Acidic Conditions in the NHE2^-/-Mouse Intestine Result in an Altered Mucosa-Associated Bacterial Population with Changes in Mucus Oligosaccharides

Abstract

This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Acidic Conditions in the NHE2- Abstract:Background: The mechanisms bacteria use to proliferate and alter the normal bacterial composition remain unknown. The ability to link changes in the intestinal micro-environment, such as ion composition and pH, to bacterial proliferation is clinically advantageous for diseases that involve an altered gut microbiota, such as Inflammatory Bowel Disease, obesity and diabetes. In human and mouse intestine, the apical Na + /H + exchangers NHE2 and NHE3 affect luminal Na + , water, and pH. Loss of NHE2 results in acidic luminal pH. Since acid resistance systems in gram-positive bacteria are well documented, we hypothesize that grampositive bacteria would increase in representation in the acidic NHE2 -/-intestine. Methods: Intestinal ion composition was measured by flame photometry and chloridometry and pH measured electrochemically. DNA extracted from intestinal flushes or from mucosal scrapings was analyzed by qRT-PCR to examine luminal and mucosa-associated bacterial populations. Epithelial mucus oligosaccharide patterns were examined by histology with FIT-C labeled lectins. Results: Although total luminal and mucosa-associated bacteria were unchanged in NHE2 -/-intestine, gram-positive bacterial phyla were increased in the mucosa-associated bacterial population in a region-specific manner. The genera Clostridium and Lactobacillus were increased in the cecum and colon which corresponded to changes in NHE2 -/-mucus oligosaccharide composition of mannose, N-acetyglucosamine, N-acetygalactosamine and galactose. Conclusions: Together these data indicate that changes in ion transport induce region-specific bacterial changes, which alter host mucus oligosaccharide patterns. These hostbacterial interactions provide a possible mechanism of niche-development and shed insight on how certain groups proliferate in changing environments and maintain their proliferation by altering the host.

Role of epithelial ion transports in inflammatory bowel disease

“…Later studies on the colonic microbiota of NHE3 Ϫ/Ϫ mice found increased Bacteroidetes but decreased Firmicutes bacteria (40) and overall lower bacterial diversity (81), which goes along with reports of reduced and altered microbiota in patients with IBD (107). Curiously, NHE2 Ϫ/Ϫ mice (which are not a model of IBD) featured radically different microbiota changes (41).…”

(Patho-)Physiology of Na+/H+ Exchangers (NHEs) in the Digestive System

“…NHEmediated alterations in the intestinal microenvironment, such as changes in luminal ion concentration and pH, could damage the gut microbiota. For instance, gram-positive bacteria such as Clostridium and Lactobacillus are increased in cecum and colon of NHE2 knockout mice although the total luminal and mucosaassociated bacteria remain unchanged (Engevik et al, 2013b). Also NHE3 knockout has an impact on the murine gut microbial environment, which includes a decrease in Lachnospiraceae and Ruminococcaceae (Firmicutes) and an increase in Bacteroidaceae.…”

Biochemical Features of Beneficial Microbes: Foundations for Therapeutic Microbiology

“…Additionally L-lactic acid suppresses immune cell mediated pro-inflammatory responses (309). Modulation of the immune system and alteration in local GIT pH has been speculated to selectively manipulate the gut microbiota composition (120,121,310), which may further promote colonization resistance and inhibition of pathogens. In addition to the antimicrobial effects of lactic acid itself, several studies have demonstrated that unidentified bacterial substances, bacteriocins and hydrogen peroxide act in concert with lactic acid to inhibit the growth of pathogens (301, 304, 308).…”

“…Mucus provides a viscoeleastic gel barrier that prevents luminal contents and microbiota from interacting directly with the epithelium and immune cells of the lamina propia. The mucin proteins are heavily O-glycosylated and these glycans can serve as adhesion sites for commensal bacteria (118)(119)(120)(121)(122)(123). Several studies have shown that intestinal communities can be visualized as biofilms of sessile microorganisms within the mucus layer (116,(124)(125)(126).…”