Biology subjects

Versalovic, J.

Publications and source records attributed to Versalovic, J..

3 recordsLinked to original sources

bioRxiv2026

Pan-repository analysis reveals a drug-activating function of microbial bile acid conjugation

Microbially modified bile acids shape host physiology by regulating nutrient absorption, glucose homeostasis, circadian rhythms and thermoregulation. Here we identify a previously unrecognized drug-activating function of microbial bile acid conjugation. By systematically mining human LC-MS/MS datasets across public repositories and linking uncharacterized bile acid spectra to health-associated metadata, we discovered conjugates of the >75-year-old anti-inflammatory drug 5-aminosalicylic acid (5-ASA) with primary and secondary bile acids, including cholic, deoxycholic and lithocholic acids. These bile acid-drug conjugates were detected specifically in individuals treated with 5-ASA or its prodrugs. Multiple gut bacteria, including members of the Bacteroidota and Bacillota, generated cholyl-5-ASA in vitro, and bile salt hydrolase-associated transaminase activity was required for conjugate formation. In a mouse model of colitis, cholyl-5-ASA was associated with reduced intestinal inflammatory pathology and showed markedly enhanced activation of PPAR-{gamma} in cell-based reporter assays compared with 5-ASA alone. Consistent with this activity, cholyl-5-ASA elicited selective immunophenotypic changes in CD4 T cells in vitro, including increased Foxp3+ regulatory T cells. Together with prior evidence that 5-ASA efficacy depends on the microbiome, these findings support a model in which microbial bile acid conjugation represents a key activation step for 5-ASA therapy. More broadly, this work demonstrates how pan-repository metabolomics can uncover previously unrecognized microbiome-dependent chemical functions with direct therapeutic relevance.

biochemistry↗

bioRxiv2020

ROTAVIRUS INDUCES INTERCELLULAR CALCIUM WAVES THROUGH ADP SIGNALING

Rotavirus causes severe diarrheal disease in children by broadly dysregulating intestinal homeostasis. However, the underlying mechanism(s) of rotavirus-induced dysregulation remains incompletely characterized. Here we show that rotavirus-infected cells produce paracrine signals that manifest as intercellular calcium waves (ICWs); which are observed in both cell lines and human intestinal enteroids. Rotavirus ICWs are caused by the release of extracellular adenosine diphosphate (ADP) that activates P2Y1 purinergic receptors on neighboring cells and are blocked by P2Y1 antagonists or CRISPR/Cas9 knockout of P2Y1. Blocking the paracrine ADP signal reduces rotavirus replication, inhibits rotavirus-induced serotonin release and fluid secretion, and reduces diarrhea severity in neonatal mice. This is the first evidence that viruses exploit ICWs to amplify diarrheal signaling; a finding which has broad implications for gastrointestinal physiology. SummaryRotavirus triggers the extracellular release of ADP from infected cells to dysregulate nearby uninfected cells and activate pro-disease pathways.

microbiology↗

bioRxiv2019

Human intestinal enteroids with inducible neurogenin-3 expression as a novel model of gut hormone secretion

BackgroundEnteroendocrine cells (EECs) are specialized epithelial cells that produce molecules vital for intestinal homeostasis, but due to their limited numbers, in-depth functional studies have remained challenging. Human intestinal enteroids (HIEs) that are derived from intestinal crypt stem cells are a biologically relevant in vitro model of the intestinal epithelium. HIEs contain all intestinal epithelial cell types; however, like the intestine, HIEs spontaneously produce few EECs, which limits their study.\n\nMethodsTo increase the number of EECs in HIEs, we used lentivirus transduction to stably engineer jejunal HIEs with doxycycline-inducible expression of neurogenin-3 (NGN3), a transcription factor that drives EEC differentiation (tetNGN3-HIEs). We examined the impact of NGN3 induction on EECs by quantifying the increase in the enterochromaffin cells and other EEC subtypes. We functionally assessed secretion of serotonin and EEC hormones in response to norepinephrine and rotavirus infection.\n\nResultsTreating tetNGN3-HIEs with doxycycline induced a dose-dependent increase of chromogranin A (ChgA)-positive and serotonin-positive cells, demonstrating increased enterochromaffin cell differentiation. Despite increased ChgA-positive cells, other differentiated cell types of the epithelium remained largely unchanged by gene expression and immunostaining. RNA sequencing of doxycycline-induced tetNGN3- HIEs identified increased expression of key hormones and enzymes associated with several other EEC subtypes. Doxycycline-induced tetNGN3-HIEs secreted serotonin, monocyte chemoattractant protein-1, glucose-dependent insulinotropic peptide, peptide YY, and ghrelin in response to norepinephrine and rotavirus infection, further supporting the presence of multiple EEC types.\n\nConclusionsWe have combined HIEs and inducible-NGN3 expression to establish a flexible in vitro model system for functional studies of EECs in enteroids and advance the molecular and physiological investigation of EECs.\n\nSynopsisEnteroendocrine cells have low abundance but exert widespread effects on gastrointestinal physiology. We engineered human intestinal enteroids with inducible expression of neurogenin-3, resulting in increased enteroendocrine cells and facilitating investigations of host responses to the dynamic intestinal environment.

microbiology↗