SIBO: How to Make Sense of Diagnoses and Treatment Strategies

Small intestinal bacterial overgrowth (SIBO) is a condition where bacteria are seen in excess in the small intestine.1 It is associated with numerous conditions, the foremost of which are listed in Table 1. The stomach and proximal small bowel normally contain few bacteria, and when present, this overabundance of organisms can be associated with bloating, flatulence, abdominal pain, nausea, dyspepsia, fatigue, diarrhea and constipation.2

The diagnosis of SIBO can be challenging. Based on recent North American consensus, SIBO is clinically significant when bacterial counts in the jejunum exceed greater than 103 CFU/Ml.3 However, small bowel aspirate cultures, considered the gold standard for the diagnosis of SIBO, are poorly reproducible and have limitations.4 First, they are difficult to obtain without oral and proximal gut contamination.5 In addition, it is difficult to obtain the necessary amount of fluid and to sample the correct location.6

sibotable_1A more practical and simple technique for diagnosing SIBO is through breath testing.7 To date, breath testing remains the most inexpensive, non-invasive and widely available test for the diagnosis of SIBO. These tests are based on the interaction between the administered carbohydrate (lactulose or glucose) and the intestinal bacteria.8 This results in fermentation and production of gases, hydrogen and methane being the two gases most studied. A positive breath test is based on a breath hydrogen rise prior to the expected arrival time in the cecum or the presence of elevated methane in human breath.9 Breath tests, however, have never been validated against a true gold standard. In a systemic review, Khoshini, et al. found 11 studies that have attempted to validate the accuracy of lactulose breath testing for SIBO. The sensitivity ranged from 31 to 68 percent, and specificity ranged from 44 to 100 percent.10 Breath testing has also come under scrutiny with regard to whether it is truly measuring bacterial overgrowth in the small bowel or measuring oro-cecal transit time.11,12 Studies have tried to correlate scintigraphy with rises in hydrogen; however, no study has proven clearly that the arrival of a radiolabeled substance in the cecum correlated with fermentation of the carbohydrate substance by colonic rather than small bowel bacteria.13 Until recently, breath testing suffered from a lack of standardization. However, a North American consensus meeting was held recently, in which our group participated, providing easyto-follow guidelines regarding test indication, performance and interpretation.3

Multiple breath test patterns of hydrogen and methane production have been described; however, hydrogen-predominant and methanepredominant bacterial overgrowth are the two patterns that have been most widely studied. Although patients with either pattern share similar symptoms such as bloating and abdominal distension, those with excessive methane production are five times more likely to have constipation.14 Moreover, the severity of constipation directly correlates with the methane level.15 Therefore, the treatment of SIBO differs between these two groups.

Antibiotics have been the mainstay of therapy for SIBO, particularly hydrogen-predominant SIBO. However, given the limited qualitative and quantitative assessment of the bacteria that are causing the symptoms, many different antibiotics, dosing regimens and durations Of the antibiotics used in hydrogen-predominant SIBO, rifaximin is one of the most extensively studied. In the largest study that specifically addressed the effects of rifaximin on SIBO, 142 patients with SIBO diagnosed by glucose breath test were randomized to rifaximin 400mg tid or metronidazole 250mg tid for seven days. After one month, breath tests normalized in 63 percent of patients in the rifaximin group versus 44 percent in the metronidazole group (P less than 0.05).16

When there is excess methane production, however, rifaximin alone may not be as efficacious. Methanobrevibacter smithii is an archaeon that is responsible for methane production in humans and is resistant to many antibiotics. In a retrospective study conducted by Low, et al., methane-producing subjects exhibited decreased methane and constipationrelated symptoms following treatment with a combination of neomycin and rifaximin.17 Our group has also shown in a randomized control trial that this combination of antibiotics reduces patient symptoms of constipation, bloating and straining while decreasing their methane production.18 It should be noted, however, that in patients who have a blind loop and SIBO, systemic antibiotics rather than poorlyabsorbed antibiotics such as neomycin and rifaximin should be considered.

Recently, there has been interest in the use of statins as treatment for methane production in humans. Statins have been shown to inhibit growth and production of methane in several Methanobrevibacter isolates, presumably by interfering with mevalonate synthesis need for isoprenoid lipid synthesis in methanogens.

Lovastatin, specifically, has been shown to lower methanogenesis in human stool samples.19 In a Phase 2 clinical trial, modifiedrelease lovastatin lactone, SYN-010, was shown to lower the elevated breath methane in patients with irritable bowel syndrome with constipation (NCT02495623).20 Ongoing largerscale trials will further clarify the efficacy and safety of statins in management of methanepredominant SIBO.

In summary, the greatest challenge in SIBO lies in diagnosing the condition. Deep sequencing of small bowel bacteria will be able to provide us with more definitive answers as to the bacterial populations involved. Until then, breath tests and antibiotics will be the standard approach in treating these patients. We recommend either lactulose or glucose breath testing for the diagnosis of SIBO. Depending on which gases are found on breath testing, we recommend rifaximin for hydrogen-predominant bacterial overgrowth, and the combination of rifaximin and neomycin for methane-predominant bacterial overgrowth.

Dr. Pichetshote has no conflicts to disclose.

Dr. Pimentel is a consultant for Valeant Pharmaceuticals,Commonwealth Laboratories, Synthetic Biologics, Micropharma and Naia Pharmaceuticals, and is on the advisory boards for Valeant Pharmaceuticals and Commonwealth Laboratories. Cedars-Sinai has a licensing agreement with Valeant Pharmaceuticals International Inc.,Commonwealth Laboratories Inc, and Synthetic Biologics, Inc.

References

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17. Low K, Hwang L, Hua J, et al. A combination of rifaximin and neomycin is most effective in treating irritable bowel syndrome patients with methane on lactulose breath test. J Clin Gastroenterol 2010;44:547-50.

18. Pimentel M, Chang C, Chua KS, et al. Antibiotic treatment of constipation-predominant irritable bowel syndrome. Dig Dis Sci 2014;59:1278-85.

19. Marsh E, Morales W, Chua KS, et al. Lovastatin Lactone Inhibits Methane Production in Human Stool Homogenates. American Journal of Gastroenterology 2015;110:S753.

20. Gottlieb K, Wacher V, Sliman J, et al. Review article: inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders. Aliment Pharmacol Ther 2016;43:197-212.

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