tigated across studies, as well as safety concerns with administering live organisms. This review aims
to summarize the existing evidence for the use of prebiotics and probiotics in various GI disorders,
paying special attention to strain-specific effects that emerged and any adverse effects noted.

Keywords: prebiotics; probiotics; gut microbiome; dietary supplements; short-chain fatty acids;
constipation; diarrhea; irritable bowel syndrome; inflammatory bowel disease

1. Introduction
The human gastrointestinal (GI) tract can crudely be defined as the hollow viscus that
extends from the mouth to the anus which is responsible for the digestion and absorption
of nutrients and excretion of waste products. When examined more closely, the GI tract
is a highly complex, specialized, and elegant machine that is essential for survival and
well-being. While the host physiology of the GI tract and its respective organs has been
well studied and established, the role of the trillions of microbes, including bacteria, viruses,
Citation: Rau, S.; Gregg, A.; Yaceczko, fungi, and protozoa, remains an intense area of investigation. These microorganisms,
S.; Limketkai, B. Prebiotics and defined as the human microbiome, have co-evolved with humans to form diverse commu-
Probiotics for Gastrointestinal nities within the GI tract that are intimately involved with numerous aspects of metabolism,
Disorders. Nutrients 2024, 16, 778. development of our immune system, and even regulation of our behavior [1,2]. While
https://doi.org/10.3390/nu16060778 the human genome consists of ~23,000 genes, the gut microbiome provides an additional
Academic Editor: Misha D. P. Luyer
~3 million or more “exogenous” genes, contributing a remarkable diversity of metabolites
to enhance host function and health [3]. These metabolites produced by the microbiome,
Received: 16 February 2024 including metabolites produced by the host GI tract cells and tissues, are collectively known
Revised: 5 March 2024 as the GI metabolome. The metabolome, which includes small molecules, amino acids,
Accepted: 6 March 2024 lipids, carbohydrates, and hormones, is highly dynamic and is influenced by diet, environ-
Published: 9 March 2024
mental exposures, genetics, stress, and microbial diversity. It therefore stands to reason that
alterations in the microbiome and metabolome can have significant implications for human
health and disease.
Copyright: © 2024 by the authors.
Alteration of the human microbiome and metabolome can be achieved through dietary
Licensee MDPI, Basel, Switzerland. changes, medications such as antibiotics, or ingestion of microbes themselves. In fact, the
This article is an open access article first suggestion of microbial ingestion as a therapeutic intervention came in 1907 when
distributed under the terms and Nobel laureate Elie Metchnikoff reported the linkage between the ingestion of fermented
conditions of the Creative Commons milk with high levels of viable Lactobacilli and the longevity of Bulgarians [4]. Since then,
Attribution (CC BY) license (https:// the notion of possible therapeutic modulation of the microbiome and metabolome has
creativecommons.org/licenses/by/ intrigued researchers, and since the advent of DNA and RNA sequencing in the 1990s, the
4.0/). field has exploded.

Nutrients 2024, 16, 778. https://doi.org/10.3390/nu16060778 https://www.mdpi.com/journal/nutrients

Nutrients 2024, 16, 778 2 of 22

Prebiotics and probiotics, defined in more detail below, are agents that, when ingested
in adequate amounts, can influence the composition of the microbiome and metabolome,
with important implications for the maintenance of healthy states, as well as the treatment
of disease. This narrative review aims to (1) define prebiotics and probiotics as well as
their proposed mechanism of action, (2) describe their role in inflammation and the gut
metabolome, and (3) summarize the existing evidence for the use of these supplements in
GI disorders.

2. Definitions and Mechanism of Action

2.1. Prebiotics
Prebiotics are non-digestible, fermentable food ingredients that alter the composition
and/or activity of gastrointestinal bacteria that confer benefit to the host [5]. Most prebiotics
are dietary fibers; however, not all dietary fibers have prebiotic properties [6]. The main
groups of prebiotics are fructans, which include inulin and fructo-oligosaccharides (FOSs),
galacto-oligosaccharides (GOSs), lactulose, resistant starch, glucose-derived oligosaccha-
rides such as polydextrose, and pectin oligosaccharides (POSs). These compounds naturally
exist in many food products, such as garlic, onion, chicory, asparagus, Jerusalem artichoke,
tomatoes, wheat, barley, and rye [7]. However, given their low concentration in food
products, some prebiotics are also synthetically produced on a large scale and can be added
to food products [8].

2.2. Probiotics
Probiotics are live, non-pathogenic microorganisms that can also alter the gut micro-
biome, conferring host benefit [9]. They can be found in a variety of fermentable foods or
purchased in the form of pills, powders, and liquid drops, and are often enteric-coated or
microencapsulated to prevent destruction by gastric acid and intestinal bile salts [10,11].
Probiotic products primarily contain one or more microbial strains, typically belonging
to the following genera: Lactobacillus, Bifidobacterium, Lactococcus, Streptococcus, Enterococ-
cus, or Bacillus. Strains of yeast belonging to the genus Saccharomyces are also commonly
used [12]. Current evidence suggests that most probiotic supplements do not colonize the
host long-term (>6 months), most likely due to competition with existing host microbiota.
This necessitates continued supplementation for long-term benefits but also averts the
potential risk of the probiotic disrupting the surrounding microbiota or entering systemic
circulation [13].

2.3. Synbiotics
Synbiotic products are a combination of prebiotics and probiotics that may exert a
synergistic effect. The prebiotic component is thought to improve the viability of the
probiotic component, as a key property of prebiotics is resistance to acids, proteases, and
bile salts in the upper GI tract [12]. The combination of Bifidobacterium or Lactobacillus with
FOSs is commonly used in synbiotic formulations [12].

2.4. Mechanism of Action

The primary therapeutic advantages of prebiotics and probiotics include (1) mod-
ulation of the host immune system and nervous system, (2) improved intestinal barrier
function and nutritional absorption, (3) competition with pathogens for nutrients and adhe-
sion to the gut mucosa, and (4) production of antimicrobial substances [12]. While the exact
mechanism by which they exert these effects remains poorly understood, current evidence
suggests that the production of immunomodulatory metabolites plays a significant role.
Probiotic bacteria ferment prebiotics and other dietary components to produce mul-
tiple metabolites that can alter the gut microbiome and enter systemic circulation, thus
affecting other organ systems [5,8]. Among the most studied metabolites are short-chain
fatty acids (SCFAs), such as acetate, propionate, and butyrate. SCFAs modulate gene
transcription by inhibiting histone deacetylase activity and activating G-protein-coupled
Nutrients 2024, 16, 778 3 of 22

receptors (GPCRs). Through these mechanisms, SCFAs can alter colonic motility and blood
flow and reduce gastrointestinal pH, which can influence nutrient absorption. Activa-
tion of specific GPCRs expressed on enteroendocrine L-cells by SCFAs can also trigger
the release of gut peptides (such as GLP-1), which are involved in gut barrier function
and energy metabolism [14]. Furthermore, SCFAs exert anti-inflammatory functions by
modulating immune cell chemotaxis, inhibiting the release of pro-inflammatory cytokines,
and stimulating the release of IgA and IL-6. Immunoregulatory probiotics can induce
the release of IL-10 and regulatory T-cells, rendering them useful in autoimmune disease,
allergy, IBD, and inflammation. In contrast, immunostimulatory probiotics stimulate IL-12
production, which activates helper T-cells and natural killer (NK) cells, thus boosting the
response against infections or cancer cells [15–17]. Additionally, SCFAs promote accelerated
pathogen clearance by increasing the production of reactive oxygen species. There is also
evidence suggesting that butyrate may exhibit an anti-cancer effect through the induction
of apoptosis and/or upregulation of a butyrate transporter [18].
Several other metabolites have also demonstrated an immunomodulatory effect on
the host. For example, probiotic bacteria such as L. reuteri and B. infantis produce indole
derivatives from dietary tryptophan, which can promote ILC3 cells and IL-22 production
and strengthen the integrity of the intestinal mucosa via activation of the aryl hydrocarbon
receptor [19,20]. Another group of metabolites, polyamines, are derived from arginine
and have been shown to enhance intestinal mucosa and inhibit the expression of pro-
inflammatory cytokines by lipopolysaccharide (LPS)-stimulated immune cells [19]. Some
strains of L. reuteri have additionally been identified to produce antimicrobial compounds
such as reuterin and polyketides [21]. Finally, probiotic bacteria can modify bile acids pro-
duced by the host to produce secondary bile acids, such as ursodeoxycholic acid (UCDA).
A recent study demonstrated that supplementation of L. acidophilus with subsequent pro-
duction of UCDA reduced inflammation in mice with ulcerative colitis via the activation of
multiple signaling pathways and modulation of Treg cells and M1 macrophages [22].
In addition to the mechanisms described above, probiotics are thought to directly
compete with pathogens for adhesion to the gut mucosa and enhance intestinal barrier
function by promoting mucin production, as well as by upregulating tight junction protein
expression [8,10,23–27]. Lastly, probiotics and prebiotics can produce neurotransmitters,
which not only act locally in the enteric nervous system but also centrally [2,23,28–30]. These
neurotransmitters include alterations in dopamine, serotonin, and gamma-aminobutyric
acid (GABA).

3. Impact of Prebiotics and Probiotics on Intestinal Permeability, Inflammation, and

Nutrient Absorption
The intestinal mucosa is a highly regulated and specialized epithelium designed
to not only absorb critical nutrients and excrete toxins but also provide a physical and
immunologic barrier between the microbial- and pathogen-rich lumen and the submucosal
tissue and circulatory system. In healthy individuals, it is presumed that this intestinal
barrier is intact, allowing for the flow of water, small molecules, and other nutrients
between the intestinal lumen and systemic circulation, maintaining a homeostatic state
and tempering inflammation. In diseased states, this barrier can be impaired, resulting
in increased intestinal permeability, allowing pathogenic microbial components such as
LPS or even entire microbes into the systemic circulation, and causing inflammatory states
and malabsorption. Increased intestinal permeability has been implicated in numerous
disease states including autoimmune conditions such as systemic lupus erythematosus,
cardiovascular disease, obesity, fatty liver disease, and inflammatory bowel disease, to
name a few [31–40]. While there are several mechanisms by which the intestinal barrier is
regulated, the host microbiome and metabolome appear to be critically involved.
Prebiotics and probiotics therefore present an exciting and promising therapeutic
approach to mitigate the effects of increased intestinal permeability, inflammation, and
nutrient malabsorption. For instance, one study utilized high-dose aspirin to promote
Nutrients 2024, 16, 778 4 of 22

increased intestinal inflammation and permeability in human subjects [34]. When pa-
tients were treated with aspirin and a probiotic Bifidobacterium strain or prebiotic GOS,
intestinal permeability was reduced, suggesting improved barrier function [34]. Another
study utilizing non-steroidal anti-inflammatory drug (NSAID)-mediated inflammation in
mice demonstrated increased intestinal secretion of tumor necrosis factor-alpha (TNF-α),
lactate dehydrogenase (LDH), and C-reactive protein (CRP) in response to indomethacin
administration [41]. Interestingly, this heightened inflammatory response was mitigated
by the co-administration of two separate probiotic Lactobacillus strains, suggesting an
anti-inflammatory effect of these probiotic strains [41]. Lastly, several studies have demon-
strated improved micronutrient absorption with prebiotic and probiotic use. Specifically,
in children, post-menopausal women, and geriatric patients, probiotic supplementation
improved serum calcium concentration when compared to placebo controls, suggesting im-
proved absorption within the intestinal lumen, possibly due to SCFAs affecting colonic pH
and enhancing calcium solubility [42–45]. Supplementation of prebiotic GOSs was found
to increase calcium absorption in postmenopausal women and adolescent girls, thought
to be mediated by increased Bifidobacteria levels [46,47]. Additionally, some probiotics are
natural producers of B vitamins [10,12].

4. Methods
A search query was designed to capture articles pertaining to the use of pre- or
probiotics in the context of gastrointestinal disorders (Supplementary Material 1). A list
of 8506 potentially relevant articles was retrieved from PubMed for the period between
inception and 14 August 2023. There were no restrictions on article type, study design, or
language. All titles and abstracts were screened by at least one author or assistant, yielding
2302 articles for further review. Additional articles not generated by the initial search query
were included if deemed pertinent upon a non-exhaustive review of cited references. The
body of relevant articles was then used as the foundation for developing each section of
this narrative review, although it was not required that all articles be incorporated into
the manuscript.

5. Role of Prebiotics and Probiotics for Various Gastrointestinal Conditions

5.1. Diarrhea
Probiotics have been shown to confer benefits in the prevention and treatment of
some types of diarrhea, as described below; however, little to no information is available
regarding the role of prebiotics for diarrhea.

5.1.1. Infectious Diarrhea

One systematic review and meta-analysis found that Saccharomyces boulardii CNCM
I-745 significantly decreased the incidence of traveler’s diarrhea [48]. A separate meta-
analysis by Fagnant et al. found that prebiotics and probiotics modestly reduced the
risk of GI tract infection in adults; however, the study was limited by a high risk of bias
and heterogeneous interventions and could not assess the effects of specific prebiotic or
probiotic strains [49].
For the treatment of infectious diarrhea, a 2021 meta-analysis showed that multiple
single-strain and multi-strain probiotics significantly reduced the duration of acute diar-
rhea in children; Saccharomyces boulardii was the most effective probiotic strain overall;
however, Limosilactobacillus reuteri, Bifidobacterium lactis, Lactobacillus species (spp.) plus
Bifidobacterium spp. plus Saccharomyces spp., and Bacillus spp. plus Enterococcus spp. plus
Clostridium spp. were also shown to be effective [50]. Multiple other meta-analyses con-
firmed that probiotics could decrease the duration of diarrhea and length of hospitalization,
with Saccharomyces and Bifidobacterium frequently cited to be more effective than Lacto-
bacillus [51,52]. Importantly, the dose and timing of probiotic administration seemed to
impact their effect. Two meta-analyses demonstrated that higher doses of Lacticaseibacillus
rhamnosus GG (≥1010 colony-forming units [CFU]) were more effective in reducing the
Nutrients 2024, 16, 778 5 of 22

duration of diarrhea [53,54]. In contrast, a previous systematic review and meta-analysis

by the Cochrane Collaboration in 2020 found no difference in the incidence or duration of
acute infectious diarrhea in the probiotic versus control groups [55].
The effect of probiotics on infectious diarrhea in children may also be influenced by
socioeconomic status. One meta-analysis found that the combination of Saccharomyces
boulardii and zinc reduced the duration of acute diarrhea in children in low- and middle-
income countries [56]; this benefit was not seen in another meta-analysis examining the
duration of diarrhea in children in developed countries receiving probiotic supplementa-
tion [57].
Overall, there is convincing evidence that certain probiotic strains can be safe and
effective in preventing and treating infectious diarrhea. Available studies suggest that
Saccharomyces boulardii may be relatively more efficacious; however, further research is
needed to identify the most optimal strain(s) and dosage of probiotics as well as the role of
prebiotics for acute diarrhea [58].

