{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T08:30:04Z","timestamp":1788510604349,"version":"build-2803163510"},"posted":{"date-parts":[[2025,2,11]]},"group-title":"Cell Biology","reference-count":176,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Enterocolitis is a common and potentially deadly manifestation of Hirschsprung disease (HSCR) but disease mechanisms remain poorly defined. Unexpectedly, we discovered that diet can dramatically affect the lifespan of a HSCR mouse model (\n                  <jats:italic>Piebald lethal<\/jats:italic>\n                  ,\n                  <jats:italic>sl\/sl<\/jats:italic>\n                  ) where affected animals die from HAEC complications. In the\n                  <jats:italic>sl\/sl<\/jats:italic>\n                  model, diet alters gut microbes and metabolites, leading to changes in colon epithelial gene expression and epithelial oxygen levels known to influence colitis severity. Our findings demonstrate unrecognized similarity between HAEC and other types of colitis and suggest dietary manipulation could be a valuable therapeutic strategy for people with HSCR.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hirschsprung disease (HSCR) is a birth defect where enteric nervous system (ENS) is absent from distal bowel. Bowel lacking ENS fails to relax, causing partial obstruction. Affected children often have \u201cHirschsprung disease associated enterocolitis\u201d (HAEC), which predisposes to sepsis. We discovered survival of\n                    <jats:italic>Piebald lethal<\/jats:italic>\n                    (\n                    <jats:italic>sl\/sl<\/jats:italic>\n                    ) mice, a well-established HSCR model with HAEC, is markedly altered by two distinct standard chow diets. A \u201cProtective\u201d diet increased fecal butyrate\/isobutyrate and enhanced production of gut epithelial antimicrobial peptides in proximal colon. In contrast, \u201cDetrimental\u201d diet-fed\n                    <jats:italic>sl\/sl<\/jats:italic>\n                    had abnormal appearing distal colon epithelium mitochondria, reduced epithelial mRNA involved in oxidative phosphorylation, and elevated epithelial oxygen that fostered growth of inflammation-associated\n                    <jats:italic>Enterobacteriaceae<\/jats:italic>\n                    . Accordingly, selective depletion of\n                    <jats:italic>Enterobacteriaceae<\/jats:italic>\n                    with sodium tungstate prolonged\n                    <jats:italic>sl\/sl<\/jats:italic>\n                    survival. Our results provide the first strong evidence that diet modifies survival in a HSCR mouse model, without altering length of distal colon lacking ENS.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        Two different standard mouse diets alter survival in the\n                        <jats:italic>Piebald lethal<\/jats:italic>\n                        (\n                        <jats:italic>sl\/sl<\/jats:italic>\n                        ) mouse model of Hirschsprung disease, without impacting extent of distal colon aganglionosis (the region lacking ENS).\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        <jats:italic>Piebald lethal<\/jats:italic>\n                        mice fed the \u201cDetrimental\u201d diet had many changes in colon epithelial transcriptome including decreased mRNA for antimicrobial peptides and genes involved in oxidative phosphorylation. Detrimental diet fed\n                        <jats:italic>sl\/sl<\/jats:italic>\n                        also had aberrant-appearing mitochondria in distal colon epithelium, with elevated epithelial oxygen that drives lethal\n                        <jats:italic>Enterobacteriaceae<\/jats:italic>\n                        overgrowth via aerobic respiration.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Elimination of\n                        <jats:italic>Enterobacteriaceae<\/jats:italic>\n                        with antibiotics or sodium tungstate improves survival of\n                        <jats:italic>Piebald lethal<\/jats:italic>\n                        fed the \u201cDetrimental diet\u201d.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"637436v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.10.637436","type":"posted-content","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T06:15:13Z","timestamp":1739254513000},"source":"Crossref","is-referenced-by-count":3,"title":["Dietary manipulation of intestinal microbes prolongs survival in a mouse model of Hirschsprung disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9507-4103","authenticated-orcid":false,"given":"Naomi E. Butler","family":"Tjaden","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Children\u2019s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19004, USA"},{"name":"The Children\u2019s Hospital of Philadelphia Research Institute and Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19004, USA"},{"name":"Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2489-5019","authenticated-orcid":false,"given":"Megan J.","family":"Liou","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia Research Institute and Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19004, USA"},{"name":"Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, 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