COVID-19 (coronavirus disease 2019) patients exhibiting gastrointestinal symptoms are reported to have worse prognosis. Ace2 (angiotensin-converting enzyme 2), the gene encoding the host protein to which SARS-CoV-2 spike proteins bind, is expressed in the gut and therefore may be a target for preventing or reducing severity of COVID-19. Here we test the hypothesis that Ace2 expression in the gastrointestinal and respiratory tracts is modulated by the microbiome. We used quantitative PCR to profile Ace2 expression in germ-free mice, conventional raised specific pathogen-free mice, and gnotobiotic mice colonized with different microbiota. Intestinal Ace2 expression levels were significantly higher in germ-free mice compared to conventional mice. A similar trend was observed in the respiratory tract. Intriguingly, microbiota depletion via antibiotics partially recapitulated the germ-free phenotype, suggesting potential for microbiome-mediated regulation of Ace2 expression. Variability in intestinal Ace2 expression was observed in gnotobiotic mice colonized with different microbiota, partially attributable to differences in microbiome-encoded proteases and peptidases. Together, these data suggest that the microbiome may be one modifiable factor determining COVID-19 infection risk and disease severity.
Summary Gut motility is regulated by the microbiome via mechanisms that include bile acid metabolism. To localize the effects of microbiome-generated bile acids, we colonized gnotobiotic mice with different synthetic gut bacterial communities that were metabolically phenotyped using a functional in vitro screen. Using two different marker-based assays of gut transit, we inferred that bile acids exert effects on colonic transit. We validated this using an intra-colonic bile acid infusion assay and determined that these effects were dependent upon signaling via the bile acid receptor, TGR5. The intra-colonic bile acid infusion experiments further revealed sex-biased bile acid-specific effects on colonic transit, with lithocholic acid having the largest pro-motility effect. Transcriptional responses of the enteric nervous system (ENS) were stereotypic, regional, and observed in response to different microbiota, their associated bile acid profiles, and even to a single diet ingredient, evidencing exquisite sensitivity of the ENS to environmental perturbations.
The gut microbiome is an environmental driver of colorectal cancer (CRC). Although multiple gut bacterial species have been linked to CRC, each is detectable in a minority of CRC cases. Therefore, we postulated the existence of CRC-associated microbes more numerous and diverse than what is currently recognized. We performed a large-scale meta-analysis of metagenomic datasets from global gut microbiome surveys of CRC cohorts. By performing de novo clustering of co-abundant genes (CAG), we identified CRC-associated organisms with sub-species level resolution without the confounding effects of presupposed taxonomic hierarchies. This gene-level analysis disclosed 2,319 CAGs comprised of 427,261 bacterial genes significantly enriched or depleted in CRC that are widely encoded in genomes of diverse commensal organisms (an estimated 23-40% of gut bacteria), including taxa not previously linked to CRC. We demonstrated causality in gnotobiotic ApcMin/+ mice using defined bacterial consortia and human fecal samples: microbiomes harboring CRC-associated CAGs were more tumorigenic than microbiomes with health-associated genomic signatures. Bulk and single-cell RNA sequencing disclosed that tumorigenicity of the microbiome can be mediated through effects on the microenvironment rather than direct intestinal epithelial cell growth promotion. Together, these data offer proof-of-principle for microbiome-based personalized CRC risk profiling.
Background: Juvenile dermatomyositis (JDM) is a rare immune-mediated disease of childhood that is thought to result from genetic predisposition and environmental drivers, with documented links to microbial exposures. In this multi-center, prospective, observational cohort study, we evaluated whether JDM is associated with discrete oral and gut microbiome signatures.Methods: We generated 16S rRNA sequencing data from fecal, saliva, supragingival, and subgingival plaque samples from JDM probands (n=28, age range 3-18 years, mean age 10 years, 46% female). To control for genetic and environmental determinants of microbiome community structure to the greatest extent possible, we also profiled microbiomes of their unaffected family members (n=27 siblings, n=26 mothers, and n=17 fathers). We performed paired within-family comparisons as well as unpaired analyses of different cohorts. Results: Sample type (oral vs fecal) and nuclear family unit were the two most predominant variables explaining variance in microbiome diversity, more so than having a diagnosis of JDM. The oral and gut microbiomes of JDM probands were more similar to their own unaffected siblings than they were to the microbiomes of other JDM probands. Nonetheless, in a sibling-paired analysis, several potentially immunomodulatory bacterial taxa were differentially abundant in the microbiomes of JDM probands compared to their unaffected siblings, including Faecalibacterium in the gut and Streptococcus in the oral cavity. Further, compared to published microbiome datasets generated from healthy children and adults, fecal microbiomes of both JDM probands and their unaffected family members were markedly different. Conclusions: Family unit (which reflects the confluence of genetic and household effects) has a significant effect on microbiome community structure. Features of the dysbioses seen in oral and fecal microbiomes of JDM probands were shared by their unaffected family members, suggesting familial microbiome signatures. The loss or gain of specific fecal and oral bacteria may potentially play a role in disease pathogenesis and/or be secondary to immune dysfunction in susceptible individuals.
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