Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

Abstract

Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the key microbial functions influencing host energy metabolism and adiposity remain to be determined. Despite an increased understanding of the genetic content of the gastrointestinal microbiome, functional analyses of common microbial gene sets are required. We established a controlled expression system for the parallel functional analysis of microbial alleles in the murine gut. Using this approach we show that bacterial bile salt hydrolase (BSH) mediates a microbe-host dialogue that functionally regulates host lipid metabolism and plays a profound role in cholesterol metabolism and weight gain in the host. Expression of cloned BSH enzymes in the gastrointestinal tract of gnotobiotic or conventionally raised mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (Pparγ, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIγ), and circadian rhythm (Dbp, Per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in a significant reduction in host weight gain, plasma cholesterol, and liver triglycerides, demonstrating the overall impact of elevated BSH activity on host physiology. In addition, BSH activity in vivo varied according to BSH allele group, indicating that subtle differences in activity can have significant effects on the host. In summary, we demonstrate that bacterial BSH activity significantly impacts the systemic metabolic processes and adiposity in the host and represents a key mechanistic target for the control of obesity and hypercholesterolemia.

The microbiome revolution

“…Yet today medical science also is moving in the direction of the microbiome (14,15), a diverse and rapidly evolving virome (16)(17)(18)(19)(20), metagenome (14), and the microbial mycome, transcriptome, proteome, and metabolome (21)(22)(23)(24)(25)(26)(27). There is increasing evidence that the microbiome and its output (our interactome) touch many, if not most, pathways that affect health, disease, and aging.…”

The aging immune system and nutritional interventions

“…The finding that myelopoiesis is decreased in the absence of microbiota, is in line with a previous study [640]. This might be related to the finding that germfree mice have less adipose tissue than conventional mice, accompanied by lower adiponectin expression in ileum and liver [641], and lower serum levels of leptin [642]. Leptin enhances myeloid cell development [643], but is not required in normal B cell development [644].…”

“…Interestingly, leptin and IL-1β are identified by in silico analysis as activated upstream regulators in L. plantarum-treated Ercc1 -/Δ7 mice (chapter 6), and we speculate that these factors might explain the slight decrease in BM B cells after L. plantarum supplementation. Taken together, germfree mice have decreased expression of factors that stimulate myelopoiesis (leptin [642]) or block lymphopoiesis (adiponectin [641]), resulting in increased B cell development at the expense of myeloid development (Figure 3). Interestingly, Khosravi et al (2014) demonstrated that microbiota are necessary for the defense against Listeria monocytogenes.…”

Cross-talk between bile acids and intestinal microbiota in host metabolism and health

“…This study demonstrated that gut microbes, especially the Firmicutes, are beneficial for BA and glucose metabolism. Joyce et al (2014) revealed BSH enzymes expressed in the gut of GF or CONR mice noticeably changed plasma BAs and influenced gene-expression levels in both fat metabolism and metabolic signaling pathways. When CONR mice express higher levels of BSH enzymes, their weight gain, plasma cholesterol, and hepatic triglycerides reduce significantly.…”