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The gut microbiome has coevolved with humans to aid in physiologic functions and prevent disease. An increasing prevalence of gut dysbiosis in modern society exists and has strong linkages to multiple disease processes common in the developed world. Mechanisms for microbiome-human interactions that impact host homeostasis include bacterial metabolite/toxin production, biofilm formation with mucous layer infiltration, and host immune system modulation. Most of this crosstalk occurs at the epithelial layer of the gut, and as such the role of these interactions in the induction of colorectal cancer—a highly prevalent disease globally and one undergoing significant epidemiologic shifts—is under increasing scrutiny. Although multiple individual gut bacteria have been hypothesized as possible driver organisms in the oncogenic process, no bacterium has been definitively identified as a causal agent of colorectal cancer, suggesting that host lifestyle factors, microbiome community interactions, and the mucosal and/or systemic immune response may play a critical role in the process. Recent evidence has emerged implicating the ubiquitous human pathogen Clostridioides difficile as a possible promoter of colorectal cancer through chronic toxin-mediated cellular changes. Although much remains to be defined regarding the natural history of infections caused by this pathogen and its potential for oncogenesis, it provides a strong model for the role of both individual bacteria and of the gut microbial community as a whole in the development of colorectal cancer. The gut microbiome can play a crucial role in the development and prevention of human cancers through a variety of individual bacterial and broader community mechanisms. Emerging evidence suggests that Clostridioides difficile could be an important contributor to this balance. [ABSTRACT FROM AUTHOR]

Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for detecting exposure and response to microbial protein products. We designed and constructed a library of 95,601 56-amino acid peptide tiles spanning 14,430 proteins with "toxin" or "virulence factor" keyword annotations. We used PhIP-Seq to profile the antibodies of ∼1,000 individuals against this "ToxScan" library. In addition to enumerating immunodominant antibody epitopes, we studied the age-dependent stability of the ToxScan profile and used a genome-wide association study to find that the MHC-II locus modulates bacterial epitope selection. We detected previously described anti-flagellin antibody responses in a Crohn's disease cohort and identified an association between anti-flagellin antibodies and juvenile dermatomyositis. PhIP-Seq with the ToxScan library is thus an effective tool for studying the environmental determinants of health and disease at cohort scale. [Display omitted] • ToxScan phage library covers >14k toxins and virulence factors for antibody profiling • Serum antibody binding to ToxScan peptides is unique and stable in adulthood • MHC-II locus influences toxin and/or virulence factor antibody epitope selection • Crohn's-disease-associated flagellin antibodies are also found in juvenile dermatomyositis Lifelong exposures to microbes and their protein products profoundly impact human health. Angkeow et al. employed pan-toxin, pan-virulence factor PhIP-Seq to profile the antibodies of healthy volunteers and patients with autoinflammatory diseases. They report that peptide binding repertoires are unique and stable in adulthood and are modulated by the MHC-II locus. Crohn's-disease-associated flagellin antibodies are found in juvenile dermatomyositis patients. [ABSTRACT FROM AUTHOR]