Table of Contents:
What is IBS?
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and is characterized by chronic abdominal pain and discomfort, bloating and alterations in bowel habits.
A meta-analysis including 260,960 subjects showed that the prevalence of IBS was about 11.2% worldwide. IBS occurs in all age groups although 50% of patients with IBS report having first had symptoms before the age of 35 years.
IBS is more prevalent in women with 1.5- to 3-fold higher rates in women than those seen in men. Genetics may also play a significant role since up to 33% of IBS patients have a family history of IBS, compared to 2% of controls.
IBS is a heterogeneous condition and is diagnosed using the Rome criteria. Three main categories of IBS exist.
1) constipation-predominant IBS (IBS-C) where > 25% of stools are hard or lumpy and < 25% of stools are loose/mushy or watery
2) diarrhea-predominant IBS (IBS-D) where > 25% of stools are loose/mushy or watery and < 25% are hard or lumpy.
3) mixed-IBS (IBS-M) where > 25% of stools are loose/mushy or watery stools and > 25% and hard or lumpy.
Patients with IBS have overall poor quality of life and low work productivity. IBS is responsible for huge healthcare burden and higher economic costs. In addition, IBS patients usually have multiple comorbidities such as dyspepsia, fibromyalgia gastro-esophageal reflux disease, interstitial cystitis, chronic fatigue, chronic back pain insomnia and headache/migraine.
The pathophysiology and underlying mechanisms of IBS are not clearly understood. IBS appears to be multifactorial with some of the established factors including altered gut motility, psychological disorders, inflammation, altered gut microbiome, visceral hypersensitivity, altered gut immune responses, food intolerance, and dysregulated gut brain axis,.
This article discusses the role of gut microbiota in the pathogenesis of IBS and how treatment with antibiotics like rifaximin to tackle the altered gut microbial community may prove efficacious for the treatment of IBS.
SIBO and IBS
Small intestinal bacterial overgrowth (SIBO) is characterized by the presence of >105 colon forming units (CFU)/ml in the jejunal aspirate. Factors that may contribute towards the development of SIBO include resection of ileocecal valve, motor abnormalities, Systemic diseases, surgical loops, stress, smoking, and alcoholism.
SIBO is often diagnosed by hydrogen breath test (HBT) using substrates such as like glucose and lactulose. Hydrogen and methane gas appear in the breath as a result of abnormal fermentation of carbohydrates by the colonic bacteria in the small intestine in the setting of SIBO. These gases are absorbed in the bloodstream, by the lung and eventually exhaled in breath.
Interestingly, HBT is also a common diagnostic tool for patients with IBS. SIBO and IBS share common symptoms such as bloating, abdominal discomfort and flatulence. SIBO has been often observed in patients with IBS,,. It was shown that microbial composition in duodenum of patients with IBS had greater bacterial concentrations, reduced microbial diversity and high levels of Escherichia.
The prevalence of SIBO in IBS patients ranges widely between 46-84%. SIBO leads to qualitative and quantitative changes in the population of gut bacteria which causes gas, bloating, characteristics of IBS. Moreover, excessive methane production by overgrowth of methanogenic flora may be responsible for constipation observed in IBS.
Other pathophysiological mechanisms of IBS such as altered motility, visceral hypersensitivity and abnormal brain-gut interaction may also be explained by SIBO. Role of SIBO in IBS is further strengthened by studies which revealed that the treatment of SIBO relieves symptoms of IBS,.
Treatment of SIBO and IBS with Rifaximin
IBS has been treated with antibiotics. Some of these antibiotics include neomycin, metronidazole, amoxicillin and rifaximin. Among these, rifaximin, a non-systemic, broad-spectrum antibiotic seems to be the most efficacious.
Rifaximin is a non-absorbable antibiotic and thus poses minimal risk of toxicity. Rifaximin is a semisynthetic derivative of rifamycin. Rifaximin binds the β-subunit of microbial RNA polymerase and inhibits transcription and RNA synthesis. It is a broad spectrum antibiotic and is active against gram-positive and gram-negative aerobic, and anaerobic bacteria.
