Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection.

Hitoshi Tsugawa,Yuki Sugiura,Hiroshi Handa,Zenta Yasukawa,Keiyo Takubo,Hidenori Matsui,Hiroyuki Itou,Toshio Takahashi,Shun’Ichiro Taniguchi,Makoto Suematsu,Ayaka Kanai,Shigeaki Hida,Kenya Honda,Hidekazu Suzuki,Yasuaki Kabe,Matthew K Waldor

doi:10.1371/journal.pbio.3000813

Abstract

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.

Highlights

The gastrointestinal microbiota consists of nearly 100 trillion bacteria, comprising more than 1,000 species [1]
As PYRIN domain–mediated binding of associated speck-like protein (ASC) to nucleotide-binding oligomerization domain-like receptor protein (NLRP) is required for inflammasome activation, we examined the effect of short-chain fatty acid (SCFA) on ASC/NLRP binding by a glutathione-S-transferase (GST) pull-down assay
Chemical and biological approaches using high-performance affinity nanobeads revealed that SCFAs bind to the PYRIN domain of ASC and NLRP3 and thereby promote the activation of the inflammasome, resulting in inflammatory cytokine production, both in vitro and in vivo

Summary

Introduction

The gastrointestinal microbiota consists of nearly 100 trillion bacteria, comprising more than 1,000 species [1]. Mainly of the phyla Firmicutes and Bacteroidetes, abundantly produce short-chain fatty acids (SCFAs) by fermenting indigestible carbohydrates or dietary fiber [2]. These SCFA-producing bacteria protect against colonization by enteric pathogens, such as Shigella spp., Escherichia coli, and Salmonella spp. Partially hydrolyzed guar gum (PHGG), a type of dietary fiber, prevents colonization of Salmonella Enteritidis in young and laying hens [5]. These reports suggest that SCFAs play a protective role against pathogenic infection in the intestinal tract

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