Cytolethal distending toxin B inoculation leads to distinct gut microtypes and IBS-D-like microRNA-mediated gene expression changes in a rodent model

Gabriela Leite; Juliana de Freitas Germano; Walter Morales; Stacy Weitsman; Gillian M Barlow; Gonzalo Parodi; Maya L Pimentel; Maria Jesus Villanueva-Millan; Maritza Sanchez; Sarah Ayyad; Ali Rezaie; Ruchi Mathur; Mark Pimentel

doi:10.1080/19490976.2023.2293170

Cytolethal distending toxin B inoculation leads to distinct gut microtypes and IBS-D-like microRNA-mediated gene expression changes in a rodent model

Gut Microbes. 2024 Jan-Dec;16(1):2293170. doi: 10.1080/19490976.2023.2293170. Epub 2023 Dec 18.

Authors

Affiliations

¹ Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.
² Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA.
³ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA.

Abstract

Diarrhea-predominant irritable bowel syndrome (IBS-D), associated with increased intestinal permeability, inflammation, and small intestinal bacterial overgrowth, can be triggered by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by gastroenteritis-causing pathogens and may underlie IBS-D development, through molecular mimicry with vinculin. Here, we examine the effects of exposure to CdtB alone on gut microbiome composition, host intestinal gene expression, and IBS-D-like phenotypes in a rat model. CdtB-inoculated rats exhibited increased anti-CdtB levels, which correlated with increased stool wet weights, pro-inflammatory cytokines (TNFα, IL2) and predicted microbial metabolic pathways including inflammatory responses, TNF responses, and diarrhea. Three distinct ileal microbiome profiles (microtypes) were identified in CdtB-inoculated rats. The first microtype (most like controls) had altered relative abundance (RA) of genera Bifidobacterium, Lactococcus, and Rothia. The second had lower microbial diversity, higher Escherichia-Shigella RA, higher absolute E. coli abundance, and altered host ileal tissue expression of immune-response and TNF-response genes compared to controls. The third microtype had higher microbial diversity, higher RA of hydrogen sulfide (H₂S)-producer Desulfovibrio, and increased expression of H₂S-associated pain/serotonin response genes. All CdtB-inoculated rats exhibited decreased ileal expression of cell junction component mRNAs, including vinculin-associated proteins. Significantly, cluster-specific microRNA-mRNA interactions controlling intestinal permeability, visceral hypersensitivity/pain, and gastrointestinal motility genes, including several previously associated with IBS were seen. These findings demonstrate that exposure to CdtB toxin alone results in IBS-like phenotypes including inflammation and diarrhea-like stool, decreased expression of intestinal barrier components, and altered ileal microtypes that influenced changes in microRNA-modulated gene expression and predicted metabolic pathways consistent with specific IBS-D symptoms.

Keywords: Irritable bowel syndrome; cytolethal distending toxin; gut microbiome; host gene expression; microRNAs.

MeSH terms

Animals
Diarrhea
Escherichia coli
Gastroenteritis*
Gastrointestinal Microbiome*
Gene Expression
Inflammation
Irritable Bowel Syndrome* / genetics
Pain
Rats
Rodentia
Vinculin

Substances

cytolethal distending toxin
Vinculin

Grants and funding

This study was funded in part by funds from Bausch Health Companies Inc and the National Philanthropic Trust to MP. These sponsors played no role in the study design or in the collection, analysis, and interpretation of data.