Barrier Repair in ME/CFS: Lessons from Prototype Diseases

Erik Squires

doi:10.20944/preprints202509.0576.v2

Submitted:

05 September 2025

Posted:

08 September 2025

You are already at the latest version

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is marked by heterogeneous symptom clusters and only partial or short-lived responses to interventions. While gut involvement has been implicated in ME/CFS, it has not been proven to be the root cause, nor have symptoms been consistently responsive to treatment.Methods: We analyze prototype illnesses with known gut barrier dysfunctions from the duodenum to the colon to identify similarities and symptoms that are direct results of barrier dysfunction. In particular, we assess what can be learned from these prototype diseases that depends not on pathogenesis, but on barrier breakdown and metabolite leakage.Results: Prototype diseases showed consistent involvement of pore pathways, frequent histamine leakage, and parallel treatment responses, despite differing in pathogenesis.

Keywords:

ME/CFS

;

Myalgic Encephalomyelitis

;

gut barrier

;

paracellular permeability

;

proximal colon

;

microbial metabolites

;

patient clustering

;

leak pathways

;

claudin pores

Subject:

Medicine and Pharmacology - Pathology and Pathobiology

1. Introduction

Dr. Anouk W. Vaes and collaborators at CIRO performed one of the largest systematic surveys of ME/CFS symptom patterns, applying clustering methods to patient-reported outcomes to identify recurring constellations of symptoms ¹. The study demonstrated that ME/CFS can be partitioned into multiple reproducible subgroups, each with distinct symptom burdens and emphases. While this clustering approach highlighted the extent of heterogeneity in ME/CFS, it also left unresolved why certain symptoms consistently co-occur and what biological processes might underlie those patterns.

We analyzed symptom severity patterns and, like many before us, found that symptoms were strongly correlated. Several stood out as plausibly gut-related, prompting us to ask whether symptoms could localize patient clusters to a specific gut region but they were unable to. Instead, these symptoms tracked closely with overall post-exertional malaise (PEM) severity. This suggested a broader gut barrier problem rather than a localized one. We therefore turned to prototype diseases with established barrier dysfunction, asking whether they could help clarify how barrier breakdown itself contributes to illness — in other words, to distinguish root disease mechanisms from the direct consequences of barrier breach.

2. Paracellular Pathways

To explain our findings, we first review paracellular pathways. Two major types are recognized in the gut epithelium: claudin pores and the leak pathway^2,3.

2.1. Characteristics

Each pathway can be characterized by:

Size range of molecules transported
Charge selectivity (cations, anions, or both)
Potential for activation independent of overt inflammation
Mechanisms of closure or deactivation

In normal physiology, claudin pores provide regulated passage of small, charged molecules, while the leak pathway accommodates larger, less selective solutes during epithelial turnover. When dysregulated, these same routes can become conduits for gut-derived metabolites.

Anion-selective pores favor small, negatively charged solutes such as lactate and organic acids.
Cation-selective pores favor small, positively charged solutes such as histamine and polyamines.
Leak pathway is less selective, admitting medium- to large-sized molecules during periods of inflammation or cytoskeletal stress⁴.

Unlike claudin pores, leak pathways do not create high-flux channels for ions. Their permeability is passive and limited to existing gradients, so they allow entry of ions and small solutes, but less efficiently than pore pathways.

Chronic dysbiosis may alter not only pore signaling but also pore distribution. Over time, the number and type of pores in each gut segment can shift, and clinical improvement may require months of epithelial remodeling before a stable, healthy population of channels is restored.

Table 1. Summary of Gut Paracellular Pathways.

Pathway	Size Range	Activation	Closure/Deactivation
Leak	Up to a few kDa	Inflammatory / cytoskeletal stress	Requires resolution of inflammation / cytoskeletal reset
Anion Pore	Small molecules (< 6–8 Å)	Claudin isoform–specific signals	Rapid closure via tight junction proteins
Cation Pore	Small molecules (< 6–8 Å)	Claudin isoform–specific signals	Rapid closure via tight junction proteins

These pathways are not mutually exclusive—simultaneous opening of leak and pore routes provides an explanation for the partial effects of interventions that address only one pathway² as well as symptom complexity.

