Commensal-derived metabolites govern Vibrio cholerae pathogenesis in host intestine

Abstract

Background Recent evidence suggests that the commensal microbes act as a barrier against invading pathogens and enteric infections are the consequences of multi-layered interactions among commensals, pathogens, and the host intestinal tissue. However, it remains unclear how perturbations of the gut microbiota compromise host infection resistance, especially through changes at species and metabolite levels. Results Here, we illustrate how Bacteroides vulgatus, a dominant species of the Bacteroidetes phylum in mouse intestine, suppresses infection by Vibrio cholerae, an important human pathogen. Clindamycin (CL) is an antibiotic that selectively kills anaerobic bacteria, and accordingly Bacteroidetes are completely eradicated from CL-treated mouse intestines. The Bacteroidetes-depleted adult mice developed severe cholera-like symptoms, when infected with V. cholerae. Germ-free mice mono-associated with B. vulgatus became resistant to V. cholerae infection. Levels of V. cholerae growth-inhibitory metabolites including short-chain fatty acids plummeted upon CL treatment, while levels of compounds that enhance V. cholerae proliferation were elevated. Furthermore, the intestinal colonization process of V. cholerae was well-simulated in CL-treated adult mice. Conclusions Overall, we provide insights into how a symbiotic microbe and a pathogenic intruder interact inside host intestine. We identified B. vulgatus as an indigenous microbial species that can suppress intestinal infection. Our results also demonstrate that commensal-derived metabolites are a critical determinant for host resistance against V. cholerae infection, and that CL pretreatment of adult mice generates a simple yet useful model of cholera infection.

PredictingVibrio choleraeinfection and disease severity using metagenomics in a prospective cohort study

“…This finding is consistent with experiments of SCFAs applied to animal models. B. vulgatus has been shown to inhibit V. cholerae colonization in mice, an effect that was dependent upon SCFAs butyrate and propionate production (13). SCFAs are known to impact immune cell development and attenuate inflammation by inhibiting histone deacetylases and other mechanisms of altering gene expression (26–29).…”

“…For instance, a species enriched in the gut microbiota of patients recovering from cholera, Blautia obeum , was found to interfere with V. cholerae pathogenicity through quorum-sensing inhibition in a mouse model (8). Animal and in vitro experiments have demonstrated that alteration of commensal-derived metabolite levels influenced host susceptibility by affecting V. cholerae growth or colonization (9–13).…”

Dissecting serotype-specific contributions to live oral cholera vaccine efficacy

“…An important caveat underlying our findings is that GF mice lack commensal gut microbes and could have altered immune responses to immunization, especially considering recent studies that have highlighted how V. cholerae-microbiota interactions can influence colonization, disease, and development of anti-V. cholerae immunity [48][49][50][51][52] . However, the strong association of VAT induction with protection and superior efficacy of live over inactivated vaccine strains in this model, and our similar findings of OCV function in mice with transiently disrupted microbiomes reinforces the idea that the GF mouse live OCV model holds substantial translational promise 36,37 .…”

Crosstalks Between Gut Microbiota and Vibrio Cholerae

“…As the treatment progresses, the abundance of Bifidobacterium and SCFAs were return to normal levels (Monira et al, 2010). Besides, mice treated with clindamycin reduced the abundance of Bacteroides and the content of SCFAs to enhance the colonization ability of V. cholerae (You et al, 2019). All these indicate that probiotics in the host can antagonize the colonization of V. cholerae by secreting SCFAs.…”