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Microbiota-Derived Isovalerate Ameliorates Sex-Specific Gut Barrier Dysfunction in Malnutrition

ABSTRACT: Malnutrition is a major global health challenge that increases intestinal permeability and susceptibility to sepsis, yet the mechanisms driving barrier dysfunction remain poorly defined. We aimed to identify how the gut microbiome and microbiota-derived metabolites regulate intestinal barrier integrity during malnutrition. We used a low-protein, low-fat diet (LPLFD) to induce malnutrition in specific pathogen-free (SPF) and germ-free (GF) mice. Colonic permeability and mucus thickness were quantified. Metabolomics identified microbiota-derived metabolites altered by malnutrition. Human colonoids were used to test mechanistic effects of candidate metabolites. Barrier restoration was evaluated following colonic administration of isovalerate or oral supplementation with its precursor amino acid, leucine. LPLFD-induced malnutrition increased colonic permeability and reduced mucus thickness in male, but not female, SPF mice. These defects were absent in malnourished GF mice, indicating a microbiota-dependent and sexually dimorphic mechanism of barrier disruption. Metabolomic analysis revealed reduced colonic levels of branched-chain fatty acids (BCFAs) in malnourished mice. Supplementation of human colonoids with the BCFA isovalerate improved barrier function and altered expression of genes associated with epithelial junctional complexes. Restoring isovalerate levels, either directly via colonic administration or indirectly through oral leucine supplementation, partially rescued barrier defects in malnourished male mice. These findings identify BCFAs, particularly isovalerate, as essential microbiota-derived regulators of intestinal barrier integrity during malnutrition. This work reveals a sex-specific, microbiota-dependent pathway of barrier dysfunction and highlights microbial metabolites as promising therapeutic targets for mitigating sepsis risk in undernourished populations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316654 | GEO | 2026/07/24

REPOSITORIES: GEO

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Project description:Background. Recent studies demonstrated that Aquamin®, a calcium-, magnesium-, and multiple trace element-rich natural product, improves barrier structure and function in colonoids obtained from the tissue of healthy subjects. The goal of the present study was to determine if the colonic barrier could be improved in tissue from subjects with ulcerative colitis (UC). Methods. Colonoid cultures were established with colon biopsies from 9 individuals with UC. The colonoids were then incubated for a 2-week period under control conditions (i.e., in culture medium with a final calcium concentration of 0.25 mM) or in the same medium supplemented with Aquamin® to provide 1.5 – 4.5 mM calcium. Effects on differentiation and barrier improvement were determined using several approaches: phase-contrast & scanning electron microscopy, quantitative histology & immunohistology, mass spectrometry-based proteome assessment and transmission electron microscopy. Results. While there were no gross changes in colonoid appearance, there was evidence of increased differentiation (larger lumen diameter and wall thickness) and greater expression of cytokeratin 20 (CK20) and lesser expression of Ki67 with the intervention. Aquamin®-treated colonoids demonstrated a modest up-regulation of tight junctional proteins but stronger induction of adherens junction proteins and desmosomal proteins. Increased desmosomes were seen at the ultrastructural level. Proteomic analysis also demonstrated increased expression of basement membrane proteins and hemidesmosomal components. Proteins expressed at the apical surface (mucins and trefoils) were also increased as were several additional proteins with anti-microbial activity or that modulate inflammation. Similarly, growth and cell cycle regulatory proteins (e.g., Ki67, nucleophosmin, and stathmin) were significantly down-regulated. Laminin interactions, fibronectin matrix formation and extracellular matrix organization were the top three up-regulated pathways with the intervention. Conclusion. A majority of individuals including patients with UC do not reach the recommended daily intake for calcium and other minerals. To the extent that such deficiencies might contribute to the weakening of the colonic barrier, the findings employing UC tissue-derived colonoids here suggest that adequate mineral intake might improve the colonic barrier

Project description:The thymus is one of the most affected organs during malnutrition, exhibiting atrophy and thymocyte depletion, characteristics that are also observed in several infectious diseases. The detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). However, the thymus has been barely studied during malnutrition and Leishmania infantum infection association. Protein malnutrition modifies intrathymic communication in L. infantum infected BALB/c mice by altering the abundance of proteins secreted to the thymic interstitial fluid (IF). We identified and compared protein abundance in the thymic IF samples from BALB/c mice that were fed with control protein (14%, CP) or low protein (4%, LP) isocaloric diets, followed by infection with L. infantum. By means of a quantitative proteomics approach using iTRAQ we identified 280 proteins of which 81% were reported as secreted by exosomes and 42% were previously described as secreted by thymic epithelial cells. LP-infected (LPi) animals showed a significant decrease in exosomal proteins, suggesting that exosomal carrier system is dysregulated in malnourished animals. LPi mice also exhibited an increase in the relative abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed that protein malnutrition decreases the proliferation of single positive and double positive T cells. Proteins engaged in glycolysis, protein ubiquitination and mRNA processing were significantly decreased. In addition, a significant decrease in the abundance of galectin-1 and increase of plasminogen were observed in malnourished animals. Together, the reduced cortical area, decreased proliferation, increased abundance of lipid- and tricarboxylic acid cycle-related proteins, and altered abundance of galectin-1 and plasminogen indicate a dysfunctional thymic microenvironment, where T cell migration, proliferation and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.

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Microbiota-Derived Isovalerate Ameliorates Sex-Specific Gut Barrier Dysfunction in Malnutrition

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