2.2. Pathway Interventions

Leak and pore pathways differ in how they respond to interventions.

Leak: Experimental physiology shows that leak openings are driven primarily by inflammatory and cytoskeletal processes⁴. They can close rapidly once inflammation resolves but do not respond to ion-channel or charge-selective signals.

Pore: In contrast, pore-mediated transport is regulated by claudin-specific, charge-selective signaling^2,3. Pores open and close independently of inflammation, often with rapid gating in response to ionic or metabolic cues.

In practice, interventions that resolve inflammation target the leak pathway most directly, whereas interventions that alter charge-selective signaling primarily affect pores.

3. Prototype Diseases

Diseases were selected based on the following criteria:

Gut-centric in origin
Documented evidence of:

–

Barrier dysfunction

–

Metabolites exported from the lumen

–

Symptom associations for each metabolite

–

Clear identification of unique metabolites (e.g., ethanol) unlikely to be universal
Some symptom overlap with the Vaes patient clusters beyond fatigue and brain fog
Broad coverage across the gastrointestinal tract

All of the prototype diseases release metabolites that, once absorbed, can trigger host cytokine expression. These metabolites may contribute to common ME/CFS symptoms such as fatigue and brain fog, in addition to their metabolite-specific effects. We present the final list of diseases below:

Table 2. Disease and Gut Region Association

Disease	Gut Region
Celiac disease	Duodenum / Jejunum
SIBO / D-lactic acidosis	Duodenum / Jejunum
Crohn’s ileitis	Ileum
IBS-D	Proximal Colon
Microscopic / Inflammatory colitis	Colon (diffuse)
Ulcerative colitis (UC)	Distal Colon
Clostridioides difficile colitis	Distal Colon

3.1. Metabolites, Symptoms, and Paths

The set of metabolites documented in our prototype illnesses is surprisingly small — roughly a dozen. Here we list each one, the prototype illness associated with it, the path by which it is thought to reach the extra-luminal space, and the symptoms reported in that disease context.

Fatigue or brain fog are included only when directly attributed to the metabolite itself, rather than as secondary consequences of cytokine activation.

Path definitions:

Diffusion: Metabolite passes freely through the gut epithelium without requiring barrier dysfunction.
Overproduction: Metabolite is produced in excess in the gut (e.g., by enterochromaffin cells) and enters circulation independently of barrier disruption.
Pore: Metabolite crosses via small, selective paracellular channels formed by tight junctions.
Leak: Metabolite crosses via larger, non-selective paracellular defects associated with tight junction breakdown.

Table 3. Metabolites, Paths and Illnesses

Metabolite	Illnesses	Path	Documented Symptoms in Those Illnesses	Citation
Acetaldehyde	SIBO / D-lactic acidosis	Diffusion	Cognitive impairment, dizziness	^5,6
Bile acids	Crohn’s ileitis, IBS-D	Pore	Diarrhea/urgency, abdominal pain, sleep/circadian disturbance, weight change	⁷;⁸
D-lactate	SIBO / D-lactic acidosis	Pore	Neurocognitive dysfunction, dizziness, fatigue*	⁹;¹⁰
Ethanol	SIBO / D-lactic acidosis	Diffusion	Dizziness, alcohol intolerance, malaise	¹¹;¹²
Gliadin peptides	Celiac disease	Leak	Food intolerance, brain fog	¹³;¹⁴
Histamine	Celiac disease, Crohn’s ileitis, IBS-D, Microscopic colitis, SIBO	Pore	Flushing, headaches, abdominal pain, dizziness, fatigue	¹⁵;¹⁶
$H_{2}$ S (diffused)	Ulcerative colitis, Clostridioides difficile colitis	Diffusion	Nausea, toxic-feeling flares, headaches	¹⁷;¹⁸
Indoxyl sulfate	Ulcerative colitis, Clostridioides difficile colitis	Pore	Chemical/odor sensitivity, vascular headaches	¹⁹;²⁰
p-Cresol	Ulcerative colitis, Clostridioides difficile colitis	Pore	Chemical/odor sensitivity, vascular headaches	²¹;²²
SCFAs (e.g., butyrate, acetate, propionate)	IBS-D, Microscopic colitis	Over produced/pore	Bloating, abdominal pain, malaise	²³;²⁴
Serotonin	Celiac disease, IBS-D	Over produced	Sleep disturbance, mood lability, GI motility issues	²⁵;²⁶

