About

Federico Rey is a Professor of Bacteriology and Medical Microbiology & Immunology at the University of Wisconsin-Madison. He holds a Licenciado en Bioquimica, equivalent to a B.S. and M.S. in Clinical Chemistry, from the Universidad Nacional de Cordoba, Argentina, and earned his Ph.D. in Microbiology from the University of Iowa. His research focuses on understanding how variations in the gut microbiome influence host susceptibility to cardiometabolic diseases and aging-associated conditions. Rey's work employs sequencing-centered analyses of microbiomes from humans and mice, combined with proof-of-mechanism studies in gnotobiotic mouse models and classic bacteriology experiments. His key contributions include elucidating the role of bacterial choline metabolism and TMAO in cardiovascular disease and Alzheimer’s disease, investigating diet-microbiota interactions such as butyrate-producing bacteria and flavonoid metabolism, and exploring how host genetics modulate gut microbiome composition and related disease phenotypes.

Research topics

• Biology
• Biochemistry
• Microbiology
• Genetics
• Immunology
• Medicine
• Internal medicine
• Bioinformatics
• Zoology
• Cell biology
• Food science
• Endocrinology
• Mathematics
• Pharmacology

Selected publications

• 351 GUT MICROBE-DEPENDENT EFFFECTS OF DIETARY CHOLESTEROL AND SATURATED FAT DRIVE FIBROSING MASH

  Gastroenterology · 2026-05-01

  article
  PublisherDOI

• Gut-Heart Axis in Myocardial Repair: Mechanisms, Cross-Organ Networks, and Therapeutic Opportunities

  Circulation Research · 2026-02-12 · 1 citations

  articleOpen access

  Cardiovascular diseases remain the leading global cause of morbidity and mortality, placing an escalating burden on health care systems and economies. While the gut microbiota is well recognized in atherosclerosis and cardiometabolic disorders, its influence on myocardial injury, repair, and regeneration is only beginning to emerge. Growing evidence reveals that gut microbes and their metabolites regulate myocardial health through intricate cross-organ networks, including the gut-brain-heart, gut-liver-heart, and gut-lung-heart axes. These findings suggest that the heart plays a key role in systemic host-microbe communication. Advances in metagenomics, metabolomics, and single-cell transcriptomics are now defining the molecular and cellular pathways by which microbial metabolites modulate immune tone, endothelial integrity, metabolic resilience, and cardiomyocyte survival. Studies in gnotobiotic models have established causal links between specific microbial taxa and myocardial outcomes while illuminating their roles in fibrosis resolution, angiogenesis, and regeneration. In this review, we synthesize current knowledge on the bidirectional gut-heart dialogue, emphasizing immunometabolic signaling, cross-organ integration, and regenerative mechanisms. We propose that coupling high-resolution multiomics with mechanistic modeling in controlled microbial systems will be pivotal for next-generation, microbiota-informed diagnostics, and therapeutics. We explore the emerging role of the gut-myocardium axis as both a driver of disease and as a promising modifiable therapeutic target and highlight a new frontier in precision cardiovascular medicine, with the potential to transform strategies for prevention, repair, and tissue regeneration.

  PublisherDOI

• Phenotypic high-throughput screening identifies modulators of gut microbial choline metabolism

  mBio · 2026-02-23

  articleOpen access

  ABSTRACT Anaerobic metabolism of dietary choline to trimethylamine (TMA) by the human gut microbiome is a disease-associated pathway. The host’s impaired ability to oxidize TMA to trimethylamine- N -oxide (TMAO) results in trimethylaminuria (TMAU), while elevated serum TMAO levels have been positively correlated with cardiometabolic disease. Small molecule inhibition of gut bacterial choline metabolism attenuates the development of disease in mice, highlighting the therapeutic potential of modulating this metabolism. Inhibitors previously developed to target this pathway are often designed to mimic choline, the substrate of the key TMA-generating enzyme choline trimethylamine-lyase (CutC). Here, we use a growth-based phenotypic high-throughput screen and medicinal chemistry to identify distinct chemical scaffolds that can modulate anaerobic microbial choline metabolism and lower TMAO levels in vivo . These results illustrate the potential of using phenotypic screening to rapidly discover new inhibitors of gut microbial metabolic activities. IMPORTANCE Gut microbial metabolic activities play important roles in human health, prompting interest in the discovery of gut microbiome-targeted small molecule inhibitors as potential therapeutics. Anaerobic choline metabolism by the gut microbiome generates trimethylamine and its downstream metabolite trimethylamine- N -oxide (TMAO), which cause trimethylaminuria and are correlated with cardiometabolic diseases, respectively. Current strategies for modulating microbial metabolism with small molecule inhibitors typically require having a target enzyme. Here, we show that a growth-based phenotypic screen can identify inhibitors of choline metabolism with chemical scaffolds that are structurally distinct from choline and existing inhibitors. The resulting optimized compounds lower serum TMAO in gnotobiotic mice without significantly perturbing gut microbiome composition. This work highlights the potential of using phenotypic screening to rapidly discover additional inhibitors of microbial metabolic activities, which would accelerate mechanistic studies of the microbiome and deepen our understanding of disease biology from correlation to causation.

