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- Title
Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response.
- Authors
Sugino, Kameron Y.; Janssen, Rachel C.; McMahan, Rachel H.; Zimmerman, Chelsea; Friedman, Jacob E.; Jonscher, Karen R.
- Abstract
Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven, in part, by the dysregulation of the early life microbiome. Here, using a mouse model of WD-induced maternal obesity, we demonstrate that exposure to a disordered microbiome from WD-fed dams suppressed circulating levels of endogenous ligands of the aryl hydrocarbon receptor (AHR; indole, indole-3-acetate) and TMAO (a product of AHR-mediated transcription), as well as hepatic expression of Il10 (an AHR target), in offspring at 3 weeks of age. This signature was recapitulated by fecal microbial transfer from WD-fed pregnant dams to chow-fed germ-free (GF) lactating dams following parturition and was associated with a reduced abundance of Lactobacillus in GF offspring. Further, the expression of Il10 was downregulated in liver myeloid cells and in LPS-stimulated bone marrow-derived macrophages (BMDM) in adult offspring, suggestive of a hypo-responsive, or tolerant, innate immune response. BMDMs from adult mice lacking AHR in macrophages exhibited a similar tolerogenic response, including diminished expression of Il10. Overall, our study shows that exposure to maternal WD alters microbial metabolites in the offspring that affect AHR signaling, potentially contributing to innate immune hypo-responsiveness and progression of MASLD, highlighting the impact of early life gut dysbiosis on offspring metabolism. Further investigations are warranted to elucidate the complex interplay between maternal diet, gut microbial function, and the development of neonatal innate immune tolerance and potential therapeutic interventions targeting these pathways.
- Subjects
RNA analysis; LIPID metabolism; BIOLOGICAL models; FLOW cytometry; STATISTICAL models; METABOLIC disorders; RESEARCH funding; MACROPHAGES; DATA analysis; T-test (Statistics); FATTY liver; GUT microbiome; PUERPERIUM; MYELOID cells; PREGNANT women; LABOR (Obstetrics); MULTIVARIATE analysis; DESCRIPTIVE statistics; CELLULAR signal transduction; OBESITY in women; METABOLITES; LACTATION; MICE; INDOLE compounds; ANIMAL experimentation; WESTERN immunoblotting; MASS spectrometry; ANALYSIS of variance; STATISTICS; LACTOBACILLUS; TRYPTOPHAN; NATURAL immunity; METABOLOMICS; WESTERN diet; DATA analysis software; INFLAMMATION; LIVER; BIOMARKERS; CELL receptors; INTERLEUKINS; SEQUENCE analysis; BLOOD; DISEASE risk factors; DISEASE complications
- Publication
Nutrients, 2024, Vol 16, Issue 12, p1808
- ISSN
2072-6643
- Publication type
Article
- DOI
10.3390/nu16121808