New research in mice has found that a previously unknown interaction between an immune cell protein and the short-chain fatty acids (SCFAs) that are produced from dietary fiber by the actions of gastrointestinal bacteria, triggers protection against infection with Salmonella bacteria. Reporting their discovery in PLOS Biology, in a paper titled, “Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection,” Hitoshi Tsugawa, PhD, of Keio University School of Medicine in Tokyo, Japan, and colleagues say the results could point to new approaches to preventing bacterial infection. They concluded, “Although further investigation is needed to grasp the precise mechanisms by which dietary fiber and SCFAs modulate intestinal infection, our findings provide new insights into potential therapeutic interventions to prevent pathogenic infections.”
The gastrointestinal microbiome consists of nearly 100 trillion bacteria, comprising more than 1,000 species, the authors wrote. Some of these gut microbial species break down fiber eaten as part of the diet into short-chain fatty acids, which protect against pathogens like Salmonella by influencing the activity of immune cells, including macrophages. “These SCFA-producing bacteria protect against colonization by enteric pathogens, such as Shigella spp., Escherichia coli, and Salmonella spp.,” the authors wrote.
However, the mechanisms by which short-chain fatty acids interact with immune cells remained unclear. “In particular, which molecule(s) in immune cells react with SCFAs to regulate innate immunity remains incompletely understood, and authentic receptors for SCFAs must be identified to reveal their protective mechanisms against pathogen infection,” the team continued.
To better understand the protective role played by SCFAs, the researchers performed a series of laboratory experiments. First, they attached short-chain fatty acids to the surface of synthetic nanobeads, and exposed the structures to the contents of cells that had macrophage characteristics, in order to determine which proteins in the cells interacted with the SCFAs. “This study aimed to identify SCFA receptors that contribute to the regulation of innate immune responses,” they noted. “To this end, we used high-performance affinity nanobeads, which enable direct purification of binding proteins for small-molecule compounds.”
The experiments showed that short-chain fatty acids could bind to a protein called apoptosis-associated speck-like protein (ASC), as a previously unknown interaction. ASC is part of the inflammasome complex, a protein structure that helps to activate the inflammatory response to suppress pathogens. Further studies in macrophages then showed that short-chain fatty acids protected against Salmonella infection by binding to ASC and thereby triggering inflammasome activation.
The researchers confirmed and expanded their findings through experiments in mice. When Salmonella-infected mice were fed with short-chain fatty acids, or with their dietary fiber precursors, the fatty acids bound to ASC, triggered inflammasome activation, and prolonged the animals’ survival.” The administration of dietary fiber prior to bacterial infection significantly prolonged the survival of S. Typhimurium–infected mice by increasing the production of butyrate,” they commented. Specific pathogen-free (SPF) mice that lacked ASC (ASC-/-) mice were thus more susceptible to Salmonella Typhimurium infection than were wild-type SPF mice. “SPF ASC-/- mice were significantly more susceptible to S. Typhimurium infection than wild-type SPF mice, suggesting that ASC contributes to host defense against S. Typhimurium infection,” the team noted.
The tests suggested that the SCFs promote elimination of S. Typhimurium by recruiting neutrophils into the S. Typhimurium-infected cecal mucosa, by enhancing inflammasome activation in macrophages, and that this macrophage activation is required for ASC-dependent protective effects of SCFAs against the bacterium. “These findings indicated that SCFA-induced ASC-dependent activation of macrophages in the cecal mucosa promotes bacterial elimination to limit bacterial dissemination from the gastrointestinal tract to systemic sites,” the investigators wrote.
The results in mice provide new insights into the effects of dietary fiber on the immune system, although further research will be needed to determine whether the findings are also applicable to humans, and to investigate other potential effects of short-chain fatty acids on the immune system. Nevertheless, the authors concluded, “Although further study is needed to clarify the composition profile of gut microbiota associated with the induction of cecal inflammation in response to S. Typhimurium infection, our findings show that SCFAs induce cecal inflammation, which contributes to protection against bacterial infection through an ASC-dependent mechanism.”