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Ion Transport and the Gut Microbiota

Engevik, Melinda A

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
The mechanisms bacteria use to proliferate and alter the normal gut bacterial composition remain unknown. Changes in the intestinal microbiota have been linked to diabetes, obesity, inflammatory bowel disease, and Clostridium difficile (C. difficile)-associated disease. The ability to link changes in the intestinal micro-environment, such as ion composition and pH, and macro-environment, such as diet, to bacterial proliferation is clinically advantageous for diseases that involve an altered gut microbiota. To address these gaps in knowledge, mouse models of altered ion transport (Na+/H+ exchangers, NHE2 and NHE3) and mice fed prebiotic GHF7K were used to examine changes in ion composition and pH along the length of the intestine and correlate these changes to alteration of the gut microbiota. In addition to mice, patients with C. difficile-infection (CDI), which exhibit a diarrhea similar to NHE3-/- mice, were also examined to determine if altered ion transport affects C. difficile proliferation. The hypothesis was that ion transport-induced change in the intestinal environment would lead to alteration of the microbiota. The data presented herein demonstrate the gut microbiota is highly sensitive to intestinal ions (Na+, K+, and Cl-), pH, prebiotics, and pathogen toxin production. In the NHE2-/- mouse model, an acidic luminal pH was associated with increased mucosa-associated gram-positive bacterial phyla in a region-specific manner. In contrast, in the NHE3-/- mouse model, an alkaline luminal pH and high [Na+] correlated with increased gram-negative Bacteriodetes members in both luminal and mucosa-associated bacteria. An alkaline luminal pH and high [Na+] environment was observed in patients with CDI which correlated with inhibition of NHE3. These changes in the intestinal environment likewise correlated with increased gram-negative Bacteroidetes members. These studies clearly demonstrate the connection between the gut micriobiota and the intestinal environment set by ion transport. In addition to genetically altered mice, WT mice fed a dietary supplement of GHF7K showed significantly altered composition of luminal populations at the level of the phyla, with region-specific differences. This dissertation has advanced the field of gut microbiology by showing (1) altered ion transport, and thus environment, can alter the gut microbiota in region-specific manner. These changes correlate with the specific environmental change; (2) shifts in specific bacterial groups correlate with changes in mucus fucosylation and/or glycosylation; (3) diet can dramatically affect the luminal bacteria, while leaving the mucosa-associated bacteria mostly intact; (4) ion transport deficient mouse models and intestinal organoids provide key tools for dissecting the host-microbiota interaction; both models mirror closely changes observed in patients under the same conditions. Together these data indicate that changes in ion transport and prebiotics induce region-specific bacterial changes, which alter host mucus oligosaccharide patterns. These host-bacterial interactions provide a possible mechanism of niche-development and provide insights on how certain groups proliferate in changing environments and maintain their proliferation by altering the host. Therapies addressing this new host-microbiota interaction could potentially be used to rebalance the intestinal microbiota after a shift, or microbial dysbiosis.
Roger Worrell, Ph.D. (Committee Chair)
Simon Hogan, Ph.D. (Committee Member)
Marshall Montrose, Ph.D. (Committee Member)
Gary Edward Shull, Ph.D. (Committee Member)
Yana Zavros, Ph.D. (Committee Member)
279 p.

Recommended Citations

Citations

  • Engevik, M. A. (2014). Ion Transport and the Gut Microbiota [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397466973

    APA Style (7th edition)

  • Engevik, Melinda. Ion Transport and the Gut Microbiota. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397466973.

    MLA Style (8th edition)

  • Engevik, Melinda. "Ion Transport and the Gut Microbiota." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397466973

    Chicago Manual of Style (17th edition)