Various randomized, double-blind, placebo-controlled studies have shown the efficacy of rifaximin in improving symptoms of diarrhea-predominant IBS,,. A meta-analysis of randomized, placebo-controlled studies (N = 1803 patients with IBS/IBS-D) including TARGET 1 and TARGET 2 data showed global improvement of IBS in 42.2% of rifaximin-treated patients vs. 32.4% of patients receiving placebo. Significant improvement in IBS-related bloating was also observed, with 41.6% of rifaximin-treated patients vs. 31.7% of patients receiving placebo.
Clinical trials have also evaluated the effects of rifaximin on SIBO and IBS symptoms. Patients with positive lactulose breath test received rifaximin 400 mg three times a day (n = 44) or 200 mg four times daily (n = 106) for 14 days. 83–86% of patients had negative breath testing results in the follow up. Patients also reported significant improvement in IBS symptoms,.
Rifaximin Mechanism of Action
The efficacy of rifaximin in treating symptoms of IBS may be explained by its mechanism of action on gut microbiota. Rifaximin is about 100 fold more soluble in the presence of bile salts, the concentration of which is relatively high in the small intestine. Thus, rifaximin use may be ideal for treating SIBO associated with IBS. In fact, rifaximin is the most commonly studied antibiotic treatment for SIBO, with an overall breath test resolution rate of 49.5% in 8 clinical trials.
Other mechanisms of rifaximin mode of action include its anti-inflammatory role. IBS patients have increased elevated levels of pro-inflammatory cytokines such as IL-6, IL-8, IL-1β and TNF-α in comparison to healthy individuals,. Rifaximin has been shown to reduce mucosal inflammation, where it normalized levels of IL-17, IL-1β, Tumor necrosis factor alpha (TNF-α) and (gamma interferon)gIFN . In addition, rifaximin also reduces the attachment of bacteria to epithelial cells. It also has been shown to suppress bacterial virulence factors,.
How does Rifaximin stack up against herbal therapy?
Herbal antibiotics, such as grape seed extract, oil of oregano, ginger and garlic have shown to be an effective alternative to Rifaximin. This is because herbal therapy tend to lack the toxic side effects of Rifaximin. Hence side-effects such as diarrhea, gut dysbiosis and other symptoms usually associated with antibiotics are easily avoided.
Herbal therapy is also proven to be at least as effective in the gut lumen against pathogenic bacterial overgrowth as antibiotics. It selectively decontaminates the small intestine of large intestinal microflora. Hence, desirable bacterial species such as lactobacilli are not affected by herbal therapy.
There is no data to show whether herbal therapy or Rifaximin prevents a relapse of SIBO. However, it has been noted that treatments using probiotics have held off a remission of SIBO for a significant amount of time.
Long term treatments using Rifaximin or herbal therapy has shown better results rather than pushing high doses of either over the short term.
Rifaximin and Neomycin used together show broad spectrum antibiotic efficacy against anaerobic intestinal bacteria like M smithii, bacteroides like lactobacilli and clostridia. They are all thought to cause metabolic alterations in SIBO sufferers.
[table id=2 /]
Here is a case where a guy developed serious food poisoning due to unknown reasons. He received medication for the same and it cured the infection. However, he developed depression, constipation, severe fatigue and was unable to achieve anything all through his adolescent, teenage and adult years. He suffered through a wide variety of treatments without any results. He finally took a SIBO breath test and tested positive for the disease. This is because SIBO causing bacteria produces methane, which was detected by the breath test.
He was prescribed neomycin and rifaximin for 10 days. It seemed as if someone had just flipped a switch. His depression, constipation and fatigue disappeared almost immediately! He started having one bowel movement per day. The intermittent bouts of diarrhoea that he used to suffer from disappeared as well. He also had a lot of energy.
