Biology subjects

Sidebottom, A.

Publications and source records attributed to Sidebottom, A..

3 recordsLinked to original sources

bioRxiv2023

An evolution-based framework for describing human gut bacteria

The human gut microbiome contains many bacterial strains of the same species ( strain-level variants). Describing strains in a biologically meaningful way rather than purely taxonomically is an important goal but challenging due to the genetic complexity of strain-level variation. Here, we measured patterns of co-evolution across >7,000 strains spanning the bacterial tree-of-life. Using these patterns as a prior for studying hundreds of gut commensal strains that we isolated, sequenced, and metabolically profiled revealed widespread structure beneath the phylogenetic level of species. Defining strains by their co-evolutionary signatures enabled predicting their metabolic phenotypes and engineering consortia from strain genome content alone. Our findings demonstrate a biologically relevant organization to strain-level variation and motivate a new schema for describing bacterial strains based on their evolutionary history. One Sentence SummaryDescribing bacterial strains in the human gut by a statistical model that captures their evolutionary history provides insight into their biology.

systems biology↗

bioRxiv2023

Microbially-catalyzed conjugation of GABA and tyramine to bile acids

Bile acids (BAs) are cholesterol-derived molecules that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence physiology of the gut microbiota. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate BAs to other amine classes. Here, we show that Bacteroides fragilis strain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis (UC) pouchitis, conjugates standard amino acids and the neuroactive amines {gamma}-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended this analysis to other human gut isolates and identified species that are competent to conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and BA-tyramine amides in human stool. A longitudinal metabolomic analysis of J-pouch contents of the patient from whom B. fragilis P207 was isolated revealed highly reduced levels of secondary bile acids and a shifting BA amide profile before, during, and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to GABA and tyramine and demonstrates that these molecules are present in the human gut. ImportanceBile acids (BAs) are modified in multiple ways by host enzymes and the microbiota to produce a chemically diverse set of molecules that assist in the digestive process and impact many physiological functions. This study reports the discovery of bacteria isolated from the gut of human patients that conjugate the neuroactive amines, GABA and tyramine, to BAs and demonstrates that BA-GABA and BA-tyramine amides are present in the human gut. GABA and tyramine are common metabolic products of the gut microbiota and potent neuroactive molecules, and their conjugation to BAs may influence receptor-mediated regulatory mechanisms of humans and their gut microbes.

microbiology↗

bioRxiv2020

Peptide YY: a novel Paneth cell antimicrobial peptide that maintains fungal commensalism

Perturbed interactions between the intestinal microbes and host correlate with emergence of fungal virulence. Here we report a previously unknown role for peptide YY (PYY), a described endocrine molecule, as an antimicrobial peptide (AMP) expressed by gut immune epithelial Paneth Cells (PC). PC-PYY differs from other AMPs, including lysozyme, because of limited antibacterial activity, packaging in discrete secretory granules, and selective antifungal activity to virulent hyphae, but not yeast forms of Candida albicans. The latter action is through binding of cationic PC-PYY to the anionic hyphal surface, resulting in membrane disruption and killing. PC-PYY is compartmentalized to surface mucus, which optimizes activity and prevents conversion to endocrine PYY by dipeptidyl peptidase-IV (DPP-IV). We conclude PC-PYY is a unique AMP with selective antifungal activity that maintains gut fungal commensalism. Compromised PC-PYY action from PC dysfunction and/or mucus depletion in ileal Crohns disease may initiate or contribute to disease via fungal pathogenesis. Highlights Paneth Cell PYY (PC-PYY) is an antimicrobial peptide that differs from endocrine-PYY PC-PYY is a selective anti-fungal peptide, targeting the virulent form of C. albicans PC-PYY is separately packaged, retained by mucus, and released by C. albicans hyphae PC-PYY is proposed as essential for maintenance of fungal commensalism in the gut Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Model for Paneth cell (PC) PYY action and regulation of fungal commensalisms and potential role in the pathogenesis of ileal Crohns Disease (iCD) (A) In a healthy ileum, commensal yeast reside and do not stimulate PYY1-36 release from PCs. (B) Increased virulent hyphae (purple hyphae) results in PYY1-36 release from crypt PCs into the mucus. Hyphae are targeted by PYY1-36 and killed (red hyphae) to manage the increased fungi community in gut. (C) In a diseased ileum such as iCD, hyphal load induces immune activation and increased inflammation through PC dysfunction (gray PCs) and decreased PYY1-36 release or mucus depletion and PC dysfunction. C_FIG_DISPLAY

molecular biology↗