Bacterial overgrowth and irritable bowel syndrome: unifying hypothesis or a spurious consequence of proton pump inhibitors?

Abstract

Some studies indicate that small intestinal bacterial overgrowth (SIBO), as measured by hydrogen breath tests (HBT), is more prevalent in patients with irritable bowel syndrome (IBS) vs. matched controls without IBS. Although the data are conflicting, this observation has led to the hypothesis that SIBO may be a primary cause of IBS. Yet, it remains unclear whether SIBO is truly fundamental to the pathophysiology of IBS, or is instead a mere epiphenomenon or bystander of something else altogether. We hypothesize that SIBO might be a byproduct of the disproportionate use of proton pump inhibitors (PPIs) in IBS, as follows: (1) IBS patients are more likely than controls to receive PPI therapy; (2) PPI therapy may promote varying forms of SIBO by eliminating gastric acid; and (3) existing studies linking SIBO to IBS have not adjusted for or excluded the use of PPI therapy. When linked together, these premises form the basis for a simple and testable hypothesis: the relationship between SIBO and IBS may be confounded by PPIs. Our article explores these premises, lays out the argument supporting this "PPI hypothesis," discusses potential implications, and outlines next steps to further investigate this possibility.

Figure 1

Hypothesized triangle of confounding among irritable bowel syndrome (IBS), small intestinal bacterial overgrowth (SIBO), and proton pump inhibitor (PPI) use. The observed relationship between IBS and SIBO might be explained by PPIs as PPI use is common in IBS patients, and PPIs might even induce some IBS symptoms (see text). In addition, PPIs are associated with SIBO (see text). Thus, PPIs meet the basic criterion for a confounder as they are bidirectionally associated to the purported risk factor (IBS), and unidirectionally associated to the outcome (SIBO).

Figure 2

Proposed iceberg of PPI-related bacterial dysregulation. Among patients with PPI-related enteric infections, there is a small group with rare but observable events that occur above the waterline (e.g., C. difficile colitis), and a larger group with common yet covert events below the waterline. See text for details.