Abstract
There are known associations between opioids, obesity, and the gut microbiome, but the molecular connection/mediation of these relationships is not understood. To better clarify the interplay of physiological, genetic, and microbial factors, this study investigated the microbiome alongside host inflammatory responses to chronic opioid administration in genetically obese, diet-induced obese mice, and lean mice. Samples of feces, urine, colon tissue, and plasma were analyzed using targeted LC-MS/MS quantification of metabolites, immunoassays of inflammatory cytokine levels, genome-resolved metagenomics, and metaproteomics. Genetic obesity, diet-induced obesity, and morphine treatment in lean mice each showed increases in distinct inflammatory cytokines. Metagenomic assembly and binning uncovered over 400 novel gut bacterial genomes and species. Morphine impacted the microbiome’s composition, with the strongest effect observed in lean mice, as both diet- and genetic-obese mice had a greater effect on microbial composition. Based on inferred microbial physiology through the metaproteome, a high-fat diet transitioned constituent microbes from harvesting diet-derived nutrients to those present in the host mucosal layer. Considered together, these results clarify the effect of morphine on the gut microbiome, identify novel host-dependent phenotypes, and differentiate the effects of genetic obesity versus diet induced obesity on gut microbiome composition and function.