Unfortunately, this upturn lasted for only about 45 days. There was a relapse and the sufferer believe that it was caused because the overgrowth was not completely eliminated from the small intestine. He now believes that he should eat cornmeal laced with antibiotics. He thinks it will work because while the bacteria is feeding on the cornmeal, they come out of their biofilm, which allows the antibiotics to eliminate them a lot more efficiently.
Cornmeal is also a part of a low fodmap diet, which is said to be very useful for SIBO sufferers.
IBS treatment remains a challenge owing to the multifactorial nature of the condition and its unknown etiology. Growing evidence suggests a role of altered gut microbial community as the underlying mechanism. Existing data supports the role of rifaximin as a promising candidate for the treatment of IBS symptoms owing to its success in treating SIBO.
However, more clinical studies are needed to further strengthen these findings as SIBO decontaminated subjects are at high risk of replase due to underlying predisposing conditions. Moreover, studies are needed to test the efficacy of rifaximin in IBS patients who lack SIBO.
 G. F. Longstreth, W. G. Thompson, W. D. Chey, L. A. Houghton, F. Mearin, and R. C. Spiller, “Functional bowel disorders.,” Gastroenterology, vol. 130, no. 5, pp. 1480–91, Apr. 2006. [Read Here]
 R. M. Lovell and A. C. Ford, “Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis.,” Clin. Gastroenterol. Hepatol., vol. 10, no. 7, pp. 712–721.e4, Jul. 2012. [Read Here]
 P. Maxwell, M. Mendall, and D. Kumar, “Irritable bowel syndrome,” Lancet, vol. 350, no. 9092, pp. 1691–1695, Dec. 1997. [Read Here]
 P. J. Whorwell, M. McCallum, F. H. Creed, and C. T. Roberts, “Non-colonic features of irritable bowel syndrome.,” Gut, vol. 27, no. 1, pp. 37–40, Jan. 1986. [Read Here]
 D. A. Drossman and D. L. Dumitrascu, “Rome III: New standard for functional gastrointestinal disorders.,” J. Gastrointestin. Liver Dis., vol. 15, no. 3, pp. 237–41, Sep. 2006. [Read Here]
 L. J. Brandt, W. D. Chey, A. E. Foxx-Orenstein, L. R. Schiller, P. S. Schoenfeld, B. M. Spiegel, N. J. Talley, and E. M. M. Quigley, “An evidence-based position statement on the management of irritable bowel syndrome.,” Am. J. Gastroenterol., vol. 104 Suppl , pp. S1–35, Jan. 2009. [Read Here]
 W. E. Whitehead, C. K. Burnett, E. W. Cook, and E. Taub, “Impact of irritable bowel syndrome on quality of life.,” Dig. Dis. Sci., vol. 41, no. 11, pp. 2248–53, Nov. 1996. [Read Here]
 C. Canavan, J. West, and T. Card, “Review article: the economic impact of the irritable bowel syndrome.,” Aliment. Pharmacol. Ther., vol. 40, no. 9, pp. 1023–34, Nov. 2014. [Read Here]
 P. O. Vandvik, I. Wilhelmsen, C. Ihlebaek, and P. G. Farup, “Comorbidity of irritable bowel syndrome in general practice: a striking feature with clinical implications.,” Aliment. Pharmacol. Ther., vol. 20, no. 10, pp. 1195–203, Nov. 2004. [Read Here]
 S. K. Padhy, S. Sahoo, S. Mahajan, and S. K. Sinha, “Irritable bowel syndrome: Is it ‘irritable brain’ or ‘irritable bowel’?,” J. Neurosci. Rural Pract., vol. 6, no. 4, pp. 568–77, Jan. . [Read Here]