5.1.2. Antibiotic-Associated Diarrhea (AAD)

Probiotics have been associated with a significant reduction in AAD without a signifi-
cant increase in adverse effects [59,60]. Saccharomyces boulardii, Lactocaseibacillus rhamnosus
GG, and probiotic mixtures were found to be particularly effective in one meta-analysis [61].
Another randomized controlled trial (RCT) demonstrated that a probiotic drink contain-
ing Lactobacillus casei DN 114001 was effective in preventing AAD [62]. Like infectious
diarrhea, the dose and timing of probiotic administration impact their effect on antibiotic-
associated diarrhea. Probiotics were demonstrated to be particularly effective at higher
doses (≥5 billion CFUs/day) and when administered within two days of antibiotic treat-
ment for elderly adults [63,64]. No RCTs have examined the effect of prebiotics on the
prevention or treatment of antibiotic-associated diarrhea.

5.1.3. Clostridioides difficile Infection (CDI)

Saccharomyces boulardii has been shown to produce a protease that inhibits C. difficile
toxins A and B, which may underlie its potential benefit in CDI [65]. For hospitalized
patients receiving antibiotics, a 2017 meta-analysis demonstrated that administration of
probiotics closer to the first dose of antibiotics reduced the risk of CDI by >50%, with no
increased risk for adverse effects. [66]. However, the protective effect of probiotics was only
seen in patients with a >5% baseline risk of Clostridioides difficile-associated diarrhea (CDAD)
in another meta-analysis [67]. With low quality of evidence, the American Gastroentero-
logical Association (AGA) recommends using one of the following single- or multi-strain
probiotic formulations for prevention of CDI in patients receiving antibiotics: (1) S. boulardii,
(2) L. acidophilus CL1285 plus L. casei LBC80R, (3) L. acidophilus plus L. delbrueckii subsp.
bulgaricus plus Bifidobacterium bifidum, or (4) L. acidophilus plus L. delbrueckii subsp. bulgari-
cus, B. bifidum, and Streptococcus salivarius subsp. thermophilus [68]. Additionally, a recent
phase 2 clinical trial demonstrated that high-dose VE303, a combination of eight strains of
commensal Clostridia, was effective in preventing recurrent CDI in at-risk patients [69].

5.1.4. Chemotherapy- and Radiation-Induced Diarrhea

Chemotherapy and radiation therapy can cause intestinal mucositis and diarrhea by
increasing intestinal permeability via intestinal crypt apoptosis and villous atrophy and by
reducing the diversity of the gut microbiota (i.e., reduced levels of Bifidobacterium) [70]. The
mechanism by which this gut dysbiosis occurs is not entirely clear, but some chemotherapy
agents such as etoposide have demonstrated direct antibacterial activity, especially against
Gram-positive bacteria [71]. Thus, probiotics could be a useful adjunct to traditional
therapies for chemotherapy- and radiation-induced diarrhea; however, existing data are
limited. A review by the Cochrane Collaboration did not find high-quality evidence
showing a significant association between probiotics and chemotherapy- or radiation-
induced diarrhea; however, no adverse effects were seen [72].
Nutrients 2024, 16, 778 6 of 22

One Japanese RCT examining abemaciclib-induced diarrhea in patients with breast can-
cer found that supplementation with Bifidobacterium with or without trimebutine maleate
did not decrease the incidence of grade 2 or greater diarrhea [73]. Another meta-analysis
found that probiotics can prevent and treat chemotherapy-induced diarrhea without signif-
icant adverse effects, though the results were limited by heterogeneity and poor method-
ological quality amongst the included trials. Most included studies examined probiotics
containing Bifidobacterium spp. and/or Lactobacillus spp., but no further strain-specific
effects were reported [74].
For radiation-induced diarrhea, a meta-analysis in 2017 found that probiotics signifi-
cantly reduced the incidence of radiation-induced diarrhea in patients with abdominal or
pelvic cancers. The probiotic strains found to have an effect were Lactobacillus acidophilus
plus Bifidobacterium bifidum, L. acidophilus LAC-361 plus B. longum BB-536, and VSL#3®
(a multi-strain probiotic including L. paracasei, L. plantarum, L. acidophilus, L. helveticus, B.
longum, B. breve, B. infantis, and S. thermophilus). A synbiotic containing L. acidophilus and
lactulose was also found to be effective in reducing radiation-associated diarrhea [75,76].
Studies examining prebiotics were limited; however, one small RCT found that supplemen-
tation with resistant starch did not reduce the incidence of radiation-induced proctitis [77].
Taken together, there is a signal towards a benefit of probiotics for radiation-associated
diarrhea, but there is no convincing evidence for the use of probiotics for chemotherapy-
induced diarrhea.

5.2. Constipation
There are observed differences in the gut microbiome of patients with constipa-
tion, namely decreased levels of Bifidobacteria and Lactobacilli and increased levels of Bac-
teroides [78–80]. Prebiotics and probiotics are therefore thought to be helpful in constipation
by increasing levels of Bifidobacteria and Lactobacilli; the resultant production of SCFAs may
regulate motility by increasing the release of serotonin and stimulating enteric or vagal
nerves acting on colonic smooth muscle [81,82]. Studies have examined the effect of differ-
ent prebiotic types and probiotic species on various aspects of constipation including stool
frequency, stool consistency, defecation pain, overall response to treatment, and quality of
life, lending to significant heterogeneity between studies in pooled analyses.

5.2.1. Prebiotics for Constipation

One RCT demonstrated that the consumption of 15 g of chicory inulin daily for
28 days by elderly adults with constipation led to increased levels of Bifidobacterium and
an improvement in constipation and quality of life [83]. Some gastrointestinal side effects,
such as increased flatulence, were noted with inulin supplementation but did not lead to
discontinuation in the study. Two additional RCTs demonstrated that inulin consumption
led to significantly increased stool frequency in constipated adults [84,85].
In addition to inulin, Deshipu stachyose granules (DSGs), a mixture of alpha-galacto-
oligosaccharides, have also shown efficacy in constipation. An RCT from 2017 demon-
strated that treatment with 5 g per day of DSGs for 14 days led to increased levels of
fecal Bifidobacteria and Lactobacilli and decreased levels of fecal Clostridium perfringes in
healthy patients. Furthermore, treatment with 5 g of DSGs daily for 30 days in constipated
patients led to an improvement in defecation ease and frequency, as well as softer stools; no
adverse effects were noted [86]. Similarly, daily consumption of 11 g of GOSs significantly
increased stool frequency in adults with ≤3 bowel movements per week in another RCT.
The authors also found a dose–response relationship between GOSs and levels of fecal
Bifidobacterium [87]. A 2015 meta-analysis confirmed that GOSs significantly increased stool
frequency with no heterogeneity between studies. However, this benefit was not seen with
inulin, though there was significant heterogeneity noted. There were no reported adverse
effects [88].
Nutrients 2024, 16, 778 7 of 22

In summary, the existing evidence suggests that prebiotics, especially GOSs, are safe
and effective in improving constipation and may exert their effects by modulating the gut
microbiome and Bifidobacterium levels, in particular.

5.2.2. Probiotics for Constipation

A systematic review and meta-analysis found that probiotics, specifically Bifidobac-
terium lactis, significantly increased stool frequency in adults with chronic constipation. This
effect on stool frequency was not seen with other probiotic strains, such as Bacillus coagulans
Unique IS-2 or Lacticaseibacillus casei Shirota, or with mixtures of probiotics; however, B.
coagulans Unique IS-2 was noted to improve abdominal pain and defecation pain. Overall,
probiotics were also found to improve response to treatment and integrative symptom
scores, but no species- or strain-specific effects were identified for these metrics. Only minor
adverse effects were reported such as loose stools, bloating, and abdominal discomfort,
which were not significantly different between the probiotic and control groups [89,90]. The
RCT by Yoon et al., which was included in the prior meta-analysis, found that daily sup-
plementation with Streptococcus thermophilus MG510 (3 × 108 CFU) and Lactiplantibacillus
plantarum LRCC5193 (1 × 108 CFU) significantly improved stool consistency in adults with
constipation after 4 weeks of treatment. Interestingly, the relative abundance of Lactiplan-
tibacillus plantarum in the fecal microbiome persisted in the probiotic group four weeks after
discontinuation of the supplement, suggesting that it may confer a prolonged benefit [91].
A Brazilian RCT by Mitelmão et al. compared the efficacy of a probiotic mixture
containing three strains of Lactobacillus and Bifidobacterium, another mixture containing
eight strains, and conventional fiber therapy in adults with constipation. All interventions
were safe and effective in improving symptoms of constipation; however, no significant
difference was seen between the groups [92].
A separate meta-analysis found that multispecies probiotics significantly improved
defecation frequency and fecal incontinence in children with chronic constipation, but there
was no significant effect on treatment success, abdominal pain, and painful defecation [93].
Limosilactobacillus reuteri was studied in five of the included RCTs, but a subgroup analysis
could not be performed due to inconsistent outcome reporting. L. rhamnosus, B. longum,
and Saccharomyces boulardii were also included in the systematic review, in addition to
several multispecies probiotics, which were found to have a more significant benefit than
probiotics with a single species.
Duration of probiotic treatment and concomitant laxative use may also impact its
efficacy. An RCT by Šola et al. found that a liquid probiotic formulation containing
Bifidobacterium animalis susp. Lactis BLC1, Lactobacillus acidophilus LA3, and Lactobacillus
casei BGP93 significantly increased the cumulative number of bowel movements after the
10th week of treatment in elderly patients without concomitant laxative use. No adverse
events were noted in the treatment group and no significant differences were seen in the
safety-monitoring labs [94].
Taken together, these results are promising that probiotics, especially multi-strain
formulations, are likely safe and effective in alleviating some aspects of constipation;
however, more studies are needed to determine the optimal strain(s), dose, and duration
of treatment to inform clinical recommendations. Additionally, more studies comparing
probiotics to conventional fiber therapy are needed to demonstrate superiority given the
additional considerations of cost, stability, and storage associated with probiotics.

5.2.3. Synbiotics for Constipation

Data were more limited for synbiotics and results were inconclusive. An RCT by
Baştürk et al. found that a synbiotic containing L. casei, L. rhamnosus, L. plantarum, B. lactis,
fiber, polydextrose, FOSs, and GOSs significantly improved stool frequency and symptoms
of constipation in children after 4 weeks of treatment [95]. In contrast, a 2022 meta-analysis
found that synbiotics did not significantly improve stool output or integrative symptom
scores in constipated adults. Four studies were included in the pooled analysis and the
Nutrients 2024, 16, 778 8 of 22

synbiotics tested were (1) Lactiplantibacillus plantarum LP01 and Bifidobacterium lactis BB12
plus inulin and oligofructose, (2) Lacticaseibacillus casei CRL431 and B. lactis BB12 plus
inulin and oligofructose, (3) B. lactis LMG P-28149 and FOS, and (4) L. paracasei Lpc-37, L.
rhamnosus HN001, L. acidophilus NCFM, and B. lactis HN019 plus FOS [89].

5.3. Irritable Bowel Syndrome (IBS) and Disorders of Gut–Brain Interaction (DGBIs)
Per the Rome IV criteria, irritable bowel syndrome (IBS) is diagnosed in patients with
recurrent abdominal pain at least once weekly, on average, over the prior three months that
is associated with at least two of the following symptoms: pain related to defecation, change
in stool frequency, and change in stool form or appearance. It can be further classified as
constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), IBS with mixed
bowel habits (IBS-M), or IBS unclassified (IBS-U) [96]. The pathophysiology is multifactorial
and not fully understood, but is thought to involve motility dysfunction, alterations in the
gut microbiota and enteric nervous system, and low-grade inflammation—all of which
may be regulated by prebiotics and probiotics.

5.3.1. Prebiotics for IBS

The role of prebiotics for IBS is complex and not well understood, as some prebiotic
types may be beneficial and others may cause harm [97,98]. This is unsurprising, as many
patients with IBS are sensitive to FODMAPs (Fermentable Oligosaccharides, Disaccharides,
Monosaccharides, Additionally, Polyols), which include FOSs and GOSs [98]. Three RCTs
demonstrated that food products or beverages containing inulin led to improvement in
stool parameters in patients with IBS-C [99–101]. One of these studies, which tested a
functional drink containing inulin, menthol, and pyridoxine, found increased heartburn in
the treatment arm, but otherwise, no major adverse effects were noted [100]. In contrast,
oligofructose and FOSs were not effective in reducing IBS symptoms; in fact, FOS supple-
mentation led to worsening of symptoms after 4–6 weeks in one study, though there was
no difference between the intervention and placebo groups at 12 weeks [102,103]. Another
RCT demonstrated that GOS was effective in reducing global IBS symptom scores at doses
of 3.5 g/day and 7 g/day; however, the group receiving the lower dose experienced fewer
side effects [104]. Though not statistically significant, one study found that short-chain
FOSs (scFOSs) tended to reduce rectal sensitivity in patients with IBS-C. scFOSs also signif-
icantly reduced anxiety scores and increased fecal Bifidobacteria compared to placebo [105].
A 2019 systematic review and meta-analysis concluded that prebiotics did not significantly
impact symptom scores in patients with IBS, though interpretation was limited by study
heterogeneity. The study also showed that prebiotics increased the relative abundance of
Bifidobacteria in patients with IBS, with subgroup analysis highlighting that inulin-type
fructans and doses of prebiotics > 6 g/day increased levels of Bifidobacteria [106].
In summary, inulin and GOSs may be helpful for IBS, though additional studies are
needed to confirm their benefit, and adverse effects may be associated with higher doses.
Evidence for FOSs was inconsistent and suggested a possible deleterious effect of FOSs on
IBS symptoms.