* Emerging [https://biosignaling.biomedcentral.com/articles/10.1186/s12964-025-02132-z]

Not listed in this table are cytokines, which do not cross the gut barrier but are immune moderated causes for fatigue, malaise, fever/flu-like symptoms, and inflammatory flares

4. Disease, Metabolite, Path Summary

When summarized by pathway and metabolite, our prototype diseases share two broad associations: pore-mediated leakage and histamine involvement.

We infer the pathway by the metabolite and based on this all of these diseases would involve significant pore activity, and most — with the exception of the two colitis forms — are associated with histamine leakage.

Table 4. Disease, region and pathways

Disease	Gut Region	Pathways Used for Metabolite Leakage
Celiac disease	Duodenum / Jejunum	Pore (histamine), Leak (gliadin peptides), Overproduction of Serotonin
SIBO / D-lactic acidosis	Duodenum / Jejunum	Pore (D-lactate,histamine), diffusion (Ethanol, Acetaldehyde)
Crohn’s ileitis	Ileum	Pore (bile acids, histamine)
IBS-D	Proximal Colon	Pore (SCFAs, histamine, serotonin, bile acids), Overproduction of serotonin
Microscopic / Inflammatory colitis	Colon (diffuse)	Pore (SCFAs, histamine), Leak
Ulcerative colitis (UC)	Distal Colon	Pore (indoxyl sulfate, p-cresol), diffusion ( $H_{2}$ S)
Clostridioides difficile colitis	Distal Colon	Pore* (secondary bile acids, p-cresol, indoxyl sulfate); Diffusion ( $H_{2}$ S)

* Toxin-mediated epithelial injury (TcdA/TcdB) disrupts the barrier; classification reflects metabolite passage routes but the initiating damage is toxin-driven, not a canonical tight-junction pathway change.

5. Interventions

Looking across the prototypes, a consistent pattern emerges in the interventions that fail versus those that succeed (see Appendix A).

Inflammation-only strategies do not resolve the root problem
- Steroids, 5-ASA, biologics, or antihistamines alone can suppress cytokines or dampen symptoms, but they do not prevent metabolite leakage across the barrier.
- This explains relapses in UC, Crohn’s disease, and microscopic colitis, as well as only partial symptom relief in CFS-type patients.
Symptom-only drugs fail
- Agents such as loperamide in IBS-D, antidiarrheals in SIBO, or painkillers in colitis provide temporary relief but leave the underlying export of metabolites unaddressed.
- As a result, the disease process continues despite symptomatic improvement.
Barrier repair and metabolite-targeted interventions show the greatest promise
- Remove the offending metabolite (e.g., gluten-free diet in celiac).
- Reduce metabolite production (e.g., antibiotics in SIBO, low-FODMAP diet in IBS-D).
- Bind or block metabolites (e.g., bile acid sequestrants in Crohn’s disease, IBS-D, microscopic colitis).
- Normalize barrier function (e.g., larazotide in celiac, though Phase 3 trials failed).
- Restore metabolite ecology (e.g., fecal microbiota transplantation in C. difficile and UC).

