Other than gut microbiota’s well-known functions, which include nutrient metabolism and absorption, xenobiotic and drug metabolism, and immune development, its role in protecting against pathogens has been poorly characterized. Previous research has identified some microbiota-mediated colonization resistance mechanisms, while little is known about whether microbial metabolites may also limit pathogen colonization.
A new study, led by Dr. Denise Monack from the Department of Microbiology and Immunology at Stanford University (California, USA), has found that the short-chain fatty acid propionate limits Salmonella colonization and expansion in mice.
The researchers utilized a mouse model of oral Salmonella typhimurium, in which two mice strains were not pre-treated with antibiotics prior to infection. Interestingly, the type of mouse strain affected S. typhimurium levels in cecum and feces differently: The so-called “129 mice” strain harbored more S. typhimurium in the cecum and colon and in the feces throughout infection when compared with the B6N strain. These findings made scientists suspect that a distal intestine-specific factor might be driving Salmonella colonization.
When exploring whether the composition of the gut microbiota may control intestinal Salmonella colonization, a fecal microbiota transplant from B6N mice into 129 mice limited S. typhimurium intestinal expansion and its feces levels in those mice. These findings were also observed when 129 mice were cohoused with B6N mice.
Gut microbiota analysis through 16S ribosomal ribonucleic acid sequencing in 129 and B6N recipient mice revealed that microbiota community composition (measured by b-diversity) appeared to mediate colonization resistance to Salmonella rather than overall species richness (measured by a-diversity).
Analysis of community composition also showed that Bacteroidales spp. were more abundant in B6N microbiota recipients. Specifically, genera Bacteroides and Prevotella and family Rikenellaceae were predictive of B6N microbiotas and more abundant in mice receiving B6N microbiotas.
Organic extracts from Bacteroidales spp. limited S. typhimurium growth in vitro. This effect was specific to Bacteroides species and was only targeted to Salmonella while other enteric pathogens were not. These findings support the role of Bacteroides‘ direct antibacterial mechanisms using antagonistic molecules against Salmonella growth.
In uninfected mice, fecal levels of the short-chain fatty acid propionate were higher in the B6N group, allowing scientists to explore whether propionate production may be responsible for limiting Salmonella growth in vitro. S. typhimurium growth was limited in a dose-dependent manner when co-cultured with supernatant-containing products from wild-type B. thetaiotaomicron, while its growth was not limited by products from B. thetaiotaomicron that cannot produce propionate. These data suggest that propionate production by Bacteroides spp. is necessary to limit S. typhimurium growth in vitro.
Propionate mediated colonization resistance against Salmonella by diffusing across Salmonella membrane into the cytoplasm and the subsequent acidification of its cytoplasm, which finally affected bacterial growth and division.
The role of Bacteroides spp. in limiting intestinal S. typhimurium infection was also demonstrated in vivo when administering a live cocktail of Bacteroides spp. compared with heat-killed Bacteroides spp. In line with findings from in vitro data, higher levels of propionate mediated Bacteroides colonization resistance against Salmonella.
In conclusion, this mice study has shown for the first time the direct mechanism via microbial metabolites used by the gut microbiota to defend the host against well-known enteric pathogen Salmonella. Propionate is the primary bacterial growth inhibitor of Salmonella growth at the intestinal level and other traditional mechanisms involved in colonization resistance did not take part.
Jacobson A, Lam L, Rajendram M, et al. A gut commensal-produced metabolite mediates colonization resistance to Salmonella infection. Cell Host Microbe. 2018; 24(2):296-307. doi: 10.1016/j.chom.2018.07.002.
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