Regulation of Adaptive Thermogenesis by the Gut Microbiome
Authors: Nicholls Hayley T , Krisko Tibor I , LeClair Katherine B , Banks Alexander S , Cohen David E 
Published: November 2023

BackgroundAlterations in the gut microbiome contribute to obesity, but the mechanisms by which the gut microbiome regulates energy expenditure and balance are unclear. Adaptive thermogenesis in both humans and mice occurs when changes in ambient temperatures activate thermogenic brown and beige adipose tissue to dissipate energy as heat.AimsThis study was designed to examine the influence of cold ambient temperature on the gut microbiome and to elucidate the contribution of the gut microbiome to adaptive thermogenesis.MethodsC57BL/6 mice were maintained for 3 d at ambient temperatures of 30 °C (thermoneutral), 22 °C (mild cold stress), or 4 °C (severe cold stress). Temperature‐conditioned gut microbiomes were analyzed for predominant gut microbial phyla by qPCR of extracted fecal DNA and were transplanted into commensal‐depleted (antibiotic treated) recipient mice housed at 22 °C. The mice were fed a high fat‐diet, and after 5 w, intraperitoneal glucose tolerance tests were performed. Germ‐free and commensal depleted mice were housed at 30 °C, 22 °C, and 4 °C within a temperature‐controlled comprehensive laboratory animal monitoring system that was custom‐designed to maintain sterile conditions. Indirect calorimetry was performed to determine rates of O2 consumption (VO2) and CO2 production (VCO2). Energy expenditures and respiratory exchange ratios (RER) were calculated using VO2 and VCO2 values. Physical activity was measured according to beam breaks from light sensors within the cages. Core body temperatures were measured using rectal probes. Fecal metabolites were measured by gas chromatography.ResultsHousing mice for 3 d at 4 °C resulted in a dramatic 95% reduction in the abundance of Bacteroidetes and a 62% increase in Firmicutes, the two predominant microbial phyla in the gut. Mice that received a 4 °C‐conditioned microbiome gained less body weight in response to high fat‐feeding and exhibited improved glucose tolerance compared to mice that received the 30 °C‐ or 22 °C‐conditioned microbiomes. Without appreciable changes in core body temperatures, germ‐free and commensal‐depleted mice exhibited reduced energy expenditures at both 30 °C and 4 °C. This occurred despite increased physical activities in germ‐free mice, which were most pronounced at 4 °C. Indicative of preferential utilization of lipids as energy substrates, RER values were reduced in germ free mice at 30 °C and 4 °C, as were fecal contents of short‐chain fatty acids.ConclusionsThe gut microbiome plays a fundamental role in regulating adaptive thermogenesis, potentially by altering intestinal lipid availability or absorption. These effects may be transferred among mice and influence the metabolic response to over‐nutrition. We speculate that impaired thermogenesis in the setting of microbial dysbiosis contributes to the pathogenesis of obesity.Support or Funding InformationBrigham and Women's Hospital, Department of Medicine, Innovation Evergreen Fund and The Harvard Digestive Diseases Center (NIH P30 DK034854).