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Paneth cell-microbiota crosstalk orchestrates intestinal homeostasis
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Balasubramanian, Iyshwarya. Paneth cell-microbiota crosstalk orchestrates intestinal homeostasis. Retrieved from https://doi.org/doi:10.7282/t3-bevb-3b43

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TitlePaneth cell-microbiota crosstalk orchestrates intestinal homeostasis
NameBalasubramanian, Iyshwarya (author); Gao, Nan (chair); Wong, Ching-On (member); Bonder, Edward M (member); Ivanov, Ivaylo (member); Rutgers University; Graduate School - Newark
Date Created2022
Other Date2022-05 (degree)
SubjectBiology, Cellular biology, Molecular biology, Epithelial cells, Homeostasis
Extent253 pages : illustrations
DescriptionPaneth cells are specialized intestinal epithelial cells that are the primary source of lysozyme, a β-1,4-N-acetylmuramoylhydrolase that targets bacterial cell walls. Paneth cell metaplasia in the distal colon and aberrant lysozyme production have been linked to Inflammatory Bowel Disease (IBD) and other gastrointestinal diseases. However, the causal relationship between Paneth cell defects and disease pathogenesis is not well understood. First, the role of abnormal lysozyme production in perpetuating colonic inflammation was investigated. Targeted disruption of Paneth cell-produced lysozyme protected mice from DSS-induced colitis by eliciting a type 2 immune response. Lysozyme deficiency impaired innate immune responses to microbe-associated molecular patterns and facilitated the expansion of lysozyme-sensitive bacterial species, notably Ruminococcus gnavus, a pathobiont enriched in IBD patients. Ectopic lysozyme production in the colonic epithelium, a hallmark of IBD, abrogated the lysozyme-sensitive bacteria and exacerbated colitis in mice. While R. gnavus colonization of antibiotics-treated Lyz1-/- mice elicited a type 2 immune response and impeded experimental colitis, it drove a pro-inflammatory response in antibiotics-treated WT mice. Thus, Paneth cell-specific lysozyme defines the microbial landscape, which modulates the inflammatory response.
Determining and understanding the molecular cues that enable Paneth cells to participate in this immune surveillance would have a significant consequence on human health and disease. Single-cell RNA sequencing of Paneth cells from different microbial milieus revealed regional and functional heterogeneity in subsets of Paneth cells dictated by commensal microbiota and sensitivity to antibiotics-induced dysbiosis while robustly altered by an enteric pathogen. The induction of CD74 in subsets of Paneth cells after Salmonella infection was also found in murine enteritis models caused by enteric pathogens, exaggerated TNF production, allogeneic T cell transplantation, or radiation. In addition, these CD74-expressing Paneth cell subsets exhibited profound secretion of atypical antimicrobial peptides and reactive oxygen species and communicated with immune cells to regulate the inflammatory response. Ablating MyD88-mediated bacterial sensing in Paneth cells diminished the inflammation-activated Paneth cell subset and systemic inflammation. Thus, microbiota-driven Paneth cell heterogeneity modulates the host’s inflammatory response. Together, this study highlights the reciprocal crosstalk present between Paneth cells and gut microbiota and its subsequent regulation of the intestinal inflammatory tone.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-bevb-3b43
LanguageEnglish
CollectionGraduate School - Newark Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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