 D. A. Drossman, M. Camilleri, E. A. Mayer, and W. E. Whitehead, “AGA technical review on irritable bowel syndrome.,” Gastroenterology, vol. 123, no. 6, pp. 2108–31, Dec. 2002. [Read Here]
 R. S. Choung, K. C. Ruff, A. Malhotra, L. Herrick, G. R. Locke, W. S. Harmsen, A. R. Zinsmeister, N. J. Talley, and Y. A. Saito, “Clinical predictors of small intestinal bacterial overgrowth by duodenal aspirate culture.,” Aliment. Pharmacol. Ther., vol. 33, no. 9, pp. 1059–67, May 2011. [Read Here]
 H. C. Lin, “Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome.,” JAMA, vol. 292, no. 7, pp. 852–8, Aug. 2004. [Read Here]
 E. Pyleris, E. J. Giamarellos-Bourboulis, D. Tzivras, V. Koussoulas, C. Barbatzas, and M. Pimentel, “The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome.,” Dig. Dis. Sci., vol. 57, no. 5, pp. 1321–9, May 2012. [Read Here]
 E. D. Shah, R. J. Basseri, K. Chong, and M. Pimentel, “Abnormal breath testing in IBS: a meta-analysis.,” Dig. Dis. Sci., vol. 55, no. 9, pp. 2441–9, Sep. 2010. [Read Here]
 A. Pistiki, I. Galani, E. Pyleris, C. Barbatzas, M. Pimentel, and E. J. Giamarellos-Bourboulis, “In vitro activity of rifaximin against isolates from patients with small intestinal bacterial overgrowth.,” Int. J. Antimicrob. Agents, vol. 43, no. 3, pp. 236–41, Mar. 2014. [Read Here]
 M. Pimentel, “Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea.,” Aliment. Pharmacol. Ther., vol. 43 Suppl 1, pp. 37–49, Jan. 2016. [Read Here]
 Y. Ringel, R. E. Williams, L. Kalilani, and S. F. Cook, “Prevalence, characteristics, and impact of bloating symptoms in patients with irritable bowel syndrome.,” Clin. Gastroenterol. Hepatol., vol. 7, no. 1, pp. 68–72; quiz 3, Jan. 2009. [Read Here]
 S. Chatterjee, S. Park, K. Low, Y. Kong, and M. Pimentel, “The degree of breath methane production in IBS correlates with the severity of constipation.,” Am. J. Gastroenterol., vol. 102, no. 4, pp. 837–41, Apr. 2007. [Read Here]
 G. Barbara, V. Stanghellini, G. Brandi, C. Cremon, G. Di Nardo, R. De Giorgio, and R. Corinaldesi, “Interactions between commensal bacteria and gut sensorimotor function in health and disease.,” Am. J. Gastroenterol., vol. 100, no. 11, pp. 2560–8, Nov. 2005. [Read Here]
 M. Pimentel, E. J. Chow, and H. C. Lin, “Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome.,” Am. J. Gastroenterol., vol. 95, no. 12, pp. 3503–6, Dec. 2000. [Read Here]
 L. Cuoco and M. Salvagnini, “Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with rifaximin.,” Minerva Gastroenterol. Dietol., vol. 52, no. 1, pp. 89–95, Mar. 2006. [Read Here]
 R. J. Basseri, S. Weitsman, G. M. Barlow, and M. Pimentel, “Antibiotics for the treatment of irritable bowel syndrome.,” Gastroenterol. Hepatol. (N. Y)., vol. 7, no. 7, pp. 455–93, Jul. 2011. [Read Here]
 C. Scarpignato and I. Pelosini, “Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential.,” Chemotherapy, vol. 51 Suppl 1, pp. 36–66, Jan. 2005. [Read Here]
 H. Umezawa, S. Mizuno, H. Yamazaki, and K. Nitta, “Inhibition of DNA-dependent RNA synthesis by rifamycins.,” J. Antibiot. (Tokyo)., vol. 21, no. 3, pp. 234–6, Mar. 1968. [Read Here]
