Why does the gut microbiome lose its balance as we age? Researchers at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena now present a new explanation in a paper published in “PLoS Biology”. According to the study, the age-related destabilization of the microbiome is not primarily due to changes in the microorganisms themselves, but rather to a decline in immune surveillance. When the aging immune system loses its control function, individual microorganisms can gain the upper hand and disrupt the microbial balance. The study opens new perspectives for understanding healthy aging.

Jena. Trillions of microorganisms live in the human gut, collectively forming the gut microbiome. They support important bodily functions, including digestion, metabolism, and the immune system. While this microbial community remains stable for many years, it often becomes unbalanced with age: diversity declines, certain microorganisms gain the upper hand, and the risk of inflammation increases. Why the gut microbiome loses its balance with age is one of the central unanswered questions in aging research.

In a study now published in “PLoS Biology”, researchers from the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) and the Cluster of Excellence “Balance of the Microverse” at Friedrich Schiller University Jena propose a new theoretical explanatory framework. They focus on the hypothesis that the immune system actively monitors and regulates the stability of the microbiome—and that the gradual deterioration of the gut microbiome in old age is attributable more to the failure of the host’s active control mechanism—immune surveillance—than to a passive change in the microbial community itself.

The article was published in the “Unsolved Mystery” series of the above-mentioned journal, which presents conceptual frameworks for important biological problems that remain incompletely understood. The authors emphasize, however, that their model—which is based on existing findings and provides specific, testable predictions—does not yet constitute a definitive explanation.

Immune surveillance as the key to microbiome stability

The study combines insights from immunology and ecosystem ecology and suggests that immune surveillance acts as an organizing principle for the stability of the microbiome throughout life. The concept of immune surveillance is known from cancer biology, where it describes the immune system’s ability to detect and eliminate abnormal cells at an early stage.

The authors now apply this principle to the interaction between the host and the microbiome. According to their hypothesis, surveillance in the gut is not directed against specific microbial species, but against excessive dominance. Microorganisms that grow particularly rapidly or begin to dominate the community are specifically limited by immune mechanisms. In this way, microbial diversity is preserved, and the ecosystem remains stable. As the immune system ages, its ability to enforce this principal decline, and the microbiome becomes destabilized as a predictable consequence.

“We argue that the immune system does not primarily distinguish between ‘good’ and ‘bad’ microbes, but rather continuously monitors which organisms are beginning to dominate the community,” explains Prof. Dr. Dario Riccardo Valenzano, head of the “Evolutionary Biology / Microbiome-Host Interactions in Aging” research group at the FLI. “This creates a dynamic equilibrium that ensures the long-term stability of the microbiome.”

To illustrate this principle, the researchers developed a simple computational model. Within this model, microbial species compete for limited space. If a rule is introduced specifically limits disproportionately fast-growing competitors, the community remains diverse and stable over long periods of time. If this control is removed, individual species dominate and diversity collapses.

“Aging does not only affect the host itself but also reshapes how the immune system interacts with resident microbes. Our work suggests that the gradual loss of immune control may be a key driver of microbiome instability during aging,” adds Dr. Siqi Liu, first author of the study.

A new explanation for dysbiosis in old age

The model provides a concrete hypothesis regarding biological aging. With increasing age, the immune system undergoes profound changes—though not in the form of a uniform loss of function. While certain inflammatory responses are maintained or even increase, other finely regulated functions decline. The researchers suspect that the mechanisms responsible for detecting and controlling rapidly growing and dominant microorganisms are particularly weakened.

This creates an imbalance: the part of the immune system that responds to the total number of microorganisms remains active or even becomes overactive. This contributes to the chronic, low-grade inflammation typical of old age, known as “inflammaging.” At the same time, the immune system increasingly loses its ability to specifically keep individual dominant microbes under control. The result is persistent inflammation coupled with a decline in control over the microbial ecosystem in the gut.

“In our model, the immune system keeps the microbiome in balance by continuously limiting particularly dominant microorganisms,” explains Valenzano. “With age, this control function loses precision. As a result, more persistent bacteria can spread more widely and reduce the diversity of the community. Age-related dysbiosis would then not mean that the microbes turn against their host—rather, the host increasingly loses control over its microbial ecosystem. This is a hypothesis that research must now test.”

Implications for interventions

The hypothesis could also have implications for microbiome-based therapies in older adults. According to the researchers, it may not be sufficient to simply alter the composition of the gut community. Rather, it could be crucial to simultaneously strengthen those functions of the immune system that maintain the balance of the microbiome. If immune surveillance is already severely impaired, restoring microbial diversity alone may not lead to a permanently stable community. Observations in immunocompromised patients suggest that the close interaction between the microbiome and the immune system should be taken into account in such treatment approaches.

“The study points to a potentially important principle for future microbiome therapies: a stable and resilient gut ecosystem likely requires cooperation between microbial communities and the ageing immune system. Understanding that interaction could help improve interventions aimed at promoting healthy ageing,” explains Dr. Flávio Silva Costa, co-author of the study.

Roadmap for future research

To test the hypothesis, the researchers propose experimental studies in short-lived model organisms with defined microbiomes as the next step. A particularly suitable model system could be the African turquoise killifish (Nothobranchius furzeri), which is extensively used at the FLI for aging research. With its short lifespan, it offers ideal conditions for investigating which immune surveillance mechanisms are crucial for the stability of microbiomes. Furthermore, longitudinal studies in humans are needed to jointly track changes in the immune system and microbiome over time. Only in this way it will be possible to clarify whether the loss of immune surveillance actually precedes age-related changes in the microbiome.

If the hypothesis is confirmed, it could fundamentally change our understanding of age-related changes in the microbiome. The stability of the microbiome would then not be solely a property of the microbes themselves, but rather the result of a lifelong interaction between host and microbiome—an interaction over which control is increasingly lost with age. Thus, this work opens up new perspectives for strategies that could promote healthy aging and counteract age-related diseases.

Publication
Immune surveillance and microbial escape in the aging host: Why does the microbiome lose its balance? Liu S, Costa FS, Valenzano DR. PLoS Biol. 2026 May 20;24(5):e3003815. doi: 10.1371/journal.pbio.3003815. https://doi.org/10.1371/journal.pbio.3003815