These pattenrs mimic what we see for ME/CFS, and other diseases.

6. Discussion

If ME/CFS gut involvement parallels the patterns observed in our prototype diseases, then effective interventional trials should prioritize two strategies: normalizing pore pathway function and reducing histamine activity.

Moreover, the relatively small number of distinct metabolites identified across prototypes suggests that metabolite leakage in ME/CFS may also be limited in scope, even when multiple gut regions are involved. This constraint may help explain why patients exhibit overlapping symptom clusters despite heterogeneous overall presentations.

7. Conclusions

We have presented a survey of prototype diseases that shed light on ME/CFS interventions and potentially other chronic illnesses. Although these diseases differ in pathogenesis, they share two key features: gut barrier disruption and metabolite leakage. Their treatment responses are also broadly shared with ME/CFS, in that anti-inflammatory agents fail to provide durable benefit or yield only limited improvements.

Author Contributions

Erik K. Squires conceived the study, performed the analysis, and wrote the manuscript. This work presents an original investigative method and resulting framework which were both developed and first reported by the author in this preprint.

Funding

This work received no external funding.

Informed Consent Statement

his study reanalyzed publicly available trial reports and published symptom cluster data (Vaes 2023). No new patient data were collected.

Acknowledgments

This paper could not exist without the foundational work of Dr. Anouk W. Vaes and her colleagues at CIRO, whose clustering study and publicly available cluster summary data provided the basis for our analysis. We are deeply grateful for their contribution to the field. Dr. Vaes had no role in the writing of this paper, and all errors or misinterpretations are the responsibility of the author.

Conflicts of Interest

The author declares no competing interests.

Appendix A. Appendix A: Barrier-targeted interventions by prototype

Appendix A.1

Celiac disease (Duodenum/Jejunum)

Barrier pathway focus	Successful / promising	Failed / limited
Leak (gliadin peptides); Pore (histamine)	Gluten-free diet (GFD): normalizes permeability and resolves symptoms in adherent patients1. Larazotide (TJ modulator): Phase 2 RCTs showed symptom benefit during gluten challenge2.	Larazotide Phase 3: discontinued for lack of efficacy3. Anti-inflammatories/biologics: not effective for routine CeD, do not address barrier leak4.

SIBO / D-lactic acidosis (Duodenum/Jejunum)

Barrier pathway focus	Successful / promising	Failed / limited
Pore (D-lactate, histamine); Diffusion (ethanol, acetaldehyde)	Antibiotics such as rifaximin and metronidazole reduce bacterial overgrowth and improve symptoms5. Dietary carbohydrate restriction (low-FODMAP, low simple sugars) reduces fermentation and metabolite load6. Some probiotics reduce D-lactate producers, though evidence is mixed7.	Anti-inflammatories do not address metabolite production or permeability8. Symptomatic drugs (antidiarrheals) do not address underlying leakage9.

Crohn’s ileitis (Ileum)

Barrier pathway focus	Successful / promising	Failed / limited
Pore (bile acids, histamine)	Bile-acid sequestrants (cholestyramine, colesevelam) reduce bile-acid diarrhea in ileal Crohn’s and resection patients10. Nutritional therapy (exclusive enteral nutrition) improves barrier integrity and reduces inflammation11.	Antihistamines (H1/H2) alone have not shown consistent benefit in IBD12. Anti-TNF and other biologics reduce inflammation but do not directly normalize bile-acid–driven barrier leakage13.

Barrier pathway focus	Successful / promising	Failed / limited
Pore (SCFAs, histamine, bile acids); Overproduction (serotonin)	Rifaximin improves global symptoms and bloating in IBS-D14 15. Bile-acid sequestrants (e.g., colesevelam/cholestyramine) help IBS-D subsets with bile-acid excess16. Low-FODMAP diet reduces fermentation load → symptom improvement17 18. 5-HT3 antagonists (e.g., alosetron; ondansetron in smaller trials) reduce urgency/diarrhea19 20.	Anti-inflammatory/biologic therapies (cytokine-targeted) are not effective for IBS-D21. Symptom-only meds (e.g., loperamide) don’t address metabolite production or permeability22.