 M. Pimentel, S. Park, J. Mirocha, S. V Kane, and Y. Kong, “The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial.,” Ann. Intern. Med., vol. 145, no. 8, pp. 557–63, Oct. 2006. [Read Here]
 A. I. Sharara, E. Aoun, H. Abdul-Baki, R. Mounzer, S. Sidani, and I. Elhajj, “A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence.,” Am. J. Gastroenterol., vol. 101, no. 2, pp. 326–33, Feb. 2006. [Read Here]
 E. Scarpellini, M. Gabrielli, C. E. Lauritano, A. Lupascu, G. Merra, G. Cammarota, I. A. Cazzato, G. Gasbarrini, and A. Gasbarrini, “High dosage rifaximin for the treatment of small intestinal bacterial overgrowth.,” Aliment. Pharmacol. Ther., vol. 25, no. 7, pp. 781–6, Apr. 2007. [Read Here]
 S. B. Menees, M. Maneerattannaporn, H. M. Kim, and W. D. Chey, “The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis.,” Am. J. Gastroenterol., vol. 107, no. 1, pp. 28–35; quiz 36, Jan. 2012. [Read Here]
 P. Meyrat, E. Safroneeva, and A. M. Schoepfer, “Rifaximin treatment for the irritable bowel syndrome with a positive lactulose hydrogen breath test improves symptoms for at least 3 months.,” Aliment. Pharmacol. Ther., vol. 36, no. 11–12, pp. 1084–93, Dec. 2012. [Read Here]
 C. Darkoh, L. M. Lichtenberger, N. Ajami, E. J. Dial, Z.-D. Jiang, and H. L. DuPont, “Bile acids improve the antimicrobial effect of rifaximin.,” Antimicrob. Agents Chemother., vol. 54, no. 9, pp. 3618–24, Sep. 2010. [Read Here]
 S. C. Shah, L. W. Day, M. Somsouk, and J. L. Sewell, “Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth.,” Aliment. Pharmacol. Ther., vol. 38, no. 8, pp. 925–34, Oct. 2013. [Read Here]
 T. G. Dinan, E. M. M. Quigley, S. M. M. Ahmed, P. Scully, S. O’Brien, L. O’Mahony, S. O’Mahony, F. Shanahan, and P. W. N. Keeling, “Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?,” Gastroenterology, vol. 130, no. 2, pp. 304–11, Feb. 2006. [Read Here]
 T. Liebregts, B. Adam, C. Bredack, A. Röth, S. Heinzel, S. Lester, S. Downie-Doyle, E. Smith, P. Drew, N. J. Talley, and G. Holtmann, “Immune activation in patients with irritable bowel syndrome.,” Gastroenterology, vol. 132, no. 3, pp. 913–20, Mar. 2007. [Read Here]
 D. Xu, J. Gao, M. Gillilland, X. Wu, I. Song, J. Y. Kao, and C. Owyang, “Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.,” Gastroenterology, vol. 146, no. 2, pp. 484–96.e4, Feb. 2014. [Read Here]
 J. Gao, M. G. Gillilland, and C. Owyang, “Rifaximin, gut microbes and mucosal inflammation: unraveling a complex relationship.,” Gut Microbes, vol. 5, no. 4, pp. 571–5, Jul. 2014. [Read Here]
 E. L. Brown, Q. Xue, Z.-D. Jiang, Y. Xu, and H. L. Dupont, “Pretreatment of epithelial cells with rifaximin alters bacterial attachment and internalization profiles.,” Antimicrob. Agents Chemother., vol. 54, no. 1, pp. 388–96, Jan. 2010. [Read Here]
 Z.-D. Jiang, S. Ke, and H. L. Dupont, “Rifaximin-induced alteration of virulence of diarrhoea-producing Escherichia coli and Shigella sonnei.,” Int. J. Antimicrob. Agents, vol. 35, no. 3, pp. 278–81, Mar. 2010. [Read Here]
 E. A. Debbia, E. Maioli, S. Roveta, and A. Marchese, “Effects of rifaximin on bacterial virulence mechanisms at supra- and sub-inhibitory concentrations.,” J. Chemother., vol. 20, no. 2, pp. 186–94, Apr. 2008. [Read Here]