Metabolomic and transcriptomic alterations in the colon of mice with metabolic syndrome in the absence of inflammation

Abstract

Metabolic syndrome (MetS) is characterized by a cluster of conditions including abdominal obesity, elevated blood pressure, altered lipid profiles and high blood sugar levels. These factors collectively elevate risks for cardiovascular diseases, diabetes, and metabolic dysfunction associated steatotic liver disease (MASLD). MetS impacts approximately a third of the US populace and a quarter of the global population. Despite its widespread prevalence, there are no existing medications to specifically treat MetS. With the global rise in MetS cases, understanding its underlying mechanisms is paramount. Our research emphasizes the potential physiological and metabolic disruptions within the gastrointestinal (GI) tract that might contribute to MetS manifestation. Using a mouse model of MetS (MS NASH) and healthy lean controls (C57BL/6J), we investigated the colon environment. 16S rRNA sequencing from fecal samples revealed a distinct microbiota profile in MS NASH mice, highlighted by an increase in the Lactobacillus genus. Colonic metabolome and transcriptome in MS NASH mice displayed an upregulation in anabolic pathways, like glycolysis, the pentose phosphate pathway, and the tryptophan/kynurenine pathway. Subsequent integrated analysis of these datasets unveiled potential compensatory mechanisms and pathway crosstalk, within the colonic environment. Despite these alterations, MS NASH mice showed no signs of intestinal inflammation, a finding confirmed through detailed histological and LCN-2 assessments. Additionally, there were no changes detected in genes typically associated with increased intestinal inflammation or permeability. This study provides insight in the nuanced relationship between the metabolic state, gut microbiota, and potential progression towards other metabolic disorders. Our findings highlight the significance of multi-omics data convergence in understanding the changes within the colonic environment and their implications for MetS onset and/or progression. Supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) through grant no. UL1TR001449 (E.F.C.) and in part by NIH grant P20GM121176 (E.F.C.), and the University of New Mexico Comprehensive Cancer Center with grant P30CA118100. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.