Microbial Regulation of Glucose Metabolism and Cell-Cycle Progression in Mammalian Colonocytes

Abstract

A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, 13C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO2 production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G1-to-S-phase transition that was rescued by a butyrate-fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells.

Shigella reroutes host cell central metabolism to obtain high-flux nutrient supply for vigorous intracellular growth

“…Some 80% of ATP produced in colonocytes comes from mitochondrial oxidation of butyrate, which is derived from gut microbiota. However, experiments with germ-free mice have shown that, in the absence of microbiotaderived butyrate, colonocytes switch from burning butyrate to fermenting glucose to lactate (36). It is possible that the flushing action of diarrhea during dysentery removes much of the microbiota, thereby lowering butyrate levels in the colon and triggering colonocyte metabolism similar to HeLa cell metabolism in our in vitro model.…”

The impact of intestinal inflammation on the nutritional environment of the gut microbiota

“…For example, some metabolic end products of Bacteroidia and Clostridia, such as butyrate, confer benefit to the host by providing nutrition for colonocytes, which mitochondrially oxidize this compound to carbon dioxide [34] (Fig. 1A).…”

“…Hydrogen produced by Clostridia and Bacteroidia fuels the growth of sulfate-reducing bacteria ( Desulfovibrio ), which produce hydrogen sulfide [35-37], a toxic gas oxidized by colonocytes to form harmless thiosulfate [38,39]. Butyrate is a fermentation product of obligate anaerobic bacteria that serves as nutrient for colonocytes [34]. (B) The metabolic niche occupied by facultative anaerobic Enterobacteriaceae in the healthy intestine.…”

Function and Phylogeny of Bacterial Butyryl Coenzyme A:Acetate Transferases and Their Diversity in the Proximal Colon of Swine

“…Butyrate in particular has potent effects on host tissues. As with other SCFAs, butyrate is consumed by the host as an energy source; however, unlike the other common SCFAs, such as propionate and acetate, butyrate is the preferred energy source for colonocytes (2) and is rapidly absorbed and used by the colonic epithelium. This rapid oxidation of butyrate reduces local oxygen concentrations, causing the epithelia to become hypoxic and thus limiting the growth of facultative aerobic pathogens, such as Salmonella species (3,4).…”