IBS-D (Proximal Colon)

Barrier pathway focus	Successful / promising	Failed / limited
Pore (SCFAs, histamine, bile acids); Overproduction (serotonin)	Rifaximin improves global symptoms and bloating in IBS-D23 24. Bile-acid sequestrants (e.g., colesevelam, cholestyramine) help subsets with bile-acid excess25. Low-FODMAP diet reduces fermentation load and improves symptoms26 27. 5-HT3 antagonists (e.g., alosetron; ondansetron in smaller trials) reduce urgency and diarrhea28 29.	Anti-inflammatory/biologic therapies (cytokine-targeted) are not effective in IBS-D30. Symptom-only meds (e.g., loperamide) do not address metabolite production or permeability31.

Microscopic / Inflammatory colitis (Colon, diffuse)

Barrier pathway focus	Successful / promising	Failed / limited
Pore (SCFAs, histamine); Leak	Budesonide is first-line therapy and effective at inducing remission, though relapse is common after withdrawal32 33. Bile-acid sequestrants are helpful in patients with bile-acid malabsorption, with ~2/3 showing benefit34 35.	Mesalamine and other anti-inflammatories show inconsistent or minimal efficacy36. Probiotics have not shown consistent benefit37.

Ulcerative colitis (Distal Colon)

Barrier pathway focus	Successful / promising	Failed / limited
Pore (indoxyl sulfate, p-cresol); Diffusion ( $H_{2}$ S)	5-ASA (mesalamine) and steroids induce remission by reducing inflammation, though they do not prevent metabolite leakage38 39. Dietary modulation (e.g., low-sulfur diets) may reduce $H_{2}$ S burden, limited supportive evidence40. FMT shows benefit in some patients, likely by restoring bile-acid and SCFA metabolism41.	Biologics (anti-TNF, anti-integrin) are effective for inflammation but do not address barrier dysfunction or metabolite leakage42. Barrier-directed agents (e.g., larazotide) have not been tested in UC.

Clostridioides difficile colitis (Distal Colon)

Barrier pathway focus	Successful / promising	Failed / limited
Pore* (secondary bile acids, p-cresol, indoxyl sulfate); Diffusion ( $H_{2}$ S)	FMT is highly effective for recurrent CDI, restoring secondary bile acid metabolism that inhibits C. difficile germination43 44. Standard antibiotics (vancomycin, fidaxomicin) resolve acute infection but do not restore barrier or metabolite balance45. Bezlotoxumab (anti-toxin B monoclonal) reduces recurrence in high-risk patients46.	Anti-inflammatories provide no benefit as they do not address toxin or metabolite leakage47. Recurrence rates remain high with antibiotics alone.

* Toxin-mediated epithelial injury (TcdA/TcdB) disrupts the barrier; classification reflects metabolite passage routes but the initiating damage is toxin-driven, not classic tight junction dysfunction.

