Analyzing Proton pump inhibitor (PPI) induced dysbiosis and growing role of probiotics: Review

Comprising a diverse plethora of bacterial species, the human intestinal microecology is considered to be a complex community (1). Sudden disruption of the small intestinal microbial flora can upset the homeostasis leading to significant clinical consequences. Small interstitial bacterial overgrowth (SIBO) is defined as the presence of more than 105 colony-forming units (CFU)/ml of proximal jejunal aspirate and is characterized by an imbalance between the host defense mechanisms and symbiotic bacteria, causing excessive concentration of bacteria in the small intestine (1,2).

Among the many underlying etiologies that can lead to SIBO, Proton pump inhibitors (PPI) have come under the scanner owing to recent study results showing that PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating NSAID-induced small intestinal injury (3). Frequently prescribed by both primary care physicians and gastroenterologists, either as monotherapy or combined therapy, for treatment of gastroduodenal ulcer, erosive esophagitis, gastroesophageal reflux disease, gastric hypersecretory syndromes, and part of the treatment regimen for Helicobacter pylori; the possible association between PPI use and risk of SIBO has been noted as early as 1994 (4). Owing to the widespread use and easy availability of over-the-counter PPI, a better assessment of its side-effect profile and awareness of its link to SIBO, is essential (4).

Empirical drug therapies with broad-spectrum, antibiotic regimens have been used conventionally as popular choices to manage SIBO (1). However, the fact remains that absence of an adequate evidence base has led to indiscriminate use of antibiotics on a long term basis which lack standardization; causing poor patient tolerance, disruption of the commensal microbiota, antibiotic-associated diarrhea, the development of antibiotic resistance, and the potential for rebound colonization once the antibiotic is stopped (1). Such inadequacies related to antibiotic therapy have made the search for alternative therapy in managing SIBO more efficiently the need of the hour.

Association between PPI and small interstitial bacterial overgrowth (SIBO)-Recent reports indicate that PPIs can provoke dysbiosis of the small intestinal bacterial flora, with research highlighting a higher frequency of SIBO among PPI treated patients (3). Hence, PPI-induced dysbiosis is now considered a type of SIBO, and has further been linked to serious diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, nonalcoholic fatty liver disease, and autoimmune diseases (3).

Chronic acid suppression and the resultant hypochlorhydria associated with PPI use have been hypothesized to alter the intraluminal environment to promote the growth of the bacterial flora in the small intestine (4). Several reports have linked hypochlorhydria to increased gastric and duodenal bacterial colonization, predisposing patients to SIBO development (4).

In a notable meta-analysis,6 of 11 included studies reported a statistically significant increase in SIBO risk with PPI use, when the diagnosis was made with duodenal/jejunal aspirate culture, the current gold standard (4).

With accumulating reports confirming the statistical relationship between the use of PPIs and SIBO, the negative influence of acid suppression therapy, especially PPIs, can no longer be overlooked while attempting to control a disrupted small intestinal bacterial flora.

Therapeutic efficacy of probiotics in SIBO- How does it work?

Probiotics are nonpathogenic microorganisms that, when ingested, exert a positive influence on the health or physiology of the host. They can influence intestinal physiology either directly or indirectly through modulation of the endogenous ecosystem or immune system (7). It has also been documented that probiotics work by suppressing pro-inflammatory cytokines, modulating gut microbiota, sustaining the integrity of intestinal epithelium, and altering visceral hypersensitivity (5). Probiotics inhibits colonization of disease- causing bacteria through nutrient competition, immune system stimulation , and production of antitoxins (6,7). Probiotics have distinct advantages in SIBO as they avoid the disruption of gut microflora and combat opportunistic pathogens.

Acknowledging the beneficial effects of probiotics, certain studies recommend treatment with rifaximin along with probiotics as standard therapy for the management of SIBO (5).

What do studies say?

Encouraging results supporting the benefits of using probiotics in SIBO have been pouring in from global studies.

Gabrielli and colleagues (8) provided promising data from a study on Bacillus clausii which produced a rate of normalization of hydrogen breath tests that were comparable to antibiotics.

In another study, both Lactobacillus casei and L. acidophilus strains proved effective in treating chronic diarrhea related to bacterial overgrowth; yet others showed efficacy in terms of symptomatic benefit among patients with SIBO and functional intestinal distention (1).