5.3.2. Probiotics for IBS

A systematic review and meta-analysis from 2018 found that probiotics significantly re-
duced the risk of persistent symptoms compared to placebo in patients with IBS. The study
identified that the combination probiotic, LacClean Gold (contains Bifidobacterium longum, B.
bifidum, B. lactis, Lactobacillus acidophilus, Lacticaseibacillus rhamnosus, and Streptococcus ther-
mophilus), and a seven-strain combination of three Bifidobacterium strains, three Lactobacillus
strains, and one Streptococcus strain showed a significant benefit over placebo. Additionally,
the individual strains Lactiplantibacillus plantarum DSM 9843, Escherichia coli DSM 17252,
and Streptococcus faecium were superior in reducing the risk of persistent symptoms. While
there was a trend towards benefit for Bifidobacterium (p = 0.05), no significant strain-specific
effects were identified for global IBS and abdominal pain scores. Pooled analysis of com-
Nutrients 2024, 16, 778 9 of 22

binations of probiotics demonstrated a benefit for this outcome, with VSL#3® showing a
trend towards benefit [107]. Another small RCT demonstrated that a combination probiotic,
Bifiform (containing Enterococcus faecium and Bifidobacterium longum), was more effective in
treating post-infectious IBS compared to standard complex therapy alone, which included
an antispasmodic drug, an antibiotic, and a drug to normalize the consistency of feces [108].
Overall, probiotics appear to improve IBS symptoms, with certain single-strain and
combination-strain probiotics emerging as superior.

5.3.3. Synbiotics for IBS

A 2021 review article summarized the results of 10 clinical studies examining different
synbiotic formulations in IBS [97]. Most studies demonstrated a significant improvement
in at least one IBS marker, from abdominal bloating and pain to SCFA levels. More studies
are needed to confirm the benefit of each synbiotic formulation and better define their
clinical impact.

5.4. Small Intestinal Bacterial Overgrowth (SIBO)

SIBO is characterized by an increase in the number of bacteria in the small bowel
in a distribution more commonly associated with the colon, leading to gastrointestinal
symptoms and malabsorption. Antibiotics are the mainstay of therapy, however, recurrence
of SIBO is extremely common, often necessitating re-treatment which can increase the
risk of antibiotic resistance, diarrhea, and food intolerances [109]. As a result, there is
interest in harnessing probiotics in the treatment of SIBO, given their ability to produce
antimicrobial substances, compete with pathogenic microbes for nutrients and adhesion to
the gastrointestinal mucosa, increase motility, and help restore balance in the gut microbiota
after antibiotic therapy. Unfortunately, research on prebiotics and probiotics for SIBO
is scarce, underlining the need for additional research to confirm their clinical safety
and efficacy.

5.4.1. Prebiotics for SIBO

Only one RCT examined the role of prebiotic supplementation for SIBO. Rosania et al.
showed that treatment with rifaximin for seven days followed by FOSs for seven days led
to a significant improvement in four out of six symptoms evaluated (diffuse abdominal
pain, left iliac pain, meteorism, and flatulence) in patients with SIBO [110].

5.4.2. Probiotics for SIBO

A 2017 systematic review and meta-analysis found that probiotics led to higher rates of
SIBO decontamination compared to placebo and metronidazole; probiotics plus antibiotics
were more effective than probiotics alone. Additionally, there was a significant decrease in
H2 levels detected on hydrogen breath testing after taking probiotics and an improvement
in abdominal pain scores, but there was no significant impact on daily stool frequency.
Probiotics were not found to have a significant effect on SIBO incidence in the pooled
analysis [111].
Among patients with SIBO in the setting of systemic sclerosis, one RCT showed that
treatment with Saccharomyces boulardii with or without metronidazole led to a significant
improvement in pain and bloating compared to metronidazole alone, with no serious
adverse effects [112]. Notably, one RCT demonstrated that supplementation with the
Bifidobacterium triple-viable capsule (contains B. longum, L. acidophilus, and Enterococcus
faecalis) significantly improved symptoms and rates of SIBO resolution compared to placebo
in patients with SIBO and GI malignancies [113,114]. An RCT by Rosania et al. showed that
rifaximin followed by Lacticaseibacillus casei improved symptoms of diffuse abdominal pain,
left iliac pain, meteorism, flatulence, and nausea in patients with SIBO. Rifaximin followed
by Lacticaseibacillus casei was found to be more effective in improving symptoms than
rifaximin followed by FOSs, though this difference was not statistically significant [110].
Nutrients 2024, 16, 778 10 of 22

Available evidence suggests that probiotics, especially L. casei, can improve symptoms
associated with SIBO and may exhibit a synergistic effect when used with antibiotics for
SIBO treatment.

5.4.3. Synbiotics for SIBO

A small RCT demonstrated that the addition of a synbiotic containing Bacillus coagulans
and FOSs to maintenance antibiotic therapy led to a significant improvement in abdominal
pain and gastrointestinal symptoms, such as flatulence, belching, and diarrhea, compared
to antibiotics alone. A greater proportion of patients in the probiotic group had a negative
hydrogen breath six months after treatment, though this difference was not statistically
significant [115].

5.5. Inflammatory Bowel Disease (IBD)

The role of specific gut microbial communities in defining the metabolomic products
of dietary intake, which can in turn exert pro- or anti-inflammatory effects, has motivated
the exploration of microbiome manipulation approaches for IBD [116]. The conversion
of some prebiotics by microbial fermentation into SCFAs provides a mechanistic basis for
their anti-inflammatory effects. SCFAs modulate inflammation through the induction of
regulatory T-cells in the colon, partial suppression of macrophage activation, and inhibition
of nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) activation in lamina
propriate macrophages [117–119]. SCFAs can also regulate intestinal epithelial barrier
function, thus reducing bacterial translocation and mucosal antigen presentation [120].

5.5.1. Prebiotics for IBD

Given the potential immunological benefits, several RCTs and an open-label observa-
tional trial investigated the role of prebiotics for the induction and maintenance of remission
in IBD.
For ulcerative colitis (UC), a Japanese RCT with 40 participants found the FOS 1-
kestose at 10 g/day to be superior to a maltose placebo for the induction of clinical remis-
sion [121]. Three RCTs did not otherwise find a difference between oligofructose-enriched
inulin (OF-IN) at 10–12 g/day with their respective controls (OF-IN at 7.5 g/day, maltodex-
trin placebo, no intervention) for the induction of clinical remission [122–124]. There was
nonetheless a reduction in fecal calprotectin concentrations observed in two of the RCTs
with OF-IN at 12–15 g/day but not with the lower-dose OF-IN at 7.5 g/day or maltodex-
trin placebo [122,123]. As for other prebiotics, two RCTs with 59 participants found that
germinated barley foodstuff (GBF) at 20–30 g/day for 2–4 weeks decreased gastrointestinal
symptoms [125,126]. In an RCT with 51 participants with active UC, roasted Plantago ovata
seeds at 3.6 g/day led to less abdominal tenderness than the roasted wheat flour control by
week 8 [127]. More granular data on rates of remission comparing both prebiotics and their
respective controls were not reported.
For maintenance of remission in UC, an open-label observational trial with 59 par-
ticipants found GBF at 20 g/day to be associated with lower clinical activity scores and
cumulative relapse rates than the no-intervention control by week 52 [128]. RCTs did not
otherwise find relapse rates for those who received OF-IN, oat bran, or Plantago ovata seeds
to differ from their respective controls [129–132].
For Crohn’s disease (CD), the data on prebiotics are even more sparse. Two RCTs
evaluated OF-IN at 15–20 g/day and found no benefit for the induction of clinical re-
mission [133,134]. There are no controlled trials evaluating the role of prebiotics in the
prevention of clinical relapse in CD.
While prebiotics are generally considered safe, pooled analyses indicate that OF-IN
may lead to an increased risk of adverse events compared to their respective
controls [122,123,133,134]. The complaints included bloating and flatulence, which are
not surprising from the consumption of oligosaccharides. There were otherwise no serious
Nutrients 2024, 16, 778 11 of 22

adverse effects. As for 1-kestose, lactulose, GBF, Plantago seeds, and psyllium, adverse
event rates were no different than those of controls in RCTs.
Due to the very small sample sizes and some risk of bias among these studies of
prebiotics for IBD, the certainty of evidence is generally very low and no conclusions can
be made about the efficacy of prebiotic supplementation for IBD at this time. There are
nonetheless some data to support the use of plant-based diets, which are rich in dietary
fibers, for reductions in symptoms and, potentially, inflammation [135,136]. Fruits and
vegetables are also a consistently important component of anti-inflammatory diets found
to be helpful for IBD. Care should nonetheless be exercised when recommending fiber for
patients with stricturing CD [137].

5.5.2. Probiotics for IBD

Unlike with prebiotics, there are more data on the use of probiotics for IBD, although
there is still much need for additional investigation. In a systematic review and meta-
analysis by the Cochrane Collaboration, probiotics were overall effective for the induction
of clinical remission in UC [138]. Probiotics were also effective for achieving clinical
improvement, endoscopic improvement, and histologic improvement, but not histologic
remission. However, in subgroup analysis, single-strain probiotics (including E. coli Nissle
1917, L. reuteri ATCC 55730, B. longum, and L. casei) were not effective individually or in
aggregate for the induction of clinical remission [139–142]. By contrast, two RCTs with 29
and 147 participants, respectively, found VSL#3® at 450–3600 × 109 CFU/day to be effective
for the induction of clinical remission in UC [143,144]. Another RCT with 144 participants
also found VSL#3® at 3600 × 109 CFU/day to improve disease activity scores and rectal
bleeding, although the differences were not significantly different from placebo [145]. There
were no overall differences in minor or serious adverse events when comparing probiotics
with placebo [138]. In a separate systematic review and meta-analysis by the Cochrane
Collaboration, three RCTs of three different multi-strain probiotics did not identify any that
were effective individually or in aggregate for the maintenance of remission in UC [146].
There is no RCT that specifically examined the efficacy of VSL#3® for the prevention
of clinical relapse in patients who were in remission at baseline; however, an RCT that
included a longitudinal follow-up after initial randomization to evaluate the induction of
remission found that those assigned to the VSL#3® arm had lower rates of relapse within
1 year (21.4% vs. 73.3%; p = 0.014) [143].
For patients who underwent ileal pouch anal anastomosis and subsequently developed
pouchitis, there are some RCTs that demonstrated the benefit of probiotics for primary
prevention [147,148]. The AGA, however, graded the available evidence to have very
low certainty and thus has not provided a specific recommendation for this [149]. One
RCT with 20 participants of a single-strain probiotic with L. rhamnosus GG did not find a
benefit for the treatment of pouchitis [150]. A pooled analysis with two observational trials
nonetheless found a benefit of probiotics for clinical response, albeit with very low certainty
of evidence [149]. In this scenario, the AGA similarly has no formal recommendation.
On the other hand, guidelines from the AGA suggest consideration of probiotics for the
prevention of recurrent pouchitis [149]. This conditional recommendation was based on
three RCTs that evaluated the efficacy of VSL#3® for recurrent pouchitis [151–153].
Similar to prebiotics, evidence for probiotic use in CD is sparse and appears less
promising. In a systematic review and meta-analysis by the Cochrane Collaboration on
probiotics for induction of remission in CD, only two RCTs with 46 participants met the
inclusion criteria [154]. One RCT with 11 participants evaluated a single-strain probiotic
with L. rhamnosus GG [155], while the other RCT with 35 participants evaluated a synbiotic
with B. longum and OF-IN [156]. The very small sample sizes and use of single-strain
probiotics indicate that the data are currently far too scarce to yet make any conclusions
about the efficacy—or lack thereof—of probiotics for CD.
Nutrients 2024, 16, 778 12 of 22

5.5.3. Synbiotics for IBD

Given the theoretical and demonstrated benefits of prebiotics and probiotics, respec-
tively, the synergistic benefit of synbiotics has also been investigated. In one RCT with
94 participants that compared psyllium at 8 g/day, a probiotic with Bifidobacterium longum
at 2 × 109 CFU/day, and their synbiotic for 4 weeks, CRP and quality-of-life measures
improved from baseline among those who received the synbiotics, but not among those in
the other treatment arms [157].

5.6. Celiac Disease

Patients with celiac disease may experience ongoing gastrointestinal symptoms despite
following a strict gluten-free diet. Therefore, researchers have investigated the use of
probiotics as an adjuvant treatment for celiac disease. In 2020, Seiler et al. completed
a systematic review and meta-analysis and found that supplementation with B. infantis
or a probiotic strain containing L. casei, L. plantarum, B. lactis, B. breve Bbr8, and B. breve
B110 improved GI symptoms when assessed by the GI Symptoms Rating Scale (p = 0.0002)
including abdominal distention, bloating, constipation, vomiting, and diarrhea [158–161].
The authors reported the quality of evidence was low for the effect of probiotics on overall
gastrointestinal symptoms with a high risk of bias. Bifidobacteria levels were increased after
the use of probiotics in two meta-analyses [158,162]. Another systematic review reported
that a gluten-free diet in children with celiac disease supplemented by probiotic therapy
can alter fecal microbiota to typical conditions of healthy individuals and reduce serum pro-
inflammatory cytokines [163]. It should be noted that there are limited available prospective
studies conducted in North America, Asia, or Africa, thus reducing the generalizability of
the available literature. At this time, considering the limited body of evidence available, a
recommendation cannot be made on the use of probiotics in adult and pediatric patients
with celiac disease as a complementary therapy to a strict gluten-free diet. High-quality,
prospective clinical trials, including large RCTs, are greatly needed to better explore the use
of probiotics in individuals with celiac disease.