References

Vaes, A. W.; Van Herck, M.; Deng, Q.; Delbressine, J. M.; Jason, L. A.; Spruit, M. A. Symptom-based clusters in people with ME/CFS: An illustration of clinical variety in a cross-sectional cohort. J. Transl. Med. 2023, 21, 112. [CrossRef]
Shen, L.; Black, E. D.; Witkowski, E. D.; Lencer, W. I.; Guerriero, V.; Schneeberger, E. E.; Turner, J. R. Myosin light chain kinase-dependent epithelial barrier dysfunction is regulated by NF-κ B. Proc. Natl. Acad. Sci. USA 2011, 108, 409–414.
Van Itallie, C. M.; Anderson, J. M. Claudins and epithelial paracellular transport. Annu. Rev. Physiol. 2006, 68, 403–429. [CrossRef]
Günzel, D.; Yu, A. S. L. Claudins and the regulation of tight junction permeability. Physiol. Rev. 2013, 93, 525–569. [CrossRef]
Kim, H.; Lee, J.; Park, C. Acetaldehyde production by intestinal microbes and its toxic effects. Toxicol. Res. 2019, 35, 1–10.
Toth, B.; others. Acetaldehyde as a carcinogen in gastrointestinal tract. World J. Gastroenterol. 2010, 16, 583–589.
Camilleri, M. Bile acid diarrhea: Prevalence, pathogenesis, and therapy. Gut Liver 2015, 9, 332–339. [CrossRef]
Walters, J. R. F.; Pattni, S. S. Managing bile acid diarrhoea. Ther. Adv. Gastroenterol. 2009, 2, 439–447. [CrossRef]
Kowlgi, G. N.; Chhabra, L. D-lactic acidosis: An underrecognized complication of short bowel syndrome. Clin. Exp. Gastroenterol. 2015, 8, 129–136. [CrossRef]
Uribarri, J.; Oh, M. S.; Carroll, H. J. D-lactic acidosis: A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine 1998, 77, 73–82. [CrossRef]
Logan, B.; Jones, M. Endogenous ethanol production in clinical conditions. Med. Hypotheses 2007, 69, 682–690.
Abad, C. L.; Safdar, N. The role of endogenous ethanol in disease. Clin. Liver Dis. 2017, 9, 41–44.
Fasano, A. Leaky gut and autoimmune diseases. Clin. Rev. Allergy Immunol. 2012, 42, 71–78. [CrossRef]
Ludvigsson, J. F.; others. The Oslo definitions for coeliac disease and related terms. Gut 2013, 62, 43–52. [CrossRef]
Maintz, L.; Novak, N. Histamine and histamine intolerance. Am. J. Clin. Nutr. 2007, 85, 1185–1196. [CrossRef]
Sanchez-Perez, S.; Comas-Baste, O.; Latorre-Moratalla, M. L.; Veciana-Nogues, M. T.; Vidal-Carou, M. C. Histamine intolerance: The current state of the art. Biomolecules 2021, 11, 1186.
Wallace, J. L.; Wang, R. Hydrogen sulfide-based therapeutics: Exploiting a unique but ubiquitous gasotransmitter. Nat. Rev. Drug Discov. 2018, 17, 823–839. [CrossRef]
Levitt, M. D.; Furne, J.; Springfield, J.; Suarez, F. L. Detrimental effects of hydrogen sulfide in the gut. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, G873–G878.
Wikoff, W. R.; Anfora, A. T.; others. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA 2009, 106, 3698–3703. [CrossRef]
Barrios, C.; Spector, T. D.; Menni, C. Indole metabolites: Link between diet, microbiome and health. Nutrients 2020, 12, 3790.
Smith, E.; Macfarlane, G. T. Formation of phenols and cresols by human gut microbiota. Environ. Microbiol. 2019, 21, 2712–2725.
De Létang, A.; others. p-Cresyl sulfate: A protein-bound uremic toxin. Toxins 2013, 5, 233–246.
Morrison, D. J.; Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 2016, 7, 189–200. [CrossRef]
Parada Venegas, D.; De la Fuente, M. K.; Landskron, G.; others. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front. Immunol. 2019, 10, 277.
Mawe, G. M.; Hoffman, J. M. Serotonin signalling in the gut: What’s new? Curr. Opin. Endocrinol. Diabetes Obes. 2013, 20, 14–21.
Camilleri, M. Serotonin in the gastrointestinal tract. Neurogastroenterol. Motil. 2009, 21, 123–129. [CrossRef]

