Roshini Thiagarajan

Background: Small Intestinal Bacterial Overgrowth (SIBO) is a disease that consists of excessive bacterial overgrowth within the small intestine and causes dysbiosis, or an imbalance in the gut microbiome. Irritable Bowel Syndrome (IBS) is one of the most chronic GI disorders and presents with symptoms such as abdominal pain, cramping, and altered bowel habits. Both disorders lead to activation of pro-inflammatory cytokines that cause an overall increase in inflammation in the gut. Currently, the gold-standard treatment for SIBO and IBS is a broad-spectrum antibiotic called Rifaximin; however, there is some discrepancy in the efficacy of Rifaximin as recurrence rates are high and some studies show that the drug does not seem to decrease gut inflammation. Recurrence rates for SIBO are persistent and may lead to a chronic state of inflammation due to increased pro-inflammatory cytokines, decreased anti-inflammatory cytokines, and dysfunction within epithelial barriers such as Trypsin-3, Claudin-2, and other tight junctions.

Objectives: The mechanisms of inflammation and disrupted epithelial function were explored to determine why recurrence seems to be an issue.

Search Methods: An online search in the PubMed database was conducted with results from 2017-2023 using the following keywords: “SIBO,” “IBS,” “recurrence.”

Results: Biopsies were taken from the duodenum, ileum, cecum, and sigmoid colon and analyzed for cytokine levels. Pro-inflammatory cytokines were markedly increased in the gut mucosa: IL-1B was found to be elevated in patients with SIBO as compared to patients without SIBO. Klebsiella pneumonia, a strain commonly found in SIBO patients, was positively correlated to IL-6 and TNF-a. The lack of anti-inflammatory cytokines was also discovered, especially IL-10, an important anti-inflammatory cytokine that was found to be significantly lower within the gut mucosa of IBS patients compared to control. The integrity of the epithelial barrier also seems to play a role in the gut, especially via Trypsin-3, a protease that signals enteric and sensory neurons, inducing an increase in the permeability of the epithelial barrier. Trypsin-3 is shown to be overexpressed in the colonic tissue of IBS patients, therefore increasing the permeability of the epithelial barrier, and allowing for a continuous influx of bacteria. Tight junctions regulate the passage of molecules in and out of the cell; therefore, tight junctions could be a reason for recurrence of disease if the epithelial barrier is not secure. CDL-3 and CDL-5, two tight junction proteins, were decreasingly expressed in biopsies of IBS patients throughout the GI tract. Claudin-2, a pore-forming tight junction protein, is also found to be upregulated in the ileal mucosa of IBS-D patients, further confirming the lack of intestinal regulation within the gut mucosa.

Conclusion: Both SIBO and IBS are connected and result in a constant state of inflammation as well as increased permeability in the gut. Rifaximin, the current treatment for both disorders, does not seem to eliminate the issue as recurrence seems to be the result of inadequate elimination of either inflammatory or permeability issues. Therefore, any potential drug therapy to effectively treat both SIBO and IBS should be able to both decrease pro-inflammatory cytokines and seal off the epithelial barrier to eliminate increased permeability.

Works Cited:

1. Skrzydło-Radomańska B, Cukrowska B. How to Recognize and Treat Small Intestinal Bacterial Overgrowth?. J Clin Med. 2022;11(20):6017. Published 2022 Oct 12. doi:10.3390/jcm11206017
2. Rizos E, Pyleris E, Pimentel M, Triantafyllou K, Giamarellos-Bourboulis EJ. Small Intestine Bacterial Overgrowth Can Form an Indigenous Proinflammatory Environment in the Duodenum: A Prospective Study. Microorganisms. 2022;10(5):960. Published 2022 May 2. doi:10.3390/microorganisms10050960
3. Chey WD, Shah ED, DuPont HL. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review. Therap Adv Gastroenterol. 2020;13:1756284819897531. Published 2020 Jan 23. doi:10.1177/1756284819897531
4. Bruzzese E, Pesce M, Sarnelli G, Guarino A. Pharmacokinetic drug evaluation of rifaximin for treatment of diarrhea-predominant irritable bowel syndrome. Expert Opin Drug Metab Toxicol. 2018;14(7):753-760. doi:10.1080/17425255.2018.1488964
5. Wang J, Zhang L, Hou X. Efficacy of rifaximin in treating with small intestine bacterial overgrowth: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2021;15(12):1385-1399. doi:10.1080/17474124.2021.2005579
6. Rolland-Fourcade C, Denadai-Souza A, Cirillo C, et al. Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut. 2017;66(10):1767-1778. doi:10.1136/gutjnl-2016-312094
7. Ivashkin V, Poluektov Y, Kogan E, et al. Disruption of the pro-inflammatory, anti-inflammatory cytokines and tight junction proteins expression, associated with changes of the composition of the gut microbiota in patients with irritable bowel syndrome. PLoS One. 2021;16(6):e0252930. Published 2021 Jun 11. doi:10.1371/journal.pone.0252930
8.  Ishimoto H, Oshima T, Sei H, et al. Claudin-2 expression is upregulated in the ileum of diarrhea predominant irritable bowel syndrome patients. J Clin Biochem Nutr. 2017;60(2):146-150. doi:10.3164/jcbn.16-92
9. Jørgensen SF, Macpherson ME, Bjørnetrø T, et al. Rifaximin alters gut microbiota profile, but does not affect systemic inflammation – a randomized controlled trial in common variable immunodeficiency. Sci Rep. 2019;9(1):167. Published 2019 Jan 17. doi:10.1038/s41598-018-35367-7