Control of Host Lipid Metabolism by Gut Commensal Bacteroides acidifaciens

Abstract

In human, the composition of gut commensal bacteria is closely correlated with obesity through the modulation of microbial community and host immunity. However, a direct correlation between certain commensal bacteria and host metabolism remains unclear. In this study, I found significantly reduced body weight and fat mass overtime in conditional knock-out mice with CD11c+ cells with specific deletion of autophagy-related gene 7 (Atg7ΔCD11c) when compared with littermate control (Atg7f/f) mice. Interestingly, the level of insulin in serum from Atg7ΔCD11c mice having low body weight and fat mass was increased, but simultaneously the glucose in serum was low resulting insulin resistance improved. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both Atg7f/f and Atg7ΔCD11c mice, indicating that commensal bacteria is closely related to lipid metabolism. By pyrosequencing analysis, Bacteroides acidifaciens, one of the commensal bacteria isolated from mouse cecum, were significantly increased (>5%) in feces of Atg7ΔCD11c mice compared with those of control Atg7f/f mice. However, the ratio of B. sartorii, belonging to the Bacteroides genus, was shown a similar level between Atg7ΔCD11c and Atg7f/f mice. To clarify the efficacy of B. acidifaciens I selected in pyrosequencing analysis to control the host metabolism, I orally administrated these commensal bacteria to C57BL/6 (B6) mice. Most interestingly, while wild-type B6 mice fed with B. sartorii were shown similar body weight, B6 mice fed B. acidifaciens daily for 10 weeks were significantly lose body weight and fat mass than control, even though both groups consumed the same amount of food (i.e., normal chow diet or high-fat diet). Enhanced insulin sensitivity was also detected in serum of B6 mice following B. acidifaciens administration by glucose tolerance test (GTT) and insulin tolerance test (ITT). Of note, predominant expression of peroxisome proliferator-activated receptor alpha (PPARα), a key molecule of fat consumption through β-oxidation, was consistently found in the adipose tissues of Atg7ΔCD11c mice, wild-type B6 mice transferred with fecal microbiota of Atg7ΔCD11c mice, and B. acidifaciens-fed wild-type B6 mice. However, the expression levels of PPARα were not shown any significant difference between group in liver and small intestine. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) assay also revealed that the enhanced level of cholate, a primary bile acid, was detected in feces of B6 mice fed with B. acidifaciens for 10 weeks. In addition, the bile acid-responsive G protein-coupled receptor TGR5 was significantly activated in adipose tissues of B6 mice following B. acidifaciens short-term feeding, indicating that administration of B. acidifaciens resulted in activation of fat oxidation through the bile acid-TGR5-PPARα axis in adipose tissues, possibly leading to higher energy expenditure. B. acidifaciens also inactivated dipeptidyl peptidase-4 (DPP-4) in the gut and subsequently increased glucagon-like peptide-1 (GLP-1), which may contribute to glucose homeostasis. These findings strongly suggest that B. acidifaciens plays an active role in the prevention and therapy of metabolic diseases such as diabetes and obesity.