  PublisherDOI

• Linking interpersonal differences in gut microbiota composition and drug biotransformation activity

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-21 · 3 citations

  articleOpen access

  Individuals vary widely in their responses to drugs, and growing evidence implicates the gut microbiome as a contributor to this variability. While prior studies show that gut bacteria can metabolize drugs, how differences in microbial community composition influence drug metabolism remains poorly understood. Here, we characterize the biotransformation of 271 drugs by 89 gut microbial communities derived from human donors and preclinical animal models. Over 90% of tested drugs were metabolized by at least one microbiome. We identified 66 drugs exhibiting highly variable metabolism across human-derived microbiomes and several drugs whose biotransformation differed markedly between human and animal microbiomes. To enable prediction of microbiota-mediated drug metabolism, we developed and compared multiple modeling approaches based on metagenomic data. These results, together with the provided data and analytical resources contribute to a better understanding of microbiome-drug interactions and support their future integration into drug discovery, personalized prescription, and therapeutic drug monitoring.

  PublisherDOI

• Atlas of one-carbon metabolism in conventional and germ-free mice reveals folate as a key determinant of biochemical pathways

  Nature Metabolism · 2026-03-26 · 1 citations

  articleOpen access

  Folates participate in the one-carbon metabolism (OCM) cycle, supporting many biochemical pathways. Existing methods to profile folate are limited in the diversity of vitamers they measure and the samples they profile. Here we present a metabolomics workflow for stable extraction, separation and measurement of folates, along with precursors and products of OCM-associated pathways. We profile these metabolites in 37 mouse tissues to chart an interactive 'OCM atlas' ( https://chaudharilab.com/folate-atlas/ ), revealing vast heterogeneity across organs and an uncharacterized folate derivative. We discover that, in adult mice, the gut microbiota is a consumer of folate and folate polyglutamylation in the host is not regulated by folate availability. Germ-free mice show tissue-specific shifts in methyl donor abundances relative to conventionally raised mice, indicative of altered DNA methylation. Correlation analyses uncover the central roles of folates in potentially modulating other biochemical pathways in tissues, thus linking microbial folate consumption directly to its global impacts on host metabolism.

  PublisherOA PDFDOI

• 351 GUT MICROBE-DEPENDENT EFFFECTS OF DIETARY CHOLESTEROL AND SATURATED FAT DRIVE FIBROSING MASH

  Gastrointestinal Endoscopy · 2026-05-01

  article
  PublisherDOI

• Investigation of bile salt hydrolase activity in human gut bacteria reveals production of conjugated secondary bile acids

  Nature Communications · 2026-02-23 · 1 citations

  articleOpen access

  Through biochemical transformation of host-derived bile acids, gut bacteria mediate host-microbe crosstalk and function at the interface of nutrition and host metabolic regulation. Bile acids play a crucial role in human health by facilitating the absorption of dietary lipophilic nutrients, interacting with hormone receptors to regulate host physiology, and shaping gut microbiota composition through antimicrobial activity. Bile acids deconjugation by bacterial bile salt hydrolase has long been recognized as the first necessary bile acid modification required before further transformations can occur. Here, we show that bile salt hydrolase activity is common among human gut bacterial isolates spanning seven major phyla. However, we observed variation in both the extent and the specificity of deconjugation of bile acids among the tested taxa. Unexpectedly, we discovered that certain strains were capable of directly dehydrogenating conjugated bile acids via hydroxysteroid dehydrogenases to produce conjugated secondary bile acids both in vitro and in vivo. These results challenge the prevailing notion that deconjugation is a prerequisite for further bile acid modifications and lay a foundation for new hypotheses regarding how bacteria act individually or in concert to diversify the bile acid pool and influence host physiology. Here, the authors show that bile salt hydrolase activity is common among human gut bacterial isolates spanning seven major phyla and identify strains capable of directly dehydrogenating conjugated bile acids via hydroxysteroid dehydrogenases to produce conjugated secondary bile acids, challenging the notion that deconjugation is a prerequisite for further bile acid modifications.