1	Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2013.
2	Leffler DA, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Gastroenterology. 2012.
3	Innovate Biopharmaceuticals press release; Larazotide Phase 3 discontinued, 2022.
4	Ludvigsson JF, et al. Biologics and anti-inflammatory agents in celiac disease: limited efficacy. Curr Opin Gastroenterol. 2020.
5	Pimentel M, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011.
6	Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol. 2010.
7	Hove H, Mortensen PB. Colonic lactate metabolism and D-lactic acidosis. Dig Dis Sci. 1995.
8	Quigley EMM. The spectrum of small intestinal bacterial overgrowth (SIBO). Curr Gastroenterol Rep. 2019.
9	Grace E, et al. Small intestinal bacterial overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013.
10	Fernandez-Banares F, et al. Cholestyramine in the treatment of bile acid malabsorption in Crohn’s disease. Gastroenterology. 1991.
11	Ruemmele FM, et al. Enteral nutrition as primary therapy for Crohn’s disease: impact on mucosal healing and barrier function. Gut. 2004.
12	Sander LE, et al. Histamine H4 receptor antagonism reduces inflammation in murine colitis but has not translated to clinical efficacy in IBD. Inflamm Bowel Dis. 2015.
13	Peyrin-Biroulet L, et al. Anti-TNF therapy in Crohn’s disease: long-term outcomes. J Crohns Colitis. 2011.
14	Pimentel M, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011.
15	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
16	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
17	Halmos EP, et al. A diet low in FODMAPs reduces symptoms of IBS: a randomized controlled trial. Gastroenterology. 2014.
18	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
19	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
20	Garsed K, et al. Randomized, placebo-controlled trial of ondansetron in IBS-D. Gut. 2014.
21	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
22	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
23	Pimentel M, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011.
24	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
25	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
26	Halmos EP, et al. A diet low in FODMAPs reduces symptoms of IBS: a randomized controlled trial. Gastroenterology. 2014.
27	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
28	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
29	Garsed K, et al. Randomized, placebo-controlled trial of ondansetron in IBS-D. Gut. 2014.
30	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
31	Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021.
32	Münch A, et al. Microscopic colitis: current status, present and future challenges: statements of the European Microscopic Colitis Group. J Crohns Colitis. 2012.
33	Chande N, et al. Budesonide for induction of remission in microscopic colitis. Cochrane Database Syst Rev. 2008.
34	Fernandez-Banares F, et al. Bile acid malabsorption in microscopic colitis and benefit of cholestyramine. Gut. 2001.
35	Wildt S, et al. Bile acid malabsorption in patients with microscopic colitis. Gut. 2003.
36	Münch A, Aust D, Bohr J, et al. Microscopic colitis: Current status, present and future challenges. J Crohns Colitis. 2012.
37	Wildt S, Munck LK, Vinter-Jensen L, et al. Probiotic treatment of collagenous colitis: randomized, double-blind, placebo-controlled trial. Gut. 2006.
38	Sutherland LR, et al. Mesalazine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2000.
39	Truelove SC, et al. Cortisone in ulcerative colitis: final report on a therapeutic trial. BMJ. 1955.
40	Pitcher MC, Cummings JH. Hydrogen sulphide: a bacterial toxin in ulcerative colitis? Gut. 1996.
41	Paramsothy S, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomized placebo-controlled trial. Lancet. 2017.
42	Sands BE, et al. Infliximab maintenance therapy for ulcerative colitis: results from the ACT-1 and ACT-2 trials. N Engl J Med. 2005.
43	van Nood E, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013.
44	Weingarden AR, et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent C. difficile infection. Am J Physiol Gastrointest Liver Physiol. 2014.
45	Johnson S, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) for Clostridioides difficile infection in adults. Clin Infect Dis. 2021.
46	Wilcox MH, et al. Bezlotoxumab for prevention of recurrent C. difficile infection. N Engl J Med. 2017.
47	Kelly CP, LaMont JT. Clostridium difficile — more difficult than ever. N Engl J Med. 2008.

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