Researchers headed by a team at Icahn School of Medicine at Mount Sinai have discovered that many gut bacteria use a flexible survival strategy—known as epigenetic “bet-hedging”—to withstand disruptions such as antibiotics and diet changes.
Studying infant and gut microbiomes, the investigators showed that microbes can switch between functional states, rather than relying solely on genetic mutations, to try to survive shifting conditions. While bet-hedging has been observed in disease-causing bacteria, this is the first study to show that it is widespread among the beneficial microbes that make up the healthy human gut.
The findings shed light on a previously hidden layer of microbiome biology and may help explain why probiotics and fecal microbiota transplantation (FMT) produce inconsistent benefits across individuals.
Gang Fang, PhD, professor of genetics and genomic sciences and director of the Center for Genomic AI and Microbiome Medicine at the Icahn School of Medicine at Mount Sinai, is senior and corresponding author of the team’s published paper in Cell Host & Microbe, titled “Epigenetic phase variation in the gut microbiome enhances bacterial adaptation.”
The human gut microbiome is constantly being disturbed—by medications, illness, and shifts in diet. Yet it often rebounds, the investigators noted. “In response to these alterations, the gut microbiome shows a remarkable adaptive capacity,” they wrote. “Characterizing this adaptive capacity is crucial for understanding the dynamic relationship between the gut microbiome and host physiology, especially in the context of human health and disease.”
Until now, scientists largely attributed this resilience to genetic mutations that accumulate over time. But, as the authors continued, “Another mechanism of bacterial adaptation involves DNA methylation, which can regulate gene expression, enhance clonal heterogeneity, and mediate epigenetic phase variation (ePV, intra-strain epigenetic variation that leads to phenotypic differences … ePVs have been characterized in human pathogens, but their roles in commensals remain unclear.”
Fang continued, “Our study shows that there is another mechanism at work. Even within a single group of genetically identical bacteria, a small subset of cells exists in a different epigenetic state—where chemical tags on the DNA change how genes are turned on or off without altering the genetic code itself. That means some cells are essentially preprogrammed to respond differently to stress, giving the population a built-in survival advantage when conditions suddenly change.”
So when a stressor such as an antibiotic is introduced, this small subgroup can quickly become dominant because it is already primed to survive. When conditions change again, the population can shift back. This reversible strategy, known as “bet-hedging,” allows microbial communities to adapt rapidly to uncertainty.
To carry out their work, the researchers combined advanced DNA sequencing, large-scale data analysis, and laboratory experiments. They used long-read sequencing technology to analyze stool samples from infants before and after antibiotic treatment, as well as from FMT donor-recipient pairs. This approach allowed them to detect both genetic structure and epigenetic modifications simultaneously.
The scientists then analyzed more than 2,300 microbiome samples from previously published studies to determine how common this phenomenon is across individuals and bacterial species. To understand the mechanism in detail, the team isolated a beneficial gut bacterium, Akkermansia muciniphila, and tracked how its epigenetic states shifted in response to different antibiotics—identifying a specific gene involved in the process.
“Focusing on an Akkermansia muciniphila isolate, we find a specific ePV regulating mucC, a gene of unknown function but whose heterologous expression enhances bacterial tolerance to antibiotics via a bet-hedging strategy,” they stated. “Our results indicate that in the human gut, ePVs may help bacterial populations regain heterogeneity after bottlenecks encountered during colonization of a new host or severe perturbations due to antibiotic exposures.”
“Our work is the first to systematically demonstrate epigenetic bet-hedging across the human gut microbiome,” Fang noted. “It also identifies a specific gene that controls this switch in a beneficial bacterium and shows that the process is reversible—shifting in different directions depending on the type of antibiotic exposure. We were struck by how quickly small subpopulations could take over. In some cases, bacteria representing less than one percent of a population became dominant under changing conditions.”
The research team also found significant diversity within what had been considered a single bacterial strain. Even closely related cells could behave differently, with distinct gene activity and stress responses—highlighting how much remains to be understood about the microbiome at a deeper level. The findings help explain why the microbiome is resilient yet difficult to predict, and why microbiome-based treatments can produce variable results.
“At the same time, our study does not suggest that people should avoid antibiotics when they are medically necessary, nor does it recommend for or against any specific probiotic. Our research is aimed at understanding fundamental biology, not changing current medical care,” added Fang.
“Compared with genetic phase variation, ePV offers several advantages in enhancing clonal heterogeneity,” the team noted. “The reversibility of ePV, without altering DNA sequence or incurring mutation costs, serves as an additional way for individual bacterial strains to adapt to diverse stresses … Our results indicate that in the human gut, ePVs may help bacterial populations regain heterogeneity after bottlenecks encountered during colonization of a new host or severe perturbations due to antibiotic exposures.”
The discoveries have several important implications for human health. In the field of probiotics, it may be that bacteria in a probiotic capsule are not in the same functional state as those that successfully establish themselves in the gut—potentially explaining inconsistent results. “Ultimately, our goal is to design probiotics that are better equipped to establish themselves in the gut and to develop therapies that support beneficial microbes while limiting harmful ones,” Fang said.
For FMT-based treatments, differences in these epigenetic states between donors and recipients may influence how well microbiota transplants work. And when considering antibiotic recovery, some gut bacteria may survive antibiotic treatment not because they are genetically resistant, but because a subset of cells is already in a protective epigenetic state that allows rapid rebound after treatment ends.
The research team plans to study larger groups of patients over time, particularly during and after antibiotic treatment and FMT. They also aim to explore whether similar mechanisms exist in other gut bacteria and to investigate how these epigenetic switches might be harnessed. In the longer term, understanding and potentially controlling these reversible switches could lead to more effective microbiome-based therapies, the investigators suggest.
“These ePV-driven regulatory mechanisms open new opportunities for targeted epigenetic interventions to improve the desired functions of beneficial bacteria,” the scientists stated. “For example, by manipulating ePV, we may strategically boost the resilience and functional capabilities of beneficial bacteria, which might improve the success rates of probiotic engraftment and the efficacy of treatments for microbiota-associated conditions.”
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