Critical appraisal of the SIBO hypothesis and breath testing: A clinical practice update endorsed by the European society of neurogastroenterology and motility (ESNM) and the American neurogastroenterology and motility society (ANMS)

Abstract

Background: There is compelling evidence that microbe-host interactions in the intestinal tract underlie many human disorders, including disorders of gut-brain interactions (previously termed functional bowel disorders), such as irritable bowel syndrome (IBS). Small intestinal bacterial overgrowth (SIBO) has been recognized for over a century in patients with predisposing conditions causing intestinal stasis, such as surgical alteration of the small bowel or chronic diseases, including scleroderma and is associated with diarrhea and signs of malabsorption. Over 20 years ago, it was hypothesized that increased numbers of small intestine bacteria might also account for symptoms in the absence of malabsorption in IBS and related disorders. This SIBO-IBS hypothesis stimulated significant research and helped focus the profession's attention on the importance of microbe-host interactions as a potential pathophysiological mechanism in IBS.

Purpose: However, after two decades, this hypothesis remains unproven. Moreover, it has led to serious unintended consequences, namely the widespread use of unreliable and unvalidated breath tests as a diagnostic test for SIBO and a resultant injudicious use of antibiotics. In this review, we examine why the SIBO hypothesis remains unproven and, given the unintended consequences, discuss why it is time to reject this hypothesis and its reliance on breath testing. We also examine recent IBS studies of bacterial communities in the GI tract, their composition and functions, and their interactions with the host. While these studies provide important insights to guide future research, they highlight the need for further mechanistic studies of microbe-host interactions in IBS patients before we can understand their possible role in diagnosis and treatment of patient with IBS and related disorders.

Keywords: bloating; disorders of gut‐brain interaction; irritable bowel syndrome; lactulose hydrogen breath test; microbiome; small intestinal bacterial overgrowth.

Figure 1.. Basic concept underlying the LBT for diagnosing SIBO and negative impact of transit time on validity.

Lactulose, a non-absorbable carbohydrate, is ingested (left) and fermented within a few minutes by the high numbers of microbes upon reaching the cecum. Fermentation produces hydrogen gas (H₂; as well as other gases, including CH₄ and H₂S, not shown), which rapidly diffuses into the circulation and can be collected in exhaled breath samples. The transit time from the mouth to the cecum (right panel, dark blue line) is the time from ingestion to the rise in H2 PPM about the specified cut-off level (e.g., 20 PPM). It is proposed in cases of SIBO that fermentation occurs earlier because the microbes are now increased in the small intestine. The result is an earlier rise in the H₂ in the breath samples (right panel, purple line) above the specified cut-off value. However, transit time is highly variable in healthy subjects, resulting in a “false positive” early rise in H₂ levels that are being attributed to increased bacteria in the small intestine rather than simply a faster transit time to reach the cecum (right panel, light blue lines).

Figure 2.. Combined Lactulose – ^99mTc scintigraphy shows the test meal is in the cecum before H₂ rises in IBS patients.

A. Schematic drawing showing gamma counter placed over cecum to detect ^99mTc sulfur colloid in the lactulose test meal, enabling the precise time lactulose has arrived in the cecum to be recorded. The time course panel below shows that in 39 of 40 IBS cases, the ⁹⁹Tc was in the cecum before the H₂ began to rise. This confirmed that lactulose was being fermented in the cecum and thus provided a measure of transit time and not overgrowth of bacteria in the small intestine. If the latter occurred, H₂ gas would have risen before the test meal reached the cecum. B. The transit time is highly variable in IBS patients, and more than half of the patients have a transit time, as measured by the ^99mTc in the cecum, that is less than the specified 90 min for the rise in H2 levels for a positive SIBO test. C. .5 g of lactulose in the cecum (5% of the 10 g test meal) is sufficient to cause a significant rise in H₂ levels within a few minutes (see text). The validation study shows that at least 5% of the meal was in the cecum in all cases before the H₂ levels rose, and in the majority of cases was > 20%. Reproduced with permission from BMJ Publishing Group Ltd. [Simrén M, Barbara G., Flint HJ, Spiegel BMR, Spiller RC, Vanner S, Verdu EF, Whorwell PJ, Zoetendal EG. Intestinal microbiota in functional bowel disorders: a Rome foundation report, Gut, 62(1):159–176, 2013, doi: 10.1136/gutjnl-2012-302167; and Yu D, Cheeseman F, Vanner S. Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS, Gut, 60(3):334–340, 2011, doi: 10.1136/gut.2009.205476].

Figure 3.. Criteria for a positive LBT for diagnosing SIBO: a moving target over time.

Proponents of the LBT have over time changed the criteria for a positive test, presumably to improve the accuracy. None of these criteria have, however, been validated, leading to confusion in the field. In parallel, it has been recognized that the “gold standard” using jejunal cultures with >105 CFU/ml also lacked sufficient accuracy, and proponents have introduced new criteria for culture techniques. However, these too have not been validated.

Figure 4.. LBT studies in IBS patients showing that no time point differentiates healthy controls from IBS patients.

Three independent studies, one from Canada, Sweden and the US, show that the recommended 90-minute cut-off for a rise in H₂ does not discriminate between healthy controls and IBS patients and that no time point appears to offer any discriminative value. Reproduced and adapted with permission from BMJ Publishing Group Ltd. [Posserud I, Stotzer P-O, Björnsson ES, Abrahamsson H, Simrén M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome, Gut, 56(6):802 – 808, 2007, https://gut.bmj.com/content/56/6/802.long]; and from Wolters Kluwer Health, Inc. [Walters B, Vanner SJ. Detection of bacterial overgrowth in IBS using the lactulose H2 breath test: Comparison with 14C-d-xylose and healthy controls, Amer J Gastroenterol, 100(7): 1566 – 1570, https://journals.lww.com/ajg/abstract/2005/07000/detection_of_bacterial_overgrowth_in_ibs_using_the.25.aspx; and Bratten JR, Spanier, J, Jones MP. Lactulose breath testing does not discriminate patients with irritable bowel syndrome from health controls, Amer J Gastroenterol, 103(4):958 – 963, https://journals.lww.com/ajg/abstract/2008/04000/lactulose_breath_testing_does_not_discriminate.21.aspx].

Figure 5.. Case-control studies comparing glucose H₂ breath tests in patients with IBS compared to other GI disease controls.

All of the GERD cases were on a PPI.