Liou, M. J. | Search bioRxiv

bioRxiv2025

Dietary manipulation of intestinal microbes prolongs survival in a mouse model of Hirschsprung disease

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 (Piebald lethal, sl/sl) where affected animals die from HAEC complications. In the sl/sl 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. AbstractHirschsprung 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 "Hirschsprung disease associated enterocolitis" (HAEC), which predisposes to sepsis. We discovered survival of Piebald lethal (sl/sl) mice, a well-established HSCR model with HAEC, is markedly altered by two distinct standard chow diets. A "Protective" diet increased fecal butyrate/isobutyrate and enhanced production of gut epithelial antimicrobial peptides in proximal colon. In contrast, "Detrimental" diet-fed sl/sl had abnormal appearing distal colon epithelium mitochondria, reduced epithelial mRNA involved in oxidative phosphorylation, and elevated epithelial oxygen that fostered growth of inflammation-associated Enterobacteriaceae. Accordingly, selective depletion of Enterobacteriaceae with sodium tungstate prolonged sl/sl 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. HighlightsO_LITwo different standard mouse diets alter survival in the Piebald lethal (sl/sl) mouse model of Hirschsprung disease, without impacting extent of distal colon aganglionosis (the region lacking ENS). C_LIO_LIPiebald lethal mice fed the "Detrimental" diet had many changes in colon epithelial transcriptome including decreased mRNA for antimicrobial peptides and genes involved in oxidative phosphorylation. Detrimental diet fed sl/sl also had aberrant-appearing mitochondria in distal colon epithelium, with elevated epithelial oxygen that drives lethal Enterobacteriaceae overgrowth via aerobic respiration. C_LIO_LIElimination of Enterobacteriaceae with antibiotics or sodium tungstate improves survival of Piebald lethal fed the "Detrimental diet". C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/637436v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@d95251org.highwire.dtl.DTLVardef@1ab58caorg.highwire.dtl.DTLVardef@5260b0org.highwire.dtl.DTLVardef@49ce42_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Interactions between the gut microbiome, dietary restriction, and aging in genetically diverse mice

The intestinal microbiome changes with age, but the causes and consequences of microbiome aging remain unclear. Furthermore, the gut microbiome has been proposed to mediate the benefit of lifespan- extending interventions such as dietary restriction, but this hypothesis warrants further exploration. Here, by analyzing 2997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice, we provide new insights into the interplay between the microbiome, aging, dietary restriction, host genetics, and a wide range of health parameters. First, we find that microbiome uniqueness increases with age across datasets and species. Moreover, age-associated changes are better explained by cumulative exposure to stochastic events (neutral theory) than by the influence of an aging host (selection theory). Second, we unexpectedly find that the majority of microbiome features are significantly heritable and that the amount of variation explained by host genetics is as large as that of aging and dietary restriction. Third, we find that the intensity of dietary restriction parallels the extent of microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is significantly associated with multiple health parameters -- including body composition, immune parameters, and frailty -- but not with lifespan. In summary, this large and multifaceted study sheds light on the factors influencing the microbiome and aspects of host physiology modulated by the microbiome.

microbiology↗