  PublisherOA PDFDOI

• Gut microbiota–derived metabolite trimethylamine N-oxide alters the host epigenome through inhibition of S-adenosylhomocysteine hydrolase

  Journal of Biological Chemistry · 2025-07-25 · 5 citations

  articleOpen access

  The gut microbiota profoundly influences host metabolism through the production of bioactive metabolites that modulate cellular pathways. Among these, trimethylamine N-oxide (TMAO) has emerged as an enigmatic molecule linking dietary factors to cellular dysfunction in cardiovascular, neurological, and oncologic disorders. Here, we investigate the cellular and systemic impact of TMAO on metabolic pathways and epigenetic landscapes. Using cultured cells and a mouse model that simulates endogenous TMAO production, we demonstrate that TMAO disrupts the methionine cycle and dynamically remodels chromatin states via histone posttranslational methylation and acetylation. Compared to liver, brain cortex and hippocampus show greater sensitivity to TMAO levels. Mechanistically, TMAO noncompetitively inhibits S-adenosylhomocysteine hydrolase, leading to accumulation of SAH and subsequent reduction in global methylation capacity. In vitro overexpression of SAM synthase, methionine adenosyltransferase 2A, rescues many of these epigenetic defects by boosting SAM/SAH, highlighting the tissue/cell-specific importance of balancing SAM synthesis and SAH clearance. These mechanistic findings reveal that TMAO targets S-adenosylhomocysteine hydrolase and disrupts the methionine cycle, expanding our understanding of how gut-derived metabolites modulate chromatin states and identifying potential avenues to mitigate TMAO-associated disease.

  PublisherOA PDFDOI

• Gut bacterial metabolite imidazole propionate potentiates Alzheimer’s disease pathology

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-08 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer’s disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.

  PublisherOA PDFDOI

• Gut microbes mediate the synergistic effects of dietary cholesterol and saturated fat in driving fibrosing MASH

  Gut Microbes · 2025-07-21

  preprintOpen access

  ABSTRACT Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population and can progress to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, increasing risk of cirrhosis, hepatocellular carcinoma, and mortality. Gut microbes driven by diets high in saturated fat, simple sugar, and cholesterol contribute to disease progression, yet underlying mechanisms remain undefined. We explored the independent and synergistic effects of dietary saturated fat and cholesterol on MASH development using specific pathogen-free (SPF) and germ-free (GF) mice. We demonstrate that 1) both dietary cholesterol and saturated fat are required to induce fibrosing MASH in SPF mice, whereas GF mice are protected, 2) saturated fat and cholesterol individually alter gut microbial membership, potentially via altered bile acid metabolism, while their combination promotes a distinct composition, including an increase in Parasutterella spp. which correlates with hepatic fibrosis, and 3) diluted cecal contents from SPF, but not GF, mice fed high-fat, high-cholesterol diets are enriched in deoxycholic acid and activate human hepatic stellate cells in vitro , suggesting a mechanistic link between dietary lipid-induced microbiota and liver fibrogenesis. These findings reveal how specific Western dietary components shape the gut microbiota and contribute to hepatic liver fibrosis via stellate activation, offering potential targets for therapeutic intervention in MASLD/MASH.

  PublisherDOI

Recent grants

• Establishing mechanistic links between the gut microbiome and atherosclerosis

  NIH · $2.6M · 2020–2025

• Collaborative Cross of the Microbiome and Metabolic Disease

  NIH · $2.1M · 2015–2021

Frequent coauthors

• Eugenio I. Vivas

  University of Wisconsin–Madison

  66 shared

• Evan R. Hutchison

  University Medical Center

  45 shared

• Sanjay Asthana

  Geriatric Research Education and Clinical Center

  39 shared

• Sterling C. Johnson

  Temple University

  38 shared

• Robert L. Kerby

  University of Wisconsin–Madison

  35 shared

• Kymberleigh A. Romano

  Cleveland Clinic

  35 shared

• Patrick J. Pagano

  University of Pittsburgh

  35 shared

• Henrik Zetterberg

  UK Dementia Research Institute

  34 shared

Education

• Ph.D., Medical Microbiology & Immunology

  University of Wisconsin-Madison

  2000

• M.S., Medical Microbiology & Immunology

  University of Wisconsin-Madison

  1996

• B.S., Microbiology

  University of Wisconsin-Madison

  1993