5.7. Helicobacter pylori Infection

Helicobacter pylori is a very common infection globally and increases the risk of devel-
oping peptic ulcers or gastric cancer if not properly eradicated [164]. Every effort should
be made to address factors that might contribute to eradication failure as the odds of
successful eradication decrease with each failed treatment attempt. Several guidelines exist
to guide clinicians in selecting the recommended intervention for eradication as well as
management after failed treatments. The use of probiotics has been studied in the evalua-
tion and treatment of H. pylori infection due to their potential to promote intestinal health
and immunity. In vitro studies, animal studies, and clinical observations have reported that
probiotics may reduce side effects in combination with traditional H. pylori therapies. It is
suggested that probiotics may directly compete with H. pylori to help restore the intestinal
microbial environment, increasing IgA production and strengthening the mucosal barrier
against pathogens [165].
A prospective study including 167 patients diagnosed with H. pylori infection found
that treatment with triple-eradication therapy and probiotic cultures (Lactobacillus aci-
dophilus Rosell-52, Lactobacillus acidophilus Rosell-11, Bifidobacterium infantis Rosell-1755 and
Saccharomyces boulardii) was more successful in achieving eradication success compared
with triple-eradication therapy alone (p < 0.05). There was no significant difference in
the incidence of adverse events among both groups [166]. Additionally, 199 patients with
confirmed H. pylori infection treated with standard sequential therapy (omeprazole plus
amoxicillin for 5 days followed by omeprazole, clarithromycin, and metronidazole for
five days) and Saccharomyces boulardii had higher eradication rates (p = 0.02) and a signifi-
cantly lower overall incidence of adverse events (p < 0.001) compared to sequential therapy
alone [167].
Nutrients 2024, 16, 778 13 of 22

A meta-analysis including eight RCTs suggested that supplementation of Lactobacilli

may be effective in increasing eradication rates during the initial treatment of H. pylori with
a positive impact on some therapy-related side effects [168]. Additionally, eight tertiary
hospitals in a prospective placebo-controlled study found that four probiotic strains (Lac-
tobacillus acidophilus, Lactiplantibacillus plantarum, Bifidobacterium lactis, and Saccharomyces
boulardii) increased eradication rates (92.0% vs. 86.8%; p = 0.028) and decreased side effects
of patients (17.0% vs. 50.7%; p < 0.00001) compared with individuals who did not receive
probiotic supplementation [169]. A different probiotic therapy of four strains (Lacticaseibacil-
lus rhamnosus GG, L. rhamnosus, Bifidobacterium breve, and Propionibacterium freudenreichii)
versus placebo in 47 subjects with H. pylori infection did not find a significant change
in eradication rate (p = 0.42) but noted less treatment-related symptoms (p = 0.038) as
measured by the total symptom score change [170]. Furthermore, supplementation of a
synbiotic yogurt containing pectin, GOSs, L. acidophilus LA-5, B. lactis BB-12, L. bulgaricus,
and S. thermophilus was found to suppress H. pylori infection in 59 adults [171].
At this time, the AGA does not have a formal recommendation on the use of probiotics
or prebiotics for the treatment of H. pylori. Probiotics may become a future treatment
when used alone or in combination with best-practice treatment against H. pylori infection.
However, the many different strains, formulas, doses, and timing of probiotics available and
researched as adjuncts against H. pylori make it difficult to standardize the results and make
a definitive recommendation at this time; thus, their use should be considered experimental.

5.8. Colon Cancer Prevention

Colon cancer remains one of the most common cancer types worldwide, and evidence-
based practice guidelines consistently describe the link between diet, lifestyle, and aging
and its development. An increase in gastrointestinal mucosal permeability and subsequent
inflammation are believed to play a role in the pathophysiology of gastrointestinal cancers
including colorectal cancers. Therefore, recent research efforts have focused on exploring
interventions that may aid in the prevention of developing colon cancer. The intestinal
microbiota is widely considered for its role in maintaining balanced homeostasis and
immunomodulation and is more recently being investigated for its potential antitumor
properties. Specifically, lactic acid-producing bacteria have been shown to play a role in
the regression of carcinogenesis, highlighting the interaction between epithelial, immune,
and bacterial metabolites [172]. An increased abundance of Escherichia coli, Enterococcus
faecalis, Fusobacterium nucleatum, Bacteroides fragilis, and Streptococcus gallolyticus and a
decreased abundance of Clostridium, Roseburia, Faecalibacterium, and Bifidobacterium have
been observed in patients diagnosed with colon cancer [173]. Several in vivo, in vitro,
and clinical studies have reported that probiotics may prevent the development of colon
cancer [174]. The mechanism of action of probiotics on carcinogenesis, mainly regarding
the use of Lactobacillus and Bifidobacterium, has not been fully elucidated as their effects
are diverse and complex. In addition, there are animal studies demonstrating that dietary
intake of inulin prevents preneoplastic changes and inflammation, which promote colon
cancer development [175]. In contrast, no reduction in colon cancer risk was seen among
patients who received supplementation with oligofructose-enriched inulin for 6 months in
a phase 2 clinical trial [176].
At present, there are limited studies with sufficient follow-up results and reproducibil-
ity investigating the use of prebiotics and probiotics for cancer biotherapy. Further studies
reporting on probiotics in the field of oncology are greatly needed to explore the potential
in identifying bacterial species and strains with anti-cancer properties in the fight against
the development of cancer.

6. Safety and Adverse Effects

While many studies have demonstrated the potential benefits of prebiotics and probi-
otics, data regarding their safety and adverse effects are limited. Adverse effects are often
poorly reported in existing studies, and many often focus on short-term gastrointestinal
Nutrients 2024, 16, 778 14 of 22

side effects without monitoring for certain infections or other longer-term effects. Prebiotics
are generally considered to be safe, but a dose–response relationship exists for adverse ef-
fects, primarily diarrhea, bloating, and flatulence, owing to their osmotic properties [8,177].
Similarly, probiotics appear to be safe in average-risk patients, with a 2011 meta-analysis
reporting no significant increase in the risk of overall adverse events, including serious
adverse effects, in patients receiving short-term probiotic supplementation [178]. Probi-
otics have, however, been shown to have rare but serious consequences in vulnerable
populations, such as preterm infants and elderly, critically ill, post-surgical, and immuno-
compromised patients. A 2014 systematic review described several cases of bacteremia
with Lactobacillus strains (L. rhamnosus GG, in particular) and fungemia in ICU patients with
a central venous catheter receiving S. boulardii [179]. Another study examined the efficacy
of a synbiotic (composed of Bifidobacterium, Lactobacillus, corn starch, and maltodextrins)
for preventing infections in patients with severe acute pancreatitis; the results showed a
2.5-fold higher mortality rate (95% confidence interval: 1.2–5.3) and incidence of bowel
ischemia in the treatment arm compared to placebo [180]. In October of 2023, the FDA
released a warning advising against the use of probiotics in preterm infants due to cases
of fatal sepsis. Researchers have been investigating whether heat-killed or UV-inactivated
probiotic strains may be safer for the host while still exerting their anti-inflammatory ef-
fects [181]. Overall, prebiotics and probiotics are likely safe in most individuals, but no
definite recommendation can be made given limited safety data and significant variability
in prebiotic type, probiotic strain, doses used, and outcome reporting in existing studies.

7. Conclusions
Prebiotics and probiotics are known to alter the composition and function of the
gut microbiota, allowing them to exert local and systemic effects through the action of
molecules such as SCFAs. Prebiotics, such as inulin and GOSs, have demonstrated efficacy
in the treatment of constipation in several studies. Results were mixed for IBS, and certain
prebiotic types were shown to exacerbate symptoms of IBS. Data were sparse for IBD
and SIBO, and no conclusions could be drawn. There were very few studies examining
the utility of prebiotics for celiac disease, H. pylori infection, and colon cancer prevention.
Higher doses were associated with more gastrointestinal side effects, such as bloating
and flatulence, but prebiotics were well tolerated overall. There were far more data for
probiotics, with Lactobacilli and Bifidobacterium, as well as the yeast Saccharomyces, being
among the most-studied species for GI disorders. Available studies supported the bene-
fit of probiotics for infectious diarrhea, antibiotic-associated diarrhea, and constipation.
Probiotics demonstrated a synergistic effect when used with antibiotics for SIBO and H.
pylori infection. The strongest signal for probiotic use in IBD was for the prevention of
recurrent pouchitis. As they are live microorganisms, probiotic use raises the additional
considerations of cost, stability, and safety, particularly for high-risk populations.
In summary, prebiotics and probiotics demonstrate promise in the prevention and
treatment of certain GI disorders, as an adjunct or alternative to conventional therapies.
However, these data are difficult to translate to specific clinical guidelines given the wide
variation in prebiotic type(s), probiotic strain(s), dose, and/or duration of treatment used in
each study. Furthermore, standardized reporting of safety outcomes and studies examining
their potential long-term effects are severely lacking. For each gastrointestinal indication,
additional large-scale, high-quality, and strain-specific RCTs are needed to validate the
safety and efficacy of prebiotics and probiotics seen in these smaller RCTs, and make
recommendations for the general public.

Supplementary Materials: The following supporting information can be downloaded at https://

www.mdpi.com/article/10.3390/nu16060778/s1, Supplemental Material 1: Literature Search Query;
Figure S1: Pre-probiotics microbiome; Table S1: Summary of prebiotics, probiotics, and synbiotics
shown to be effective for GI conditions.
Nutrients 2024, 16, 778 15 of 22

Author Contributions: All authors participated in data collection, manuscript preparation, critical
revision, and final approval of the manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: The development of this manuscript received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Mazmanian, S.K.; Liu, C.H.; Tzianabos, A.O.; Kasper, D.L. An Immunomodulatory Molecule of Symbiotic Bacteria Directs
Maturation of the Host Immune System. Cell 2005, 122, 107–118. [CrossRef]
2. Bercik, P.; Verdu, E.F.; Foster, J.A.; Macri, J.; Potter, M.; Huang, X.; Malinowski, P.; Jackson, W.; Blennerhassett, P.; Neufeld, K.A.;
et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
Gastroenterology 2010, 139, 2102–2112.e1. [CrossRef] [PubMed]
3. Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, K.S.; Manichanh, C.; Nielsen, T.; Pons, N.; Levenez, F.; Yamada, T.; et al. A
human gut microbial gene catalog established by metagenomic sequencing. Nature 2010, 464, 59–65. [CrossRef] [PubMed]
4. Metchnikoff, E. The Prolongation of Life; Putnam: Boston, MA, USA, 1908.
5. Gibson, G.R.; Scott, K.P.; Rastall, R.A.; Tuohy, K.M.; Hotchkiss, A.; Dubert-Ferrandon, A.; Gareau, M.; Murphy, E.F.; Saulnier, D.;
Loh, G.; et al. Dietary prebiotics: Current status and new definition. Food Sci. Technol. Bull. Funct. Foods 2010, 7, 1–19. [CrossRef]
6. Guarino, M.P.L.; Altomare, A.; Emerenziani, S.; Di Rosa, C.; Ribolsi, M.; Balestrieri, P.; Iovino, P.; Rocchi, G.; Cicala, M. Mechanisms
of Action of Prebiotics and Their Effects on Gastro-Intestinal Disorders in Adults. Nutrients 2020, 12, 1037. [CrossRef] [PubMed]
7. Qin, Y.-Q.; Wang, L.-Y.; Yang, X.-Y.; Xu, Y.-J.; Fan, G.; Fan, Y.-G.; Ren, J.-N.; An, Q.; Li, X. Inulin: Properties and health benefits.
Food Funct. 2023, 14, 2948–2968. [CrossRef]
8. Davani-Davari, D.; Negahdaripour, M.; Karimzadeh, I.; Seifan, M.; Mohkam, M.; Masoumi, S.J.; Berenjian, A.; Ghasemi, Y.
Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods 2019, 8, 92. [CrossRef]
9. Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; et al. Expert
consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and
appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 506–514. [CrossRef]
10. Liu, Y.; Tran, D.Q.; Rhoads, J.M. Probiotics in Disease Prevention and Treatment. J. Clin. Pharmacol. 2018, 58, S164–S179. [CrossRef]
11. Williams, N.T. Probiotics. Am. J. Health Syst. Pharm. 2010, 67, 449–458. [CrossRef]
12. Markowiak, P.; Śliżewska, K. Effects of Probiotics, Prebiotics, and Synbiotics on Human Health. Nutrients 2017, 9, 1021. [CrossRef]
13. Merenstein, D.; Pot, B.; Leyer, G.; Ouwehand, A.C.; Preidis, G.A.; Elkins, C.A.; Hill, C.; Lewis, Z.T.; Shane, A.L.; Zmora, N.; et al.
Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes 2023, 15, 2185034. [CrossRef] [PubMed]
14. Wieërs, G.; Belkhir, L.; Enaud, R.; Leclercq, S.; de Foy, J.-M.P.; Dequenne, I.; deTimary, P.; Cani, P.D. How Probiotics Affect the
Microbiota. Front. Cell. Infect. Microbiol. 2019, 9, 454. [CrossRef]
15. Mantis, N.J.; Rol, N.; Corthésy, B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal
Immunol. 2011, 4, 603–611. [CrossRef]
16. Zhu, C.; Wang, L.; Wei, S.; Chen, Z.; Ma, X.; Zheng, C.; Jiang, Z. Effect of yeast Saccharomyces cerevisiae supplementation on
serum antioxidant capacity, mucosal sIgA secretions and gut microbial populations in weaned piglets. J. Integr. Agric. 2017, 16,
2029–2037. [CrossRef]
17. Mazziotta, C.; Tognon, M.; Martini, F.; Torreggiani, E.; Rotondo, J.C. Probiotics Mechanism of Action on Immune Cells and
Beneficial Effects on Human Health. Cells 2023, 12, 184. [CrossRef] [PubMed]
18. Tan, J.; McKenzie, C.; Potamitis, M.; Thorburn, A.N.; Mackay, C.R.; Macia, L. Chapter Three—The Role of Short-Chain Fatty
Acids in Health and Disease. In Advances in Immunology; Alt, F.W., Ed.; Academic Press: Cambridge, MA, USA, 2014; Volume 121,
pp. 91–119. [CrossRef]
19. Postler, T.S.; Ghosh, S. Understanding the Holobiont: How microbial metabolites affect human health and shape the immune
system. Cell Metab. 2017, 26, 110. [CrossRef]
20. Ye, X.; Li, H.; Anjum, K.; Zhong, X.; Miao, S.; Zheng, G.; Liu, W.; Li, L. Dual Role of Indoles Derived From Intestinal Microbiota
on Human Health. Front. Immunol. 2022, 13, 903526. [CrossRef]
21. Xu, L.; Liu, B.; Huang, L.; Li, Z.; Cheng, Y.; Tian, Y.; Pan, G.; Li, H.; Xu, Y.; Wu, W.; et al. Probiotic Consortia and Their Metabolites
Ameliorate the Symptoms of Inflammatory Bowel Diseases in a Colitis Mouse Model. Microbiol. Spectr. 2022, 10, e00657-22.
[CrossRef]
22. Deng, S.; Pei, C.; Cai, K.; Huang, W.; Xiao, X.; Zhang, X.; Liang, R.; Chen, Y.; Xie, Z.; Li, P.; et al. Lactobacillus acidophilus and its
metabolite ursodeoxycholic acid ameliorate ulcerative colitis by promoting Treg differentiation and inhibiting M1 macrophage
polarization. Front. Microbiol. 2024, 15, 1302998. [CrossRef]
23. Olivares, M.; Díaz-Ropero, M.A.P.; Gómez, N.; Lara-Villoslada, F.; Sierra, S.; Maldonado, J.A.; Martín, R.; López-Huertas,
E.; Rodríguez, J.M.; Xaus, J. Oral administration of two probiotic strains, Lactobacillus gasseri CECT5714 and Lactobacillus
coryniformis CECT5711, enhances the intestinal function of healthy adults. Int. J. Food Microbiol. 2006, 107, 104–111. [CrossRef]
Nutrients 2024, 16, 778 16 of 22

