Microbiota-derived acetate enhances host antiviral response via NLRP3

Abstract

Pathogenic viral infections represent a major challenge to human health. Host immune responses to respiratory viruses are closely associated with microbiome and metabolism via the gut-lung axis. It has been known that host defense against influenza A virus (IAV) involves activation of the NLRP3 inflammasome, however, mechanisms behind the protective function of NLRP3 are not fully known. Here we show that an isolated bacterial strain, Bifidobacterium pseudolongum NjM1, enriched in the gut microbiota of Nlrp3−/− mice, protects wild-type but not Nlrp3 deficient mice against IAV infection. This effect depends on the enhanced production of type I interferon (IFN-I) mediated by NjM1-derived acetate. Application of exogenous acetate reproduces the protective effect of NjM1. Mechanistically, NLRP3 bridges GPR43 and MAVS, and promotes the oligomerization and signalling of MAVS; while acetate enhances MAVS aggregation upon GPR43 engagement, leading to elevated IFN-I production. Thus, our data support a model of NLRP3 mediating enhanced induction of IFN-I via acetate-producing bacterium and suggest that the acetate-GPR43-NLRP3-MAVS-IFN-I signalling axis is a potential therapeutic target against respiratory viral infections.

The Association between Previous Antibiotic Consumption and SARS-CoV-2 Infection: A Population-Based Case-Control Study

“…These findings are within the general broader perspective of the relations of the microbiome and the rates of viral infections [ 40 , 41 , 42 , 43 ] and their severity [ 42 ]. A comprehensive review has shown that dysbiosis of the human microbiome is related to increased rates of viral infections and even suggested advanced manipulations to target gut microbiome [ 40 ]; the use of probiotics has also been suggested [ 43 ].…”

“…The decisive mechanisms involved and the gut–lung axis have been explored using a mouse model. Bifidobacterium pseudolongum NjM1-enriched gut microbiota of mice protected against influenza by acetate production and inflammasome-mediated signaling of interferon production [ 41 ]. A detailed study of the oropharyngeal metabolome in pediatric patients with or without influenza A virus pneumonia demonstrated significantly higher levels of sphingolipid and propanoate metabolites between patients with influenza pneumonia and healthy controls [ 44 ].…”

“…While the effects of antibiotic therapy on the human microbiome is prolonged, the duration of its immunomodulatory effects is unclear. It should be noted that azithromycin has an excellent tissue penetration and it accumulates within tissues and cells, particularly macrophages, with tissue concentrations about 50-fold greater than plasma concentration [ 29 , 41 ]. Its biologic half-life is long, estimated at 35–40 h in humans administered a single dose of 500 mg [ 29 , 46 ].…”

Strategies for applying probiotics in the antibiotic management of Clostridioides difficile infection

“…68 Bifidobacterium pseudolongum NjM1-derived acetate enhances the aggregation of mitochondrial antiviral signaling protein (MAVS) in response to receptor GPR43 (G protein-coupled receptor 43), leading to elevated IFN-I production and thus alleviating effects on virusinduced inflammation. 69 Whether it is a traditional probiotic or a new live biologic, mainstream clinical use has chosen to use probiotics after antibiotics, and there may be multiple reasons for such a combination order (Fig. 1): (1) the subsequent addition of probiotics can effectively occupy these ecological sites, thus competing to exclude the more resistant C. difficile strains, vegetative cells and spores; 9 (2) the addition of probiotics competes with the remaining C. difficile strains and their vegetative cells for nutrients essential for growth such as carbohydrates and amino acids, thus inhibiting the normal growth and metabolism of C. difficile; 19 (3) probiotics are able to secrete organic acids after colonization and affect the level of intestinal bile acid metabolism, especially enhancing the level of secondary bile acids, thus altering the intestinal growth environment to the detriment of C. difficile; 49,50 (4) after colonization, probiotics can secrete antimicrobial peptides, bacteriocins, extracellular polysaccharides and other types of antimicrobial substances, which have a direct killing effect on C. difficile strains; 64,[70][71][72] (5) probiotics can activate the intestinal immune system and enhance the related immune response to clear C. difficile; 73 and (6) probiotics can indirectly promote the growth of low-abundance beneficial microbes in the gut by "cross-feeding", thus co-antagonizing C. difficile.…”

“…68 Bifidobacterium pseudolongum NjM1-derived acetate enhances the aggregation of mitochondrial antiviral signaling protein (MAVS) in response to receptor GPR43 (G protein-coupled receptor 43), leading to elevated IFN-I production and thus alleviating effects on virus-induced inflammation. 69…”