2. Academic Validation
  3. Effects of intergenerational transmission of small intestinal bacteria cultured from stunted Bangladeshi children with enteropathy

Effects of intergenerational transmission of small intestinal bacteria cultured from stunted Bangladeshi children with enteropathy

  • bioRxiv. 2024 Nov 3:2024.11.01.621574. doi: 10.1101/2024.11.01.621574.
Kali M Pruss 1 2,  Clara Kao 1 2,  Alexandra E Byrne 1 2,  Robert Y Chen 1 2,  Blanda Di Luccia 1 2 3,  Laura Karvelyte 3,  Reyan Coskun 1 2,  Mackenzie Lemieux 1 2,  Keshav Nepal 1 2,  Daniel M Webber 1 2,  Matthew C Hibberd 1 2,  Yi Wang 1 2,  Dmitry A Rodionov 4,  Andrei L Osterman 4,  Marco Colonna 3,  Christian Maueroder 5,  Kodi Ravichandran 3,  Michael J Barratt 1 2,  Tahmeed Ahmed 6,  Jeffrey I Gordon 1 2
Affiliations

Affiliations

  • 1 The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine; St. Louis, MO 63110, USA.
  • 2 Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine; St. Louis, MO 63110, USA.
  • 3 Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine; St. Louis, MO 63110, USA.
  • 4 Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037 USA.
  • 5 Inflammation Research Centre, VIB, and the Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 6 International Center for Diarrhoeal Disease Research, Bangladesh (icddr,b); Dhaka 1212, Bangladesh.
PMID: 39554152 DOI: 10.1101/2024.11.01.621574
Abstract

Environmental enteric dysfunction (EED), a small intestinal disorder found at a high prevalence in stunted children, is associated with gut mucosal barrier disruption and decreased absorptive capacity due to reduced intact small intestinal villi1-4. To test the hypothesis that intergenerational transmission of a perturbed small intestinal microbiota contributes to undernutrition by inducing EED5, we characterized two consortia of Bacterial strains cultured from duodenal aspirates from stunted Bangladeshi children with EED - one of which induced local and systemic inflammation in gnotobiotic female mice. Offspring of dams that received this inflammatory consortium exhibited immunologic changes along their gut that phenocopied features of EED in children. Single nucleus plus bulk RNA-sequencing revealed alterations in inter-cellular signaling pathways related to intestinal epithelial cell renewal, barrier integrity and immune function while analyses of cerebral cortex disclosed alterations in glial- and endothelial-neuronal signaling pathways that regulate neural growth/axonal guidance, angiogenesis and inflammation. Analysis of ultrasonic vocalization calls in gnotobiotic P5-P9 pups indicated increased arousal and perturbed neurodevelopment in the offspring of dams harboring the inflammation-inducing consortium. Cohousing experiments and follow-up screening of candidate disease-promoting Bacterial isolates identified a strain typically found in the oral microbiota (Campylobacter concisus) as a contributor to enteropathy. Given that fetal growth was also impaired in the dams with the consortium that induced enteropathy, this preclinical model allows the effects of the human small intestinal microbiota on both pre- and postnatal development to be ascertained, setting the stage for identification of small intestinal microbiota-targeted therapeutics for (intergenerational) undernutrition.

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