24. Rocha-Ramírez, L.M.; Pérez-Solano, R.A.; Castañón-Alonso, S.L.; Moreno Guerrero, S.S.; Ramírez Pacheco, A.; García Garibay, M.;
Eslava, C. Probiotic Lactobacillus Strains Stimulate the Inflammatory Response and Activate Human Macrophages. J. Immunol.
Res. 2017, 2017, e4607491. [CrossRef] [PubMed]
25. Ahire, J.J.; Jakkamsetty, C.; Kashikar, M.S.; Lakshmi, S.G.; Madempudi, R.S. In Vitro Evaluation of Probiotic Properties of
Lactobacillus plantarum UBLP40 Isolated from Traditional Indigenous Fermented Food. Probiotics Antimicrob. Proteins 2021, 13,
1413–1424. [CrossRef] [PubMed]
26. Mattar, A.F.; Teitelbaum, D.H.; Drongowski, R.A.; Yongyi, F.; Harmon, C.M.; Coran, A.G. Probiotics up-regulate MUC-2 mucin
gene expression in a Caco-2 cell-culture model. Pediatr. Surg. Int. 2002, 18, 586–590. [CrossRef] [PubMed]
27. Hsieh, C.-Y.; Osaka, T.; Moriyama, E.; Date, Y.; Kikuchi, J.; Tsuneda, S. Strengthening of the intestinal epithelial tight junction by
Bifidobacterium bifidum. Physiol. Rep. 2015, 3, e12327. [CrossRef] [PubMed]
28. Bravo, J.A.; Forsythe, P.; Chew, M.V.; Escaravage, E.; Savignac, H.M.; Dinan, T.G.; Bienenstock, J.; Cryan, J.F. Ingestion of
Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc.
Natl. Acad. Sci. USA 2011, 108, 16050–16055. [CrossRef] [PubMed]
29. Laroute, V.; Beaufrand, C.; Gomes, P.; Nouaille, S.; Tondereau, V.; Daveran-Mingot, M.-L.; Theodorou, V.; Eutamene, H.; Mercier-
Bonin, M.; Cocaign-Bousquet, M. Lactococcus lactis NCDO2118 exerts visceral antinociceptive properties in rat via GABA
production in the gastro-intestinal tract. eLife 2022, 11, e77100. [CrossRef]
30. Hemarajata, P.; Versalovic, J. Effects of probiotics on gut microbiota: Mechanisms of intestinal immunomodulation and neuro-
modulation. Ther. Adv. Gastroenterol. 2013, 6, 39–51. [CrossRef] [PubMed]
31. Thim-Uam, A.; Surawut, S.; Issara-Amphorn, J.; Jaroonwitchawan, T.; Hiengrach, P.; Chatthanathon, P.; Wilantho, A.; Somboonna,
N.; Palaga, T.; Pisitkun, P.; et al. Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-
induced mouse models of lupus. Sci. Rep. 2020, 10, 777. [CrossRef]
32. Sanchez-Rodriguez, E.; Egea-Zorrilla, A.; Plaza-Díaz, J.; Aragón-Vela, J.; Muñoz-Quezada, S.; Tercedor-Sánchez, L.; Abadia-
Molina, F. The Gut Microbiota and Its Implication in the Development of Atherosclerosis and Related Cardiovascular Diseases.
Nutrients 2020, 12, 605. [CrossRef]
33. Simons, L.A.; Amansec, S.G.; Conway, P. Effect of Lactobacillus fermentum on serum lipids in subjects with elevated serum
cholesterol. Nutr. Metab. Cardiovasc. Dis. NMCD 2006, 16, 531–535. [CrossRef] [PubMed]
34. Krumbeck, J.A.; Rasmussen, H.E.; Hutkins, R.W.; Clarke, J.; Shawron, K.; Keshavarzian, A.; Walter, J. Probiotic Bifidobacterium
strains and galactooligosaccharides improve intestinal barrier function in obese adults but show no synergism when used together
as synbiotics. Microbiome 2018, 6, 121. [CrossRef] [PubMed]
35. DiMattia, Z.; Damani, J.J.; Van Syoc, E.; Rogers, C.J. Effect of Probiotic Supplementation on Intestinal Permeability in Overweight
and Obesity: A Systematic Review of Randomized Controlled Trials and Animal Studies. Adv. Nutr. Bethesda Md. 2024, 15, 100162.
[CrossRef] [PubMed]
36. Chaiyasut, C.; Sivamaruthi, B.S.; Lailerd, N.; Sirilun, S.; Khongtan, S.; Fukngoen, P.; Peerajan, S.; Saelee, M.; Chaiyasut, K.; Kesika,
P.; et al. Probiotics Supplementation Improves Intestinal Permeability, Obesity Index and Metabolic Biomarkers in Elderly Thai
Subjects: A Randomized Controlled Trial. Foods 2022, 11, 268. [CrossRef] [PubMed]
37. Le Chatelier, E.; Nielsen, T.; Qin, J.; Prifti, E.; Hildebrand, F.; Falony, G.; Almeida, M.; Arumugam, M.; Batto, J.-M.; Kennedy, S.;
et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013, 500, 541–546. [CrossRef]
38. Plaza-Díaz, J.; Solís-Urra, P.; Rodríguez-Rodríguez, F.; Olivares-Arancibia, J.; Navarro-Oliveros, M.; Abadía-Molina, F.; Álvarez-
Mercado, A.I. The Gut Barrier, Intestinal Microbiota, and Liver Disease: Molecular Mechanisms and Strategies to Manage. Int. J.
Mol. Sci. 2020, 21, 8351. [CrossRef]
39. Lepage, P.; Häsler, R.; Spehlmann, M.E.; Rehman, A.; Zvirbliene, A.; Begun, A.; Ott, S.; Kupcinskas, L.; Doré, J.; Raedler, A.; et al.
Twin Study Indicates Loss of Interaction Between Microbiota and Mucosa of Patients With Ulcerative Colitis. Gastroenterology
2011, 141, 227–236. [CrossRef]
40. Manichanh, C.; Rigottier-Gois, L.; Bonnaud, E.; Gloux, K.; Pelletier, E.; Frangeul, L.; Nalin, R.; Jarrin, C.; Chardon, P.; Marteau, P.;
et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 2006, 55, 205–211.
[CrossRef]
41. Monteros, M.J.M.; Galdeano, C.M.; Balcells, M.F.; Weill, R.; De Paula, J.A.; Perdigón, G.; Cazorla, S.I. Probiotic lactobacilli as a
promising strategy to ameliorate disorders associated with intestinal inflammation induced by a non-steroidal anti-inflammatory
drug. Sci. Rep. 2021, 11, 571. [CrossRef]
42. Ballini, A.; Gnoni, A.; De Vito, D.; Dipalma, G.; Cantore, S.; Gargiulo Isacco, C.; Saini, R.; Santacroce, L.; Topi, S.; Scarano, A.;
et al. Effect of probiotics on the occurrence of nutrition absorption capacities in healthy children: A randomized double-blinded
placebo-controlled pilot study. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 8645–8657. [CrossRef]
43. Narva, M.; Nevala, R.; Poussa, T.; Korpela, R. The effect of Lactobacillus helveticus fermented milk on acute changes in calcium
metabolism in postmenopausal women. Eur. J. Nutr. 2004, 43, 61–68. [CrossRef]
44. Gohel, M.K.; Prajapati, J.B.; Mudgal, S.V.; Pandya, H.V.; Singh, U.S.; Trivedi, S.S.; Phatak, A.G.; Patel, R.M. Effect of Probiotic
Dietary Intervention on Calcium and Haematological Parameters in Geriatrics. J. Clin. Diagn. Res. JCDR 2016, 10, LC05–LC09.
[CrossRef]
45. Barkhidarian, B.; Roldos, L.; Iskandar, M.M.; Saedisomeolia, A.; Kubow, S. Probiotic Supplementation and Micronutrient Status
in Healthy Subjects: A Systematic Review of Clinical Trials. Nutrients 2021, 13, 3001. [CrossRef] [PubMed]
Nutrients 2024, 16, 778 17 of 22

46. Whisner, C.M.; Martin, B.R.; Schoterman, M.H.C.; Nakatsu, C.H.; McCabe, L.D.; McCabe, G.P.; Wastney, M.E.; van den Heuvel,
E.G.H.M.; Weaver, C.M. Galacto-oligosaccharides increase calcium absorption and gut bifidobacteria in young girls: A double-
blind cross-over trial. Br. J. Nutr. 2013, 110, 1292–1303. [CrossRef] [PubMed]
47. van den Heuvel, E.G.; Schoterman, M.H.; Muijs, T. Transgalactooligosaccharides stimulate calcium absorption in postmenopausal
women. J. Nutr. 2000, 130, 2938–2942. [CrossRef] [PubMed]
48. McFarland, L.V. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med. Infect. Dis. 2007, 5, 97–105.
[CrossRef] [PubMed]
49. Fagnant, H.S.; Isidean, S.D.; Wilson, L.; Bukhari, A.S.; Allen, J.T.; Agans, R.T.; Lee, D.M.; Hatch-McChesney, A.; Whitney, C.C.;
Sullo, E.; et al. Orally Ingested Probiotic, Prebiotic, and Synbiotic Interventions as Countermeasures for Gastrointestinal Tract
Infections in Nonelderly Adults: A Systematic Review and Meta-Analysis. Adv. Nutr. 2023, 14, 539–554. [CrossRef] [PubMed]
50. Li, Z.; Zhu, G.; Li, C.; Lai, H.; Liu, X.; Zhang, L. Which Probiotic Is the Most Effective for Treating Acute Diarrhea in Children? A
Bayesian Network Meta-Analysis of Randomized Controlled Trials. Nutrients 2021, 13, 4319. [CrossRef] [PubMed]
51. Yang, B.; Lu, P.; Li, M.-X.; Cai, X.-L.; Xiong, W.-Y.; Hou, H.-J.; Ha, X.-Q. A meta-analysis of the effects of probiotics and synbiotics
in children with acute diarrhea. Medicine 2019, 98, e16618. [CrossRef] [PubMed]
52. Huang, R.; Xing, H.-Y.; Liu, H.-J.; Chen, Z.-F.; Tang, B.-B. Efficacy of probiotics in the treatment of acute diarrhea in children: A
systematic review and meta-analysis of clinical trials. Transl. Pediatr. 2021, 10, 3248–3260. [CrossRef]
53. Li, Y.-T.; Xu, H.; Ye, J.-Z.; Wu, W.-R.; Shi, D.; Fang, D.-Q.; Liu, Y.; Li, L.-J. Efficacy of Lactobacillus rhamnosus GG in treatment of
acute pediatric diarrhea: A systematic review with meta-analysis. World J. Gastroenterol. 2019, 25, 4999. [CrossRef]
54. Szajewska, H.; Kołodziej, M.; Gieruszczak-Białek, D.; Skórka, A.; Ruszczyński, M.; Shamir, R. Systematic review with meta-
analysis: Lactobacillus rhamnosus GG for treating acute gastroenteritis in children—A 2019 update. Aliment. Pharmacol. Ther.
2019, 49, 1376–1384. [CrossRef]
55. Collinson, S.; Deans, A.; Padua-Zamora, A.; Gregorio, G.V.; Li, C.; Dans, L.F.; Allen, S.J. Probiotics for treating acute infectious
diarrhoea. Cochrane Database Syst. Rev. 2020, 12, CD003048. [CrossRef]
56. Florez, I.D.; Veroniki, A.-A.; Khalifah, R.A.; Yepes-Nuñez, J.J.; Sierra, J.M.; Vernooij, R.W.M.; Acosta-Reyes, J.; Granados,
C.M.; Pérez-Gaxiola, G.; Cuello-Garcia, C.; et al. Comparative effectiveness and safety of interventions for acute diarrhea and
gastroenteritis in children: A systematic review and network meta-analysis. PLoS ONE 2018, 13, e0207701. [CrossRef]
57. Vassilopoulou, L.; Spyromitrou-Xioufi, P.; Ladomenou, F. Effectiveness of probiotics and synbiotics in reducing duration of acute
infectious diarrhea in pediatric patients in developed countries: A systematic review and meta-analysis. Eur. J. Pediatr. 2021, 180,
2907–2920. [CrossRef] [PubMed]
58. McFarland, L.V.; Evans, C.T.; Goldstein, E.J.C. Strain-Specificity and Disease-Specificity of Probiotic Efficacy: A Systematic Review
and Meta-Analysis. Front. Med. 2018, 5, 124. [CrossRef] [PubMed]
59. Liao, W.; Chen, C.; Wen, T.; Zhao, Q. Probiotics for the Prevention of Antibiotic-associated Diarrhea in Adults: A Meta-Analysis
of Randomized Placebo-Controlled Trials. J. Clin. Gastroenterol. 2021, 55, 469. [CrossRef] [PubMed]
60. Hempel, S.; Newberry, S.J.; Maher, A.R.; Wang, Z.; Miles, J.N.V.; Shanman, R.; Johnsen, B.; Shekelle, P.G. Probiotics for the
prevention and treatment of antibiotic-associated diarrhea: A systematic review and meta-analysis. JAMA 2012, 307, 1959–1969.
[CrossRef] [PubMed]
61. McFarland, L.V. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium
difficile disease. Am. J. Gastroenterol. 2006, 101, 812–822. [CrossRef] [PubMed]
62. Dietrich, C.G.; Kottmann, T.; Alavi, M. Commercially available probiotic drinks containing Lactobacillus casei DN-114001 reduce
antibiotic-associated diarrhea. World J. Gastroenterol. WJG 2014, 20, 15837–15844. [CrossRef]
63. Guo, Q.; Goldenberg, J.Z.; Humphrey, C.; Dib, R.E.; Johnston, B.C. Probiotics for the prevention of pediatric antibiotic-associated
diarrhea. Cochrane Database Syst. Rev. 2019, 4, CD004827. [CrossRef]
64. Zhang, L.; Zeng, X.; Guo, D.; Zou, Y.; Gan, H.; Huang, X. Early use of probiotics might prevent antibiotic-associated diarrhea in
elderly (>65 years): A systematic review and meta-analysis. BMC Geriatr. 2022, 22, 562. [CrossRef]
65. Castagliuolo, I.; Riegler, M.F.; Valenick, L.; LaMont, J.T.; Pothoulakis, C. Saccharomyces boulardii Protease Inhibits the Effects of
Clostridium difficile Toxins A and B in Human Colonic Mucosa. Infect. Immun. 1999, 67, 302. [CrossRef]
66. Shen, N.T.; Maw, A.; Tmanova, L.L.; Pino, A.; Ancy, K.; Crawford, C.V.; Simon, M.S.; Evans, A.T. Timely Use of Probiotics in Hos-
pitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis. Gastroenterology
2017, 152, 1889–1900.e9. [CrossRef] [PubMed]
67. Goldenberg, J.Z.; Yap, C.; Lytvyn, L.; Lo, C.K.-F.; Beardsley, J.; Mertz, D.; Johnston, B.C. Probiotics for the prevention of
Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst. Rev. 2017, 12, CD006095. [CrossRef]
[PubMed]
68. Su, G.L.; Ko, C.W.; Bercik, P.; Falck-Ytter, Y.; Sultan, S.; Weizman, A.V.; Morgan, R.L. AGA Clinical Practice Guidelines on the Role
of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology 2020, 159, 697–705. [CrossRef] [PubMed]
69. Louie, T.; Golan, Y.; Khanna, S.; Bobilev, D.; Erpelding, N.; Fratazzi, C.; Carini, M.; Menon, R.; Ruisi, M.; Norman, J.M.; et al.
VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical
Trial. JAMA 2023, 329, 1356–1366. [CrossRef] [PubMed]
Nutrients 2024, 16, 778 18 of 22

