Indole-3-Propionic Acid, a Functional Metabolite of Clostridium sporogenes, Promotes Muscle Tissue Development and Reduces Muscle Cell Inflammation.

Lei Du,Zhenlong Wu,Renli Qi,Zuohua Liu,Jing Wang

doi:10.3390/ijms222212435

Abstract

Clostridium sporogenes (C. sporogenes), as a potential probiotic, metabolizes tryptophan and produces an anti-inflammatory metabolite, indole-3-propionic acid (IPA). Herein, we studied the effects of C. sporogenes and its bioactive metabolite, IPA, on skeletal muscle development and chronic inflammation in mice. In the in vivo study, the muscle tissues and serum samples of mice with C. sporogenes supplementation were used to analyze the effects of C. sporogenes on muscle metabolism; the IPA content was determined by metabonomics and ELISA. In an in vitro study, C2C12 cells were exposed to lipopolysaccharide (LPS) alone or LPS + IPA to verify the effect of IPA on muscle cell inflammation by transcriptome, and the involved mechanism was revealed by different functional assays. We observed that C. sporogenes colonization significantly increased the body weight and muscle weight gain, as well as the myogenic regulatory factors’ (MRFs) expression. In addition, C. sporogenes significantly improved host IPA content and decreased pro-inflammatory cytokine levels in the muscle tissue of mice. Subsequently, we confirmed that IPA promoted C2C12 cells’ proliferation by activating MRF signaling. IPA also effectively protected against LPS-induced C2C12 cells inflammation by activating Pregnane X Receptor and restoring the inhibited miR-26a-2-3p expression. miR-26a-2-3p serves as a novel muscle inflammation regulatory factor that could directly bind to the 3′-UTR of IL-1β, a key initiator factor in inflammation. The results suggested that C. sporogenes with its functional metabolite IPA not only helps muscle growth development, but also protects against inflammation, partly by the IPA/ miR-26a-2-3p /IL-1β cascade.

Highlights

Sarcopenia is a common chronic muscle inflammation in seniors induced by lipotoxicity, in which host microbial imbalance causes the insufficient intake of protein and antioxidant nutrients [1]
The results demonstrated that C. sporogenes treatment altered aromatic amino acid (AAA) metabolism and improved inflammatory resistance in mice
To explore the effects of C. sporogenes on skeletal muscle, C. sporogenes was gavaged at a dose of 1 × 108 CFUs/200 μL for six weeks in mice, and the gavage was administered twice weekly (Figure 1A); the treatment methods refer to previous studies [7,20]

Summary

Introduction

Sarcopenia is a common chronic muscle inflammation in seniors induced by lipotoxicity, in which host microbial imbalance causes the insufficient intake of protein and antioxidant nutrients [1]. The disturbances of protein synthesis and degradation in chronic muscle inflammation result in muscle atrophy and dysfunction [2,3]. This study aimed to explore the effects of C. sporogenes and its metabolites on skeletal muscle development and inflammation. The Clostridium genus is an important cluster of intestinal symbiotic bacteria, including. The Clostridium genus is a potential probiotic, and its cellular components and metabolites, such as secondary bile acid, butyric acid, and indole-3-propionic acid (IPA), play a probiotic role by enhancing the intestinal barrier and interacting with the immune system [7]. As a member of the Clostridium genus, C. sporogenes synthesizes IPA via tryptophan catabolism and regulates the health of host intestinal cells and distal tissues [8,9]

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