The gut microbiome — made up of trillions of microbes in the digestive tract — is vital for digestion and overall health. Diet and medication shape these microbial ecosystems, but the contribution of genetics has been more difficult to ascertain. Now, a new study of rats — a model organism for understanding the human gut — has found that the composition of the rat gut microbiome is shaped not only by a rat's own genes but also by the genes of those it lives with.
The discovery reveals a novel way in which genes and social interactions intertwine: through the exchange of commensal gut microbes that move between individuals. The findings could help shed light on how genes and the microbiome interact in human disease. The study , led by researchers at the University of California San Diego and the Centre for Genomic Regulation in Barcelona, was published on December 18, 2025 in Nature Communications.
In humans, only two genes have been reliably linked to gut bacteria: the lactase gene, which influences milk-digesting microbes and determines whether adults can digest milk and the ABO blood‑group gene, which affects microbes through unknown mechanisms. More gene‑microbe associations likely exist, but have been difficult to tease apart.
To better understand how genes shape the microbiome, the researchers turned to rats, which share many features of mammalian biology, but can be raised under controlled conditions.
"The things that live in their gut are similar but not identical," said co-author Abraham Palmer, Ph.D., professor and vice chair for basic research in the Department of Psychiatry at UC San Diego School of Medicine.
Combining genetic and microbiome data from 4,000 genetically unique rats — drawn from four cohorts housed in different facilities across the U.S. — allowed the researchers to test which genetic effects held up across distinct environments.
"We were interested to know whether the genetic variability of those animals would influence what was living in their gut," said Palmer. "This was a nice opportunity because the animals are all eating the same food, so we don't have to worry about genes influencing their microbiome via their food choices, for example. It's a much simpler system."
The team identified three genetic regions that consistently influenced gut bacteria despite differences in rearing conditions across the four cohorts. The strongest link was between the St6galnac1, a gene that adds sugar molecules to gut mucus, and the abundance of Paraprevotella, a bacterium that feeds off these sugars. It was found in all four cohorts.
A second region, containing several genes that form the protective mucus layer, correlated with Firmicutes bacteria. A third region included Pip, a gene that encodes an antibacterial peptide, and was associated with Muribaculaceae, a family of bacteria commonly found in both rodents and humans.
The social lives of genes
Though genes don't jump between individuals, microbes can. The study found that some genes favor certain gut bacteria and these can spread through close social contact.
"This is the result of genetic influences spilling over to others through social contact," said senior author Amelie Baud, Ph.D., a researcher at the Centre for Genomic Regulation. "Genes shape the gut microbiome, and we found that it is not just our own genes that matter."
The large size of the study allowed the researchers to estimate how much of each rat's microbiome was explained by its own genes versus the genes of its cage‑mates.
A classic example of this phenomenon, known as "indirect genetic effects", is when a mother's genes shape her offspring's growth or immune system through the environment she provides.
The controlled conditions of the study allowed the researchers to study these effects in a completely new way by building a computational model separating direct genetic effects on an individual's microbes from indirect effects exerted by social partners.
"Because the rats in this study are assigned to random social partners, we remove all of the problems that you would have in humans, who by and large choose their own social partners," said Palmer.
The researchers discovered that the abundance of some Muribaculaceae species was shaped by genetic effects that spread socially via microbial exchange.
Accounting for these indirect social effects increased the total genetic influence in the model four-to-eight fold for the three newly identified gene‑microbe links.
"We've probably only uncovered the tip of the iceberg," said Baud, noting that many more microbes could be identified as profiling methods improve.
Implications for human health
By demonstrating that genetic influences can be coupled with gut microbe transmission, the work reveals a novel mechanism whereby the genetics of one individual can ripple through an entire social group, altering the biology of others without changing their DNA. Given increasing evidence that the gut microbiome plays an important role in health, if similar effects are found in humans, it could mean that genetic influences on disease risk may have been substantially underestimated in past studies.
"Although the details will be different in humans from what we find in rats, the study points the way towards understanding the mechanisms of how host and microbial genes work together to produce complex diseases that the microbiome is involved in, which range from cardiovascular disease to obesity to Alzheimer's," said co-author Rob Knight, Ph.D., professor in the Departments of Pediatrics, Bioengineering, and Computer Science and Engineering at UC San Diego and director of the Center for Microbiome Innovation.
Additional co-authors on the study include: Denghui Chen, Antonio Gonzalez, Tomasz Kosciolek, and Oksana Polesskaya, UC San Diego; Helene Tonnele, Centre for Genomic Regulation, Barcelona Institute of Science and Technology and Universitat Pompeu Fabra; Felipe Morillo, Jorge Garcia‑Calleja and Elena Bosch at Universitat Pompeu Fabra; Marc Jan Bonder, University of Groningen; Anthony M. George, Keita Ishiwari, Connor D. Martin, Christopher P. King, Jordan A. Tripi, and Jerry B. Richards, University at Buffalo; Wenyan Han, Angel Garcia Martinez, Tengfei Wang, and Hao Chen, University of Tennessee Health Science Center; Katie Holl, Medical College of Wisconsin; Aidan Horvath, Alexander C. C. Lamparelli, Terry E. Robinson, Shelly B. Flagel, and Paul J. Meyer, University of Michigan; Peter A. Doris, University of Texas at Houston; Oliver Stegle, European Molecular Biology Laboratory in Heidelberg; and Leah C. Solberg Woods, Wake Forest University School of Medicine.
The study was funded in part by the National Institutes of Health (grant #P50DA037844).
Disclosures: Knight is a scientific advisory board member and consultant for Biome-Sense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant for DayTwo and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a co-founder of Micronoma and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California San Diego, in accordance with its conflict-of-interest policies. The remaining authors declare no competing interests.