70. Touchefeu, Y.; Montassier, E.; Nieman, K.; Gastinne, T.; Potel, G.; Bruley des Varannes, S.; Le Vacon, F.; de La Cochetière, M.F.
Systematic review: The role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis—Current
evidence and potential clinical applications. Aliment. Pharmacol. Ther. 2014, 40, 409–421. [CrossRef] [PubMed]
71. Montassier, E.; Batard, E.; Massart, S.; Gastinne, T.; Carton, T.; Caillon, J.; Le Fresne, S.; Caroff, N.; Hardouin, J.B.; Moreau, P.; et al.
16S rRNA Gene Pyrosequencing Reveals Shift in Patient Faecal Microbiota During High-Dose Chemotherapy as Conditioning
Regimen for Bone Marrow Transplantation. Microb. Ecol. 2014, 67, 690–699. [CrossRef] [PubMed]
72. Wei, D.; Heus, P.; van de Wetering, F.T.; van Tienhoven, G.; Verleye, L.; Scholten, R.J. Probiotics for the prevention or treatment
of chemotherapy- or radiotherapy-related diarrhoea in people with cancer. Cochrane Database Syst. Rev. 2018, 8, CD008831.
[CrossRef] [PubMed]
73. Masuda, H.; Tanabe, Y.; Sakai, H.; Matsumoto, K.; Shimomura, A.; Doi, M.; Miyoshi, Y.; Takahashi, M.; Sagara, Y.; Tokunaga, S.;
et al. Efficacy of probiotics and trimebutine maleate for abemaciclib-induced diarrhea: A randomized, open-label phase II trial
(MERMAID, WJOG11318B). Breast Off. J. Eur. Soc. Mastology 2023, 71, 22. [CrossRef]
74. Lu, D.; Yan, J.; Liu, F.; Ding, P.; Chen, B.; Lu, Y.; Sun, Z. Probiotics in preventing and treating chemotherapy-induced diarrhea: A
meta-analysis. Asia Pac. J. Clin. Nutr. 2019, 28, 701–710. [CrossRef] [PubMed]
75. Liu, M.-M.; Li, S.-T.; Shu, Y.; Zhan, H.-Q. Probiotics for prevention of radiation-induced diarrhea: A meta-analysis of randomized
controlled trials. PLoS ONE 2017, 12, e0178870. [CrossRef]
76. Salminen, E.; Elomaa, I.; Minkkinen, J.; Vapaatalo, H.; Salminen, S. Preservation of intestinal integrity during radiotherapy using
live Lactobacillus acidophilus cultures. Clin. Radiol. 1988, 39, 435–437. [CrossRef]
77. Sasidharan, B.K.; Ramadass, B.; Viswanathan, P.N.; Samuel, P.; Gowri, M.; Pugazhendhi, S.; Ramakrishna, B.S. A phase 2
randomized controlled trial of oral resistant starch supplements in the prevention of acute radiation proctitis in patients treated
for cervical cancer. J. Cancer Res. Ther. 2019, 15, 1383–1391. [CrossRef]
78. Ohkusa, T.; Koido, S.; Nishikawa, Y.; Sato, N. Gut Microbiota and Chronic Constipation: A Review and Update. Front. Med. 2019,
6, 19. [CrossRef]
79. Parthasarathy, G.; Chen, J.; Chen, X.; Chia, N.; O’Connor, H.M.; Wolf, P.G.; Gaskins, H.R.; Bharucha, A.E. Relationship Between
Microbiota of the Colonic Mucosa vs Feces and Symptoms, Colonic Transit, and Methane Production in Female Patients With
Chronic Constipation. Gastroenterology 2016, 150, 367–379.e1. [CrossRef]
80. Dimidi, E.; Christodoulides, S.; Scott, S.M.; Whelan, K. Mechanisms of Action of Probiotics and the Gastrointestinal Microbiota on
Gut Motility and Constipation. Adv. Nutr. Bethesda Md. 2017, 8, 484–494. [CrossRef]
81. Erhardt, R.; Harnett, J.E.; Steels, E.; Steadman, K.J. Functional constipation and the effect of prebiotics on the gut microbiota: A
review. Br. J. Nutr. 2023, 130, 1015–1023. [CrossRef]
82. Dimidi, E.; Scott, S.M.; Whelan, K. Probiotics and constipation: Mechanisms of action, evidence for effectiveness and utilisation
by patients and healthcare professionals. Proc. Nutr. Soc. 2020, 79, 147–157. [CrossRef] [PubMed]
83. Marteau, P.; Jacobs, H.; Cazaubiel, M.; Signoret, C.; Prevel, J.-M.; Housez, B. Effects of chicory inulin in constipated elderly people:
A double-blind controlled trial. Int. J. Food Sci. Nutr. 2011, 62, 164–170. [CrossRef] [PubMed]
84. Micka, A.; Siepelmeyer, A.; Holz, A.; Theis, S.; Schön, C. Effect of consumption of chicory inulin on bowel function in healthy
subjects with constipation: A randomized, double-blind, placebo-controlled trial. Int. J. Food Sci. Nutr. 2017, 68, 82–89. [CrossRef]
85. Glibowski, P.; Skrzypek, M.; Ćwiklińska, M.; Drozd, M.; Kowalska, A. Chemical stability of fructans in apple beverages and their
influence on chronic constipation. Food Funct. 2020, 11, 3860–3866. [CrossRef] [PubMed]
86. Li, T.; Lu, X.; Yang, X. Evaluation of clinical safety and beneficial effects of stachyose-enriched α-galacto-oligosaccharides on gut
microbiota and bowel function in humans. Food Funct. 2017, 8, 262–269. [CrossRef] [PubMed]
87. Schoemaker, M.H.; Hageman, J.H.J.; Haaf, D.T.; Hartog, A.; Scholtens, P.A.M.J.; Boekhorst, J.; Nauta, A.; Bos, R. Prebiotic
Galacto-Oligosaccharides Impact Stool Frequency and Fecal Microbiota in Self-Reported Constipated Adults: A Randomized
Clinical Trial. Nutrients 2022, 14, 309. [CrossRef] [PubMed]
88. Yu, T.; Zheng, Y.-P.; Tan, J.-C.; Xiong, W.-J.; Wang, Y.; Lin, L. Effects of Prebiotics and Synbiotics on Functional Constipation. Am. J.
Med. Sci. 2017, 353, 282–292. [CrossRef]
89. van der Schoot, A.; Helander, C.; Whelan, K.; Dimidi, E. Probiotics and synbiotics in chronic constipation in adults: A systematic
review and meta-analysis of randomized controlled trials. Clin. Nutr. Edinb. Scotl. 2022, 41, 2759–2777. [CrossRef]
90. Ibarra, A.; Latreille-Barbier, M.; Donazzolo, Y.; Pelletier, X.; Ouwehand, A.C. Effects of 28-day Bifidobacterium animalis subsp.
lactis HN019 supplementation on colonic transit time and gastrointestinal symptoms in adults with functional constipation: A
double-blind, randomized, placebo-controlled, and dose-ranging trial. Gut Microbes 2018, 9, 236. [CrossRef]
91. Yoon, J.Y.; Cha, J.M.; Oh, J.K.; Tan, P.L.; Kim, S.H.; Kwak, M.S.; Jeon, J.W.; Shin, H.P. Probiotics Ameliorate Stool Consistency in
Patients with Chronic Constipation: A Randomized, Double-Blind, Placebo-Controlled Study. Dig. Dis. Sci. 2018, 63, 2754–2764.
[CrossRef]
92. Mitelmão, F.C.R.; Häckel, K.; de Bergamaschi, C.C.; Gerenutti, M.; Silva, M.T.; Balcão, V.M.; Vila, M.M.D.C. The effect of probiotics
on functional constipation in adults: A randomized, double-blind controlled trial. Medicine 2022, 101, e31185. [CrossRef]
93. Liu, L.; Wang, A.; Shi, H.; Tao, H.; Nahata, M.C. Efficacy and safety of probiotics and synbiotics for functional constipation in
children: A systematic review and meta-analysis of randomized clinical trials. Clin. Nutr. Edinb. Scotl. 2023, 42, 1817–1826.
[CrossRef]
Nutrients 2024, 16, 778 19 of 22

