When gut microbial communities encounter a challenge – from medications, biotics, stress, environmental toxins, to other disruptors – their structure and function often change in unpredictable ways. This unpredictability is one factor that underlies the variable clinical response to biotic therapies. Two recent studies used advanced computational approaches to conclude that nutrients are among the most important determinants of an intestinal microbial community’s response to challenges.
Drug-induced disruption linked to microbial nutrient competition
Handuo Shi and colleagues of KC Huang at Stanford University tested more than 700 clinically relevant drugs on stool-derived communities in vitro. They assessed the drugs’ effects on bacterial growth, community composition, and nutrients in the culture medium, then used statistical models to integrate data from more than 5,000 community-drug conditions (1). They found that most antibiotics – and many non-antibiotic medications – disrupt gut microbial community structure. In many cases, the disruptions persist even after the drug is removed from the system. This most often occurs because of nutrient competition: when a drug wipes out a bacterial species, the nutrient niche of the extinct species is freed up, granting competing bacteria a growth advantage known as “competitive release.” Post-drug recovery can be achieved in many cases by reseeding the drug-treated communities with the initial bacterial community, analogous to fecal microbiota transplantation. But in some cases, the invasive species persist, outcompeting the reintroduced strains by monopolizing their preferred nutrients. Understanding how these “strain swapping” events occur has implications for eradicating intestinal infections and for understanding why an intervention could persistently alter one’s gut microbiome.
Diet is critical for microbiome recovery
Another study led by Megan Kennedy and colleagues in the Eugene Chang laboratory at The University of Chicago used metabolic modeling to explore the dynamics of post-antibiotic gut microbiome recovery in vivo (2). Mice were fed a high-fat, low-fiber Western diet or regular chow, treated for 3 days with a triple antibiotic cocktail, and assessed for microbiome recovery for up to 9 weeks. Among the key findings, antibiotics deplete microbial biomass and alter community composition much more profoundly and persistently in mice fed the low-fiber Western diet. Fermentable fibers in the regular diet promote rapid microbiome recovery, but recovery does not occur in the absence of fermentable fibers – despite transplantation of pre-treatment microbiota. Gut bacteria ferment complex carbohydrates in regular chow into byproducts that enable the repopulation, diversification, and post-antibiotic recovery of microbial communities. In contrast, the simple sugars that make up the carbohydrate portion of the Western diet are not fermented into beneficial byproducts; rather, these sugars facilitate the overgrowth of a few species that dominate the community and prevent recovery. These experiments elegantly illustrate that transplanted microbes must have access to the nutritional resources required for engraftment, growth, and diversification. The low-fiber Western diet lacks the nutrient niche that is necessary for microbiome recovery, even when the extinct strains are re-introduced via fecal microbiota transplantation.
Considering nutrient niche in biotic interventions
Both studies leveraged advanced computational approaches, integrating multi-omics data sets to model the complex interactions between gut bacteria and their nutrient niche. Predictions regarding how gut microbes will respond to challenges become more accurate when models incorporate nutrients and metabolites.
These papers highlight concepts that are critically important because most clinical trials with biotics have not rigorously controlled for diet. Diet directly impacts nutrient competition in the gut, so dietary differences likely explain some of the variable human response to microbiome-targeting therapies. Without a sufficient nutrient niche, biotic interventions could be less likely to produce the intended beneficial effects. Future studies that aim to restore missing gut microbial species or functions should consider the nutrient niche; the consistency and efficacy of biotic therapies might improve with adjunct dietary interventions that provide essential nutrient resources.
References
(1) Shi H, Newton DP, Nguyen TH, Estrela S, Sanchez J, Tu M, Ho PY, Zeng Q, DeFelice BC, Sonnenburg JL, Huang KC. Nutrient competition predicts gut microbiome restructuring under drug perturbations. Cell 2025;188(24):6971-6986.e14.
(2) Chan FK, DeLeon O, Rubin D, Henry CS, Bergelson J, Chang EB. Diet outperforms microbial transplant to drive microbiome recovery in mice. Nature 2025;642(8068):747-755.
