Microbiota depletion shifts colonocyte substrate utilization
In the fed state, glucose is the major fuel to most cell types in the body. In contrast, colonic epithelial cells or colonocytes utilize butyrate as their major energy source. Butyrate is one of the short chain fatty acids (SCFAs), a class of microbial metabolites produced by microbial fermentation of dietary fiber in gut. When the gut microbiota is depleted, such as in germ-free (GF) mice, butyrate levels along with other SCFAs decline prompting “starved” colonocytes to shift their substrate utilization to an alternative fuel, such as glucose.
Glucose undergo oxidative metabolism in cells to produce energy. In contrast, early ex vivo experiments studying substrate utilization in isolated colonocytes of rats using radioactive tracers revealed that about 80% of glucose is rather converted into lactate in colonocytes . Later Donohoe et al., found that colonocytes from GF mice produce approx. 4 times higher lactate compared with conventionally raised mice through anaerobic glycolysis of glucose . However, lactate production is not an energy rewarding process and yields only 2-4 ATP compared with 36 ATPs from oxidative phosphorylation of glucose. Thus, the authors concluded that despite the shift in substrate utilization, the colonocytes in the GF mice remain in energy insufficient state .
In the recent article published in Nature Communications by Zarrinpar et al. , where gut microbiota (and butyrate!) was depleted using multiple gavage of antibiotics over the course of 4 weeks. The authors found that cecum tissue uses glucose as an alternative fuel in the absence of butyrate, and that the expression levels of 8 out of 10 enzymes in glycolysis pathway were upregulated in cecum of antibiotic- compared with vehicle-treated mice. Finally, they speculate that due to shift in substrate utilization in cecum, gut becomes a glucose sink that could account for overall improvement in glucose metabolism in the antibiotic-treated mice .
Perhaps this speculation needs more careful investigation. It is true that colonocytes use butyrate as their primary fuel; however, butyrate is not synthesized in isolation. Gut microbiota produces SCFAs that include acetate, propionate and butyrate. It has been shown that colonocytes prefer other SCFA such as acetate over glucose  probably because anaerobic glycolysis of glucose does not yield enough energy. In the article by Zarrinpar et al., there was a trend towards reduction of acetate in antibiotic- compared with vehicle-treated mice, but it was not depleted to the same level as butyrate . Secondly, shift in colonocyte substrate utilization from butyrate to glucose is also observed in inflammatory bowel disease and DSS colitis model. This is indicated to be due to alteration in butyrate uptake and thus colonocytes utilize glucose leading to high amount of lactate accumulation in cells . However, patients with IBS are more prone to develop glucose intolerance than the healthy people.
Studying substrate utilization in cecum/colonocytes is complex. It is true that the isolated colonocytes do not reflect the in vivo scenario. However, transcriptomic data (showing increased expression of glycolytic enzymes in intestinal tissue of antibiotic-treated mice) probably needs to be backed with enzyme activity measurements and tracer studies to understand its impact on overall metabolism.
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