94. Šola, K.F.; Vladimir-Knežević, S.; Hrabač, P.; Mucalo, I.; Saso, L.; Verbanac, D. The effect of multistrain probiotics on functional
constipation in the elderly: A randomized controlled trial. Eur. J. Clin. Nutr. 2022, 76, 1675–1681. [CrossRef]
95. Baştürk, A.; Artan, R.; Atalay, A.; Yılmaz, A. Investigation of the efficacy of synbiotics in the treatment of functional constipation
in children: A randomized double-blind placebo-controlled study. Turk. J. Gastroenterol. Off. J. Turk. Soc. Gastroenterol. 2017, 28,
388–393. [CrossRef]
96. Rome IV Criteria. Rome Foundation. Available online: https://theromefoundation.org/rome-iv/rome-iv-criteria/ (accessed on
27 January 2024).
97. Simon, E.; Călinoiu, L.F.; Mitrea, L.; Vodnar, D.C. Probiotics, Prebiotics, and Synbiotics: Implications and Beneficial Effects against
Irritable Bowel Syndrome. Nutrients 2021, 13, 2112. [CrossRef]
98. Rosa, C.D.; Altomare, A.; Terrigno, V.; Carbone, F.; Tack, J.; Cicala, M.; Guarino, M.P.L. Constipation-Predominant Irritable Bowel
Syndrome (IBS-C): Effects of Different Nutritional Patterns on Intestinal Dysbiosis and Symptoms. Nutrients 2023, 15, 1647.
[CrossRef] [PubMed]
99. Isakov, V.; Pilipenko, V.; Shakhovskaya, A.; Tutelyan, V. Efficacy of inulin enriched yogurt on bowel habits in patients with
irritable bowel syndrome with constipation: A pilot study. FASEB J. 2013, 27, lb426. [CrossRef]
100. Pilipenko, V.I.; Teplyuk, D.A.; Shakhovskaya, A.K.; Isakov, V.A.; Vorobyova, V.M.; Vorobyova, I.S.; Sarkisyan, V.A.; Kochetkova,
A.A.; Mikheeva, G.A.; Yudina, A.V. Using a multicomponent functional food in IBS patients with constipation a comparative
controlled study. Vopr. Pitan. 2016, 85, 84–91. [PubMed]
101. Pilipenko, V.I.; Teplyuk, D.A.; Shakhovskaya, A.K.; Isakov, V.A.; Vorobyova, V.M.; Vorobyova, I.S.; Glazkova, I.V.; Kochetkova,
A.A.; Mikheeva, G.A.; Yudina, A.V. Dry jelly concentrate with vitamins and dietary fiber in patients with IBS with constipation: A
comparative controlled study. Vopr. Pitan. 2015, 84, 83–91. [PubMed]
102. Olesen, M.; Gudmand-Hoyer, E. Efficacy, safety, and tolerability of fructooligosaccharides in the treatment of irritable bowel
syndrome. Am. J. Clin. Nutr. 2000, 72, 1570–1575. [CrossRef] [PubMed]
103. Hunter, J.O.; Tuffnell, Q.; Lee, A.J. Controlled trial of oligofructose in the management of irritable bowel syndrome. J. Nutr. 1999,
129, 1451S–1453S. [CrossRef] [PubMed]
104. Silk, D.B.A.; Davis, A.; Vulevic, J.; Tzortzis, G.; Gibson, G.R. Clinical trial: The effects of a trans-galactooligosaccharide prebiotic
on faecal microbiota and symptoms in irritable bowel syndrome. Aliment. Pharmacol. Ther. 2009, 29, 508–518. [CrossRef]
105. Azpiroz, F.; Dubray, C.; Bernalier-Donadille, A.; Cardot, J.-M.; Accarino, A.; Serra, J.; Wagner, A.; Respondek, F.; Dapoigny, M.
Effects of scFOS on the composition of fecal microbiota and anxiety in patients with irritable bowel syndrome: A randomized,
double blind, placebo controlled study. Neurogastroenterol. Motil. 2017, 29, e12911. [CrossRef] [PubMed]
106. Wilson, B.; Rossi, M.; Dimidi, E.; Whelan, K. Prebiotics in irritable bowel syndrome and other functional bowel disorders in
adults: A systematic review and meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2019, 109, 1098–1111. [CrossRef]
107. Ford, A.C.; Harris, L.A.; Lacy, B.E.; Quigley, E.M.M.; Moayyedi, P. Systematic review with meta-analysis: The efficacy of prebiotics,
probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment. Pharmacol. Ther. 2018, 48, 1044–1060. [CrossRef]
108. Yakovenko, E.P.; Strokova, T.V.; Ivanov, A.N.; Iakovenko, A.V.; Gioeva, I.Z.; Aldiyarova, M.A. The effectiveness of a probiotic
containing Bifidobacterium longum BB-46 and Enterococcus faecium ENCfa-68 in the treatment of post-infectious irritable bowel
syndrome. Prospective randomized comparative study. Ter. Arkh. 2022, 94, 180–187. [CrossRef]
109. Skrzydło-Radomańska, B.; Cukrowska, B. How to Recognize and Treat Small Intestinal Bacterial Overgrowth? J. Clin. Med. 2022,
11, 6017. [CrossRef] [PubMed]
110. Rosania, R.; Giorgio, F.; Principi, M.; Amoruso, A.; Monno, R.; Di Leo, A.; Ierardi, E. Effect of Probiotic or Prebiotic Supplementa-
tion on Antibiotic Therapy in the Small Intestinal Bacterial Overgrowth: A Comparative Evaluation. Curr. Clin. Pharmacol. 2013,
8, 169–172. [CrossRef] [PubMed]
111. Zhong, C.; Qu, C.; Wang, B.; Liang, S.; Zeng, B. Probiotics for Preventing and Treating Small Intestinal Bacterial Overgrowth: A
Meta-Analysis and Systematic Review of Current Evidence. J. Clin. Gastroenterol. 2017, 51, 300–311. [CrossRef] [PubMed]
112. García-Collinot, G.; Madrigal-Santillán, E.O.; Martínez-Bencomo, M.A.; Carranza-Muleiro, R.A.; Jara, L.J.; Vera-Lastra, O.;
Montes-Cortes, D.H.; Medina, G.; Cruz-Domínguez, M.P. Effectiveness of Saccharomyces boulardii and Metronidazole for Small
Intestinal Bacterial Overgrowth in Systemic Sclerosis. Dig. Dis. Sci. 2020, 65, 1134–1143. [CrossRef]
113. Liang, S.; Xu, L.; Zhang, D.; Wu, Z. Effect of probiotics on small intestinal bacterial overgrowth in patients with gastric and
colorectal cancer. Turk. J. Gastroenterol. 2016, 27, 227–232. [CrossRef]
114. Yu, J. Bifidobacterium triple viable powder/capsule: How effective it is against gastrointestinal diseases? J. Gastroenterol. Hepatol.
2023, 38, 1013–1014. [CrossRef] [PubMed]
115. Khalighi, A.R.; Khalighi, M.R.; Behdani, R.; Jamali, J.; Khosravi, A.; Kouhestani, S.; Radmanesh, H.; Esmaeelzadeh, S.; Khalighi,
N. Evaluating the efficacy of probiotic on treatment in patients with small intestinal bacterial overgrowth (SIBO)—A pilot study.
Indian. J. Med. Res. 2014, 140, 604.
116. Li, J.; Butcher, J.; Mack, D.; Stintzi, A. Functional impacts of the intestinal microbiome in the pathogenesis of inflammatory bowel
disease. Inflamm. Bowel Dis. 2015, 21, 139–153. [CrossRef]
117. Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.;
et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504, 446–450.
[CrossRef]
Nutrients 2024, 16, 778 20 of 22

118. Fernando, M.R.; Saxena, A.; Reyes, J.L.; McKay, D.M. Butyrate enhances antibacterial effects while suppressing other features of
alternative activation in IL-4-induced macrophages. Am. J. Physiol. Gastrointest. Liver Physiol. 2016, 310, G822-31. [CrossRef]
[PubMed]
119. Luhrs, H.; Gerke, T.; Muller, J.G.; Melcher, R.; Schauber, J.; Boxberge, F.; Scheppach, W.; Menzel, T. Butyrate inhibits NF-kappaB
activation in lamina propria macrophages of patients with ulcerative colitis. Scand. J. Gastroenterol. 2002, 37, 458–466. [CrossRef]
120. Lewis, K.; Lutgendorff, F.; Phan, V.; Soderholm, J.D.; Sherman, P.M.; McKay, D.M. Enhanced translocation of bacteria across
metabolically stressed epithelia is reduced by butyrate. Inflamm. Bowel Dis. 2010, 16, 1138–1148. [CrossRef] [PubMed]
121. Ikegami, S.; Nakamura, M.; Honda, T.; Yamamura, T.; Maeda, K.; Sawada, T.; Ishikawa, E.; Yamamoto, K.; Furune, S.; Ishikawa, T.;
et al. Efficacy of 1-kestose supplementation in patients with mild to moderate ulcerative colitis: A randomised, double-blind,
placebo-controlled pilot study. Aliment. Pharmacol. Ther. 2023, 57, 1249–1257. [CrossRef]
122. Valcheva, R.; Koleva, P.; Martinez, I.; Walter, J.; Ganzle, M.G.; Dieleman, L.A. Inulin-type fructans improve active ulcerative colitis
associated with microbiota changes and increased short-chain fatty acids levels. Gut Microbes 2019, 10, 334–357. [CrossRef]
123. Casellas, F.; Borruel, N.; Torrejon, A.; Varela, E.; Antolin, M.; Guarner, F.; Malagelada, J.R. Oral oligofructose-enriched inulin
supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin. Aliment. Pharmacol.
Ther. 2007, 25, 1061–1067. [CrossRef]
124. Ichim, S.; Dimitriu, A.; Gheorghe, C.; Diculescu, M.; Mateescu, B.; Cijevschi-Prelipcean, C.; Gheorghe, L. The effect of adjuvant
therapy (Sinergin® ) in induction and maintaining remission in mild and moderate IBD. J. Crohns Colitis 2019, 2019, S352.
[CrossRef]
125. Faghfoori, Z.; Shakerhosseini, R.; Navai, L.; Somi, M.H.; Nikniaz, Z.; Abadi, A. Effects of an Oral Supplementation of Germinated
Barley Foodstuff on Serum CRP Level and Clinical Signs in Patients with Ulcerative Colitis. Health Promot. Perspect. 2014, 4,
116–121. [CrossRef]
126. Kanauchi, O.; Suga, T.; Tochihara, M.; Hibi, T.; Naganuma, M.; Homma, T.; Asakura, H.; Nakano, H.; Takahama, K.; Fujiyama, Y.;
et al. Treatment of ulcerative colitis by feeding with germinated barley foodstuff: First report of a multicenter open control trial. J.
Gastroenterol. 2002, 37 (Suppl. S14), 67–72. [CrossRef]
127. Baghizadeh, A.; Davati, A.; Heidarloo, A.J.; Emadi, F.; Aliasl, J. Efficacy of Plantago major seed in management of ulcerative
colitis symptoms: A randomized, placebo controlled, clinical trial. Complement. Ther. Clin. Pract. 2021, 44, 101444. [CrossRef]
[PubMed]
128. Hanai, H.; Kanauchi, O.; Mitsuyama, K.; Andoh, A.; Takeuchi, K.; Takayuki, I.; Araki, Y.; Fujiyama, Y.; Toyonaga, A.; Sata, M.;
et al. Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. Int. J. Mol. Med. 2004, 13, 643–647.
[CrossRef] [PubMed]
129. Valcheva, R.; Kovic, O.; Veniamin, S.; Perez-Munoz, M.E.; Silva, M.; Peerani, F.; Wong, K.; Kao, D.H.; Van Zanten, S.V.; Halloran,
B.P.; et al. Prebiotic β-fructans prevent subclinical intestinal inflammation in ulcerative colitis patients who are in clinical
remission. Gastroenterology 2021, 2021, 6. [CrossRef]
130. Nyman, M.; Nguyen, T.D.; Wikman, O.; Hjortswang, H.; Hallert, C. Oat Bran Increased Fecal Butyrate and Prevented Gastroin-
testinal Symptoms in Patients With Quiescent Ulcerative Colitis-Randomized Controlled Trial. Crohns Colitis 360 2020, 2, otaa005.
[CrossRef] [PubMed]
131. Fernandez-Banares, F.; Hinojosa, J.; Sanchez-Lombrana, J.L.; Navarro, E.; Martinez-Salmeron, J.F.; Garcia-Puges, A.; Gonzalez-
Huix, F.; Riera, J.; Gonzalez-Lara, V.; Dominguez-Abascal, F.; et al. Randomized clinical trial of Plantago ovata seeds (dietary
fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn’s
Disease and Ulcerative Colitis (GETECCU). Am. J. Gastroenterol. 1999, 94, 427–433. [CrossRef] [PubMed]
132. Copaci, I.; Chiriac, G. Maintenance of remission of ulcerative colitis: Prebiotics and dietary fiber. United Eur. Gastroenterol. J. 2014,
2, A375.
133. Benjamin, J.L.; Hedin, C.R.; Koutsoumpas, A.; Ng, S.C.; McCarthy, N.E.; Hart, A.L.; Kamm, M.A.; Sanderson, J.D.; Knight, S.C.;
Forbes, A.; et al. Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn’s disease. Gut
2011, 60, 923–929. [CrossRef] [PubMed]
134. Joossens, M.; De Preter, V.; Ballet, V.; Verbeke, K.; Rutgeerts, P.; Vermeire, S. Effect of oligofructose-enriched inulin (OF-IN) on
bacterial composition and disease activity of patients with Crohn’s disease: Results from a double-blinded randomised controlled
trial. Gut 2012, 61, 958. [CrossRef] [PubMed]
135. Limketkai, B.N.; Hamideh, M.; Shah, R.; Sauk, J.S.; Jaffe, N. Dietary Patterns and Their Association with Symptoms Activity in
Inflammatory Bowel Diseases. Inflamm. Bowel Dis. 2022, 28, 1627–1636. [CrossRef]
136. Limketkai, B.N.; Godoy-Brewer, G.; Parian, A.M.; Noorian, S.; Krishna, M.; Shah, N.D.; White, J.; Mullin, G.E. Dietary Interventions
for the Treatment of Inflammatory Bowel Diseases: An Updated Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol.
2023, 21, 2508–2525.e10. [CrossRef]
137. Fansiwala, K.; Shah, N.D.; McNulty, K.A.; Kwaan, M.R.; Limketkai, B.N. Use of oral diet and nutrition support in management of
stricturing and fistulizing Crohn’s disease. Nutr. Clin. Pract. 2023, 38, 1282–1295. [CrossRef] [PubMed]
138. Kaur, L.; Gordon, M.; Baines, P.A.; Iheozor-Ejiofor, Z.; Sinopoulou, V.; Akobeng, A.K. Probiotics for induction of remission in
ulcerative colitis. Cochrane Database Syst. Rev. 2020, 3, CD005573. [CrossRef] [PubMed]
139. Matthes, H.; Krummenerl, T.; Giensch, M.; Wolff, C.; Schulze, J. Clinical trial: Probiotic treatment of acute distal ulcerative colitis
with rectally administered Escherichia coli Nissle 1917 (EcN). BMC Complement. Altern. Med. 2010, 10, 13. [CrossRef]
Nutrients 2024, 16, 778 21 of 22

