Diet outperforms microbial transplant to drive microbiome recovery in mice

M. S. Kennedy, A. Freiburger, M. Cooper, K. Beilsmith, M. L. George, M. Kalski, C. Cham, A. Guzzetta, S. C. Ng, F. K. Chan, O. DeLeon, D. Rubin, C. S. Henry, J. Bergelson and E. B. Chang ()
Additional contact information
M. S. Kennedy: The University of Chicago
A. Freiburger: Argonne National Laboratory
M. Cooper: The University of Chicago
K. Beilsmith: Argonne National Laboratory
M. L. George: The University of Chicago
M. Kalski: The University of Chicago
C. Cham: The University of Chicago
A. Guzzetta: The University of Chicago
S. C. Ng: The Chinese University of Hong Kong
F. K. Chan: The Chinese University of Hong Kong
O. DeLeon: The University of Chicago
D. Rubin: University of Chicago Medicine
C. S. Henry: Argonne National Laboratory
J. Bergelson: New York University
E. B. Chang: The University of Chicago

Nature, 2025, vol. 642, issue 8068, 747-755

Abstract: Abstract A high-fat, low-fibre Western-style diet (WD) induces microbiome dysbiosis characterized by reduced taxonomic diversity and metabolic breadth1,2, which in turn increases risk for a wide array of metabolic3–5, immune6 and systemic pathologies. Recent work has established that WD can impair microbiome resilience to acute perturbations such as antibiotic treatment7,8, although little is known about the mechanism of impairment and the specific consequences for the host of prolonged post-antibiotic dysbiosis. Here we characterize the trajectory by which the gut microbiome recovers its taxonomic and functional profile after antibiotic treatment in mice on regular chow (RC) or WD, and find that only mice on RC undergo a rapid successional process of recovery. Metabolic modelling indicates that a RC diet promotes the development of syntrophic cross-feeding interactions, whereas in mice on WD, a dominant taxon monopolizes readily available resources without releasing syntrophic byproducts. Intervention experiments reveal that an appropriate dietary resource environment is both necessary and sufficient for rapid and robust microbiome recovery, whereas microbial transplant is neither. Furthermore, prolonged post-antibiotic dysbiosis in mice on WD renders them susceptible to infection by the intestinal pathogen Salmonella enterica serovar Typhimurium. Our data challenge widespread enthusiasm for faecal microbiota transplant (FMT) as a strategy to address dysbiosis, and demonstrate that specific dietary interventions are, at a minimum, an essential prerequisite for effective FMT, and may afford a safer, more natural and less invasive alternative.

Date: 2025
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DOI: 10.1038/s41586-025-08937-9

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