Shedding valuable information on the role of probiotics in SIBO, a study by Khalighi and colleagues (9) investigated patients with symptoms suggestive of SIBO were tested for its presence using a lactulose hydrogen breath test (HBT). Thirty patients with a positive HBT were identified, all treated for three weeks with an oral broad-spectrum antibiotic. Following this, they were randomized into 2 groups- one to receive a synbiotic preparation for 15 days of each month followed by minocycline for the remaining 15 days, and the other to receive minocycline for the first 15 days of each month with no treatment for the remaining 15 days. Results indicated that those in the probiotic group had a significant reduction in pain, bloating, belching, and diarrhea in comparison to the control group. Indeed, all of those in the probiotic group reported complete resolution of abdominal pain. Further, post-treatment HBT was noted to be negative in 93.3 percent of those in the probiotic group in comparison to only 66.7 percent in the antibiotic-only group.

Four studies reported data on the incidence of SIBO, including 3 RCTs and 1 retrospective analysis. The pooled analysis suggested that patients using probiotics exhibited a predisposition toward a decreased incidence of SIBO when compared with those not using probiotics (2).

SIBO Decontamination Rate-Nine studies reported the SIBO decontamination rate, including 7 studies of probiotics alone and 2 studies of probiotics with antibiotics. The pooled rate was 53.2% (40.1% to 65.9%) for probiotics alone and 85.8% (69.9% to 94.0%) for probiotics plus antibiotic (2).

Symptoms Improvement-Studies evaluating SIBO related abdominal pain and stool frequency have concluded that the probiotic group showed superior improvements in the abdominal pain score as well as a slight inclination toward reduced daily stool frequency when compared to controls (2).

Highlights-

Ample research now underscores the fact that wide and indiscriminate use of PPIs is linked to developing SIBO.

Both clinicians and patients should be judicious in the use of PPI and consider dose-tapering whenever possible.

Owing to the multiple adverse effects linked to chronic use of antibiotics in managing SIBO, research has shifted focus to a more therapeutic alternative –probiotics. Probiotic therapy is an effective option for SIBO decontamination, reduction in H2 concentration, and abdominal pain relief.

As research continues to support the potency of probiotics in restoring the healthy microbiota in SIBO, physicians are positioned to consider this therapy while treating such patients.

Conclusion- Taking into account the potential adverse effects associated with chronic antibiotic therapies in managing PPI-induced SIBO, the addition of probiotics is regarded to be a new leap forward. Opening up new horizons in the treatment of SIBO, growing evidence now highlights the potency of probiotics in the prevention as well as eradication of SIBO.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Probiotics, click here

References

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Zhong, C., Qu, C., Wang, B., Liang, S., & Zeng, B. Probiotics for preventing and treating small intestinal bacterial overgrowth.2017. Journal of clinical gastroenterology, 51(4), 300-311.

Fujimori S. What are the effects of proton pump inhibitors on the small intestine? World J Gastroenterol 2015; 21(22): 6817-6819 Available from: URL: http://www.wjgnet.com/1007-9327/full/ v21/i22/6817.htm DOI: http://dx.doi.org/10.3748/wjg.v21.

Lo, W. K., & Chan, W. W. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. 2015. Clinical Gastroenterology and Hepatology, 11(5), 483-490.

Ghoshal, U. C., Shukla, R., & Ghoshal, U. Small intestinal bacterial overgrowth and irritable bowel syndrome: a bridge between functional organic dichotomy.2017 Gut and liver, 11(2), 196.

Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology.2006;130:S78–S90.

Marteau PR, de Vrese M, Cellier CJ, et al. Protection from gastrointestinal diseases with the use of probiotics. Am J Clin Nutr. 2001;73:430S–436S.

Gabrielli M, Lauritano EC, Scarpellini E, Lupascu A, Ojetti V, Gasbarrjni G, et al. Bacillus clausii as a treatment of small intestinal bacterial overgrowth. Am J Gastroenterol 2009;104 : 1327-8

Khalighi AR, Khalighi MR, Behdani R, Jamali J, Khosravi A, Kouhestani SH, et al. Evaluating the efficacy of probiotic on treatment in patients with small intestinal bacterial overgrowth (SIBO)-A pilot study. Indian J Med Res 2014;140 : 604-8.