Diverse high-fat diets drive multi-omic reprogramming that persists after dietary reversal

Van Camp, Andrew G, Park, Jiwoon, Ozcelik, Elif, Eskiocak, Onur, Ozler, Kadir A, Papciak, Katie, Subhash, Santhilal, Alwaseem, Hanan, Ergin, Ilgin, Chung, Charlie, Shah, Vyom, Yueh, Brian, Fein, Miriam R, Durmaz, Ceyda, Mozsary, Chris, Kilic, Ece, Garipcan, Aybuke, Damle, Namita, Najjar, Deena, Nelson, Theodore M, Ryon, Krista A, Butler, Daniel J, Patel, Chirag J, Thaiss, Christoph A, Birsoy, Kivanc, Mason, Christopher E, Meydan, Cem, Tierney, Braden T, Beyaz, Semir (March 2026) Diverse high-fat diets drive multi-omic reprogramming that persists after dietary reversal. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Dietary fat composition modulates host physiology and the gut microbiome, but the long-term effects of specific fat sources and the extent to which these changes resolve after dietary reversal remain incompletely defined. Here, we present a longitudinal multi-omic resource of mice maintained for one year on a purified control diet, seven high-fat diets differing in predominant fat source, or reversal regimens in which animals were switched from high-fat to control diet after 4 or 9 months. We further incorporated two cohorts with distinct pre-existing microbiome configurations to determine how baseline community structure shapes diet-induced remodeling of the gut microbiome ecosystem. By integrating longitudinal phenotyping, fecal metagenomics, fecal metabolomics, plasma metabolomics and lipidomics, and intestinal single-cell RNA sequencing, we defined the shared and dietary fat-specific responses across host and microbiome compartments. Baseline microbiome composition strongly influenced microbial responses to diet, indicating that pre-existing community structure is a major determinant of dietary ecosystem remodeling. Although many altered features shifted toward baseline after dietary reversal, only approximately half of diet-associated microbial changes recovered within the study window. A subset of taxa exhibited persistent alterations, including sustained depletion of Lactobacillus johnsonii and Bifidobacterium pseudolongum and sustained enrichment of Alistipes finegoldii, consistent with a “microbiome memory” of prior high-fat diet exposure. This memory effect is mirrored in the host, by sustained suppression of major histocompatibility complex class II (MHC-II) gene expression in intestinal epithelial cells after dietary reversal. These findings indicate that dietary fats leave a lasting imprint on the host-microbiome interactome that survives dietary intervention. Together, these data establish a resource for defining how dietary fat source, baseline microbiome composition, and dietary history shape host–microbiome states. The entire resource is available online as an RShiny app.

Item Type: Paper
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > major histocompatibility complex
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Beyaz lab
CSHL labs > Meyer Lab
CSHL Post Doctoral Fellows
School of Biological Sciences > Publications
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 19 March 2026
Date Deposited: 30 Mar 2026 12:08
Last Modified: 30 Mar 2026 12:08
PMCID: PMC13015288
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42125

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