140. Oliva, S.; Di Nardo, G.; Ferrari, F.; Mallardo, S.; Rossi, P.; Patrizi, G.; Cucchiara, S.; Stronati, L. Randomised clinical trial: The
effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis. Aliment. Pharmacol.
Ther. 2012, 35, 327–334. [CrossRef]
141. Tamaki, H.; Nakase, H.; Inoue, S.; Kawanami, C.; Itani, T.; Ohana, M.; Kusaka, T.; Uose, S.; Hisatsune, H.; Tojo, M.; et al. Efficacy
of probiotic treatment with Bifidobacterium longum 536 for induction of remission in active ulcerative colitis: A randomized,
double-blinded, placebo-controlled multicenter trial. Dig. Endosc. 2016, 28, 67–74. [CrossRef]
142. Vejdani, R.; Bahari, A.; Zadeh, A.M.; Azmi, M.; Ebrahimi-Daryani, N.; Hashtroudi, A.A. EKects of lactobacillus casei probiotic on
mild to moderate ulcerative colitis: A placebo controlled study. Indian J. Med. Sci. 2017, 69, 24–28. [CrossRef]
143. Miele, E.; Pascarella, F.; Giannetti, E.; Quaglietta, L.; Baldassano, R.N.; Staiano, A. Effect of a probiotic preparation (VSL#3) on
induction and maintenance of remission in children with ulcerative colitis. Am. J. Gastroenterol. 2009, 104, 437–443. [CrossRef]
[PubMed]
144. Sood, A.; Midha, V.; Makharia, G.K.; Ahuja, V.; Singal, D.; Goswami, P.; Tandon, R.K. The probiotic preparation, VSL#3 induces
remission in patients with mild-to-moderately active ulcerative colitis. Clin. Gastroenterol. Hepatol. 2009, 7, 1202–1209.e1.
[CrossRef]
145. Tursi, A.; Brandimarte, G.; Papa, A.; Giglio, A.; Elisei, W.; Giorgetti, G.M.; Forti, G.; Morini, S.; Hassan, C.; Pistoia, M.A.; et al.
Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical
treatment: A double-blind, randomized, placebo-controlled study. Am. J. Gastroenterol. 2010, 105, 2218–2227. [CrossRef]
146. Iheozor-Ejiofor, Z.; Gordon, M.; Clegg, A.; Freeman, S.C.; Gjuladin-Hellon, T.; MacDonald, J.K.; Akobeng, A.K. Interventions for
maintenance of surgically induced remission in Crohn’s disease: A network meta-analysis. Cochrane Database Syst. Rev. 2019, 9,
CD013210. [CrossRef]
147. Gionchetti, P.; Rizzello, F.; Helwig, U.; Venturi, A.; Lammers, K.M.; Brigidi, P.; Vitali, B.; Poggioli, G.; Miglioli, M.; Campieri,
M. Prophylaxis of pouchitis onset with probiotic therapy: A double-blind, placebo-controlled trial. Gastroenterology 2003, 124,
1202–1209. [CrossRef]
148. Yasueda, A.; Mizushima, T.; Nezu, R.; Sumi, R.; Tanaka, M.; Nishimura, J.; Kai, Y.; Hirota, M.; Osawa, H.; Nakajima, K.; et al. The
effect of Clostridium butyricum MIYAIRI on the prevention of pouchitis and alteration of the microbiota profile in patients with
ulcerative colitis. Surg. Today 2016, 46, 939–949. [CrossRef]
149. Barnes, E.L.; Agrawal, M.; Syal, G.; Ananthakrishnan, A.N.; Cohen, B.L.; Haydek, J.P.; Al Kazzi, E.S.; Eisenstein, S.; Hashash,
J.G.; Sultan, S.S.; et al. AGA Clinical Practice Guideline on the Management of Pouchitis and Inflammatory Pouch Disorders.
Gastroenterology 2024, 166, 59–85. [CrossRef]
150. Kuisma, J.; Mentula, S.; Jarvinen, H.; Kahri, A.; Saxelin, M.; Farkkila, M. Effect of Lactobacillus rhamnosus GG on ileal pouch
inflammation and microbial flora. Aliment. Pharmacol. Ther. 2003, 17, 509–515. [CrossRef]
151. Mimura, T.; Rizzello, F.; Helwig, U.; Poggioli, G.; Schreiber, S.; Talbot, I.C.; Nicholls, R.J.; Gionchetti, P.; Campieri, M.; Kamm,
M.A. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004, 53,
108–114. [CrossRef] [PubMed]
152. Gionchetti, P.; Rizzello, F.; Venturi, A.; Brigidi, P.; Matteuzzi, D.; Bazzocchi, G.; Poggioli, G.; Miglioli, M.; Campieri, M.
Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: A double-blind, placebo-controlled trial.
Gastroenterology 2000, 119, 305–309. [CrossRef] [PubMed]
153. Pronio, A.; Montesani, C.; Butteroni, C.; Vecchione, S.; Mumolo, G.; Vestri, A.; Vitolo, D.; Boirivant, M. Probiotic administration in
patients with ileal pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells. Inflamm.
Bowel Dis. 2008, 14, 662–668. [CrossRef] [PubMed]
154. Limketkai, B.N.; Akobeng, A.K.; Gordon, M.; Adepoju, A.A. Probiotics for induction of remission in Crohn’s disease. Cochrane
Database Syst. Rev. 2020, 7, CD006634. [CrossRef]
155. Schultz, M.; Timmer, A.; Herfarth, H.H.; Sartor, R.B.; Vanderhoof, J.A.; Rath, H.C. Lactobacillus GG in inducing and maintaining
remission of Crohn’s disease. BMC Gastroenterol. 2004, 4, 5. [CrossRef]
156. Steed, H.; Macfarlane, G.T.; Blackett, K.L.; Bahrami, B.; Reynolds, N.; Walsh, S.V.; Cummings, J.H.; Macfarlane, S. Clinical trial:
The microbiological and immunological effects of synbiotic consumption—A randomized double-blind placebo-controlled study
in active Crohn’s disease. Aliment. Pharmacol. Ther. 2010, 32, 872–883. [CrossRef] [PubMed]
157. Fujimori, S.; Gudis, K.; Mitsui, K.; Seo, T.; Yonezawa, M.; Tanaka, S.; Tatsuguchi, A.; Sakamoto, C. A randomized controlled trial
on the efficacy of synbiotic versus probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis.
Nutrition 2009, 25, 520–525. [CrossRef] [PubMed]
158. Seiler, C.L.; Kiflen, M.; Stefanolo, J.P.; Bai, J.C.; Bercik, P.; Kelly, C.P.; Verdu, E.F.; Moayyedi, P.; Pinto-Sanchez, M.I. Probiotics
for Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Am. J. Gastroenterol. 2020, 115,
1584–1595. [CrossRef] [PubMed]
159. Smecuol, E.; Hwang, H.J.; Sugai, E.; Corso, L.; Cherñavsky, A.C.; Bellavite, F.P.; González, A.; Vodánovich, F.; Moreno, M.L.;
Vázquez, H.; et al. Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis
natren life start strain super strain in active celiac disease. J. Clin. Gastroenterol. 2013, 47, 139–147. [CrossRef] [PubMed]
160. Olivares, M.; Castillejo, G.; Varea, V.; Sanz, Y. Double-blind, randomised, placebo-controlled intervention trial to evaluate the
effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease. Br. J. Nutr. 2014, 112, 30–40.
[CrossRef] [PubMed]
Nutrients 2024, 16, 778 22 of 22

161. Francavilla, R.; Piccolo, M.; Francavilla, A.; Polimeno, L.; Semeraro, F.; Cristofori, F.; Castellaneta, S.; Barone, M.; Indrio, F.;
Gobbetti, M.; et al. Clinical and Microbiological Effect of a Multispecies Probiotic Supplementation in Celiac Patients With
Persistent IBS-type Symptoms: A Randomized, Double-Blind, Placebo-controlled, Multicenter Trial. J. Clin. Gastroenterol. 2019, 53,
e117–e125. [CrossRef] [PubMed]
162. Mozafarybazargany, M.; Khonsari, M.; Sokoty, L.; Ejtahed, H.-S.; Qorbani, M. The effects of probiotics on gastrointestinal
symptoms and microbiota in patients with celiac disease: A systematic review and meta-analysis on clinical trials. Clin. Exp. Med.
2023, 23, 2773–2788. [CrossRef] [PubMed]
163. Jedwab, C.F.; de Roston, B.C.M.B.; de Toge, A.B.F.S.; Echeverria, I.F.; Tavares, G.O.G.; Alvares, M.A.; Rullo, V.E.V.; de Oliveira,
M.R.M. The role of probiotics in the immune response and intestinal microbiota of children with celiac disease: A systematic
review. Rev. Paul. Pediatr. Orgao. Soc. Pediatr. Sao Paulo 2021, 40, e2020447. [CrossRef]
164. Hooi, J.K.Y.; Lai, W.Y.; Ng, W.K.; Suen, M.M.Y.; Underwood, F.E.; Tanyingoh, D.; Malfertheiner, P.; Graham, D.Y.; Wong, V.W.S.;
Wu, J.C.Y.; et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017,
153, 420–429. [CrossRef]
165. Goderska, K.; Agudo Pena, S.; Alarcon, T. Helicobacter pylori treatment: Antibiotics or probiotics. Appl. Microbiol. Biotechnol.
2018, 102, 1–7. [CrossRef]
166. Grgov, S.; Tasić, T.; Radovanović-Dinić, B.; Benedeto-Stojanov, D. Can probiotics improve efficiency and safety profile of triple
Helicobacter pylori eradication therapy? A prospective randomized study. Vojnosanit. Pregl. 2016, 73, 1044–1049. [CrossRef]
[PubMed]
167. Seddik, H.; Boutallaka, H.; Elkoti, I.; Nejjari, F.; Berraida, R.; Berrag, S.; Loubaris, K.; Sentissi, S.; Benkirane, A. Saccharomyces
boulardii CNCM I-745 plus sequential therapy for Helicobacter pylori infections: A randomized, open-label trial. Eur. J. Clin.
Pharmacol. 2019, 75, 639–645. [CrossRef] [PubMed]
168. Zou, J.; Dong, J.; Yu, X. Meta-analysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for
Helicobacter pylori eradication. Helicobacter 2009, 14, 97–107. [CrossRef] [PubMed]
169. Viazis, N.; Argyriou, K.; Kotzampassi, K.; Christodoulou, D.K.; Apostolopoulos, P.; Georgopoulos, S.D.; Liatsos, C.; Giouleme,
O.; Koustenis, K.; Veretanos, C.; et al. A Four-Probiotics Regimen Combined with A Standard Helicobacter pylori-Eradication
Treatment Reduces Side Effects and Increases Eradication Rates. Nutrients 2022, 14, 632. [CrossRef] [PubMed]
170. Myllyluoma, E.; Veijola, L.; Ahlroos, T.; Tynkkynen, S.; Kankuri, E.; Vapaatalo, H.; Rautelin, H.; Korpela, R. Probiotic supple-
mentation improves tolerance to Helicobacter pylori eradication therapy—A placebo-controlled, double-blind randomized pilot
study. Aliment. Pharmacol. Ther. 2005, 21, 1263–1272. [CrossRef] [PubMed]
171. Wang, K.-Y.; Li, S.-N.; Liu, C.-S.; Perng, D.-S.; Su, Y.-C.; Wu, D.-C.; Jan, C.-M.; Lai, C.-H.; Wang, T.-N.; Wang, W.-M. Effects of
ingesting Lactobacillus- and Bifidobacterium-containing yogurt in subjects with colonized Helicobacter pylori. Am. J. Clin. Nutr.
2004, 80, 737–741. [CrossRef] [PubMed]
172. Górska, A.; Przystupski, D.; Niemczura, M.J.; Kulbacka, J. Probiotic Bacteria: A Promising Tool in Cancer Prevention and Therapy.
Curr. Microbiol. 2019, 76, 939–949. [CrossRef] [PubMed]
173. Gao, Z.; Guo, B.; Gao, R.; Zhu, Q.; Qin, H. Microbiota disbiosis is associated with colorectal cancer. Front. Microbiol. 2015, 6, 20.
[CrossRef]
174. Sivamaruthi, B.S.; Kesika, P.; Chaiyasut, C. The Role of Probiotics in Colorectal Cancer Management. Evid.-Based Complement.
Altern. Med. ECAM 2020, 2020, 3535982. [CrossRef] [PubMed]
175. Hijová, E.; Szabadosova, V.; Štofilová, J.; Hrčková, G. Chemopreventive and metabolic effects of inulin on colon cancer develop-
ment. J. Vet. Sci. 2013, 14, 387. [CrossRef] [PubMed]
176. Limburg, P.J.; Mahoney, M.R.; Ziegler, K.L.A.; Sontag, S.J.; Schoen, R.E.; Benya, R.; Lawson, M.J.; Weinberg, D.S.; Stoffel,
E.; Chiorean, M.; et al. Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer
chemoprevention. Cancer Prev. Res. Phila. Pa. 2011, 4, 259–269. [CrossRef] [PubMed]
177. Anadón, A.; Martínez-Larrañaga, M.R.; Ares, I.; Martínez, M.A. Chapter 54—Prebiotics: Safety and Toxicity Considerations. In
Nutraceuticals; Gupta, R.C., Ed.; Academic Press: Boston, MA, USA, 2016; pp. 757–775, ISBN 978-0-12-802147-7. [CrossRef]
178. Hempel, S.; Newberry, S.; Ruelaz, A.; Wang, Z.; Miles, J.N.V.; Suttorp, M.J.; Johnsen, B.; Shanman, R.; Slusser, W.; Fu, N.; et al.
Safety of probiotics used to reduce risk and prevent or treat disease. Evid. Rep. Technol. Assess. 2011, 200, 1–645.
179. Didari, T.; Solki, S.; Mozaffari, S.; Nikfar, S.; Abdollahi, M. A systematic review of the safety of probiotics. Expert. Opin. Drug Saf.
2014, 13, 227–239. [CrossRef]
180. Besselink, M.G.H.; van Santvoort, H.C.; Buskens, E.; Boermeester, M.A.; van Goor, H.; Timmerman, H.M.; Nieuwenhuijs, V.B.;
Bollen, T.L.; van Ramshorst, B.; Witteman, B.J.M.; et al. Probiotic prophylaxis in patients with predicted severe acute pancreatitis:
A randomised, double-blind, placebo-controlled trial. Ned. Tijdschr. Geneeskd. 2008, 152, 685–696.
181. Kataria, J.; Li, N.; Wynn, J.L.; Neu, J. Probiotic microbes: Do they need to be alive to be beneficial? Nutr. Rev. 2009, 67, 546–550.
[CrossRef]

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