Hallmark 12 of 12

Dysbiosis of the microbiome

Trillions of microorganisms live in the gut, and their composition changes over the course of life. In 2023 dysbiosis was added as the youngest of the twelve hallmarks. It has the widest gap between research momentum and practical usability: the evidence base is growing fast while the simplest question remains unanswered, namely what a healthy microbiome actually looks like.

Scientific term: Dysbiosis
Group: Integrative consequences
Hallmarks of Aging: Added in 2023

The hallmarks of aging are a research framework, not a diagnostic tool. They describe processes that occur during ageing, but they do not prove causation and are not a basis for medical decisions.

What lies behind it

The gut microbiome performs tasks the body itself cannot. It breaks fibre down into short-chain fatty acids such as butyrate, which nourish the intestinal lining and act anti-inflammatory. It produces vitamins, transforms bile acids and trains the immune system, particularly in childhood.

With age the composition shifts in several respects. Species diversity declines in many cohorts, although this finding is not consistent. Butyrate producers become rarer while potentially disease-promoting genera appear more frequently. At the same time individuality rises: the microbiomes of older people differ from one another more than those of young people.

In parallel the gut barrier becomes more permeable. Connections between mucosal cells loosen, and bacterial components such as lipopolysaccharides enter the circulation more easily. There they trigger an immune reaction. Through this route dysbiosis connects directly to chronic inflammation.

Conversely, many ageing factors act on the microbiome: altered diet with less fibre, declining chewing function and dental status, less exercise, medications such as proton pump inhibitors and antibiotics, and a move into a care facility with standardised food. This reverse direction makes causal attribution difficult.

How robust is the evidence

Early evidence

The concept is plausible, but human data are thin or inconsistent.

The most interesting human finding comes from an analysis of three cohorts totalling more than 9,000 participants. It showed that what tracked with healthy ageing was not a particular species composition but the degree of individuality. From mid-adulthood onwards microbiomes become increasingly unique, and in healthy very old people this drift continues while in less healthy ones it does not. A hallmark of the pattern is a decline in the genus Bacteroides, part of the core set found in almost everyone. Those who retained a strong Bacteroides dominance into older age, or whose microbiome was low in uniqueness, had worse survival over a four-year follow-up. That inverts the widespread notion that there is an optimal profile to aim for.

A second finding comes from comparing healthy and care-dependent older people. In an Irish study, microbiome composition differed markedly between people in long-term care and independently living peers of the same age, and the differences could largely be explained by diet. That is an indication that diet is a substantial driver rather than age itself.

Causal evidence for interventions is scarce. What is established is faecal transplantation for recurrent Clostridioides difficile infection, where it is highly effective. For other indications, and all the more for healthy ageing, controlled data are lacking. Animal experiments transferring microbiome from young to old animals show effects on immune function and cognition, which is mechanistically interesting and has not been tested in humans.

For probiotics the evidence is usable for individual indications, such as antibiotic-associated diarrhoea. A benefit for ageing trajectories or life expectancy has not been shown.

Findings in humans

In three cohorts totalling more than 9,000 people, an increasingly individual microbiome profile was part of healthy ageing, rather than any particular ideal profile.
In older people in long-term care the microbiome differed markedly from independently living peers, explicable largely through diet.
Species diversity declines with age in many but not all cohorts.
Faecal transplantation is highly effective and established for recurrent Clostridioides difficile infection.
For probiotics aimed at influencing ageing trajectories, controlled trials with clinical endpoints are lacking.

What of this is measurable at YEARS

Partly, via adjacent markers

A microbiome analysis is available at YEARS, and it is important to describe the character of this investigation correctly. It produces a robust description of composition. What it does not deliver is an evaluation, because the yardstick is missing.

Microbiome analysis by sequencing

From a stool sample the genera and species present are determined, along with diversity measures. The result describes a snapshot. Composition fluctuates considerably with diet in the preceding days, which limits the informative value of a single measurement.

Inflammatory markers as the link

High-sensitivity CRP and interleukin-6 capture the low-grade inflammation to which a permeable gut barrier can contribute. The gut’s share cannot be isolated from them, but the values belong in the same picture.

Dietary history and fibre intake

Practically the most important measure in this context, because diet is the substantial modifiable factor. A structured assessment of fibre intake and plant diversity is more useful for counselling than any species list.

Context

There is no established normal finding for a microbiome. Providers deriving a gut health score, a gut age or personalised dietary recommendations with a claim to precision from a stool sample are implying a certainty the evidence does not support. The recommendations derived from them usually match general nutritional counselling, for which no sequencing is needed.

Limits of this hallmark

The core problem is the missing reference. No definition of a healthy microbiome exists, and the most interesting human finding even argues against searching for one: a profile becoming more individual with age was linked to better survival. A test can therefore describe but not evaluate. Any score that does evaluate rests on an assumption set by the provider, not on a consensus.

The direction of causality is particularly unclear, because both directions obviously operate. An altered microbiome can promote inflammation. Conversely, diet, medications, dental status, exercise and living situation shape the microbiome massively. The Irish comparison between care home and independent living suggests a substantial part of the age differences runs through diet rather than through ageing itself.

Methodological caution is warranted. Results depend strongly on sample collection, sequencing method and analysis pipeline, and the same sample can yield different profiles in two laboratories. In addition, a stool sample primarily reflects what happens in the large intestine and says little about the small intestine.

Frequently asked questions

What does dysbiosis mean?→

Dysbiosis describes a shift of the microbial community in the gut away from a state assumed to be favourable. Typical observations with age are lower species diversity, fewer bacteria that break fibre down into short-chain fatty acids such as butyrate, and more frequently occurring potentially disease-promoting genera. In parallel the gut barrier becomes more permeable, so bacterial components enter the circulation more easily and trigger an immune reaction there. Through this route dysbiosis connects to chronic inflammation. The term has a weakness, however: it presupposes that a normal state is known, and that is precisely not the case at present.

Is a microbiome test worthwhile?→

As a description yes, as an evaluation no. Sequencing delivers a robust snapshot of the genera present and measures of diversity. What is missing is the yardstick: there is no established definition of a healthy microbiome. A score, a gut age or a traffic-light rating therefore rests on an assumption made by the provider. In addition, composition fluctuates considerably with diet over recent days, and the same sample can yield different profiles in two laboratories. The practical recommendations that emerge at the end usually match general nutritional counselling, for which no sequencing is needed.

Do probiotics help with healthy ageing?→

There are no robust data for that. For individual, clearly defined indications the evidence is usable, for instance preventing antibiotic-associated diarrhoea. Trials with clinical endpoints on ageing trajectories, frailty or life expectancy are lacking. A fundamental problem is colonisation: most probiotics do not persist in the gut but disappear again after discontinuation. In addition, effects are strain-specific, so results for one strain do not transfer to other preparations. For gut flora, a fibre-rich and plant-diverse diet is the measure with the better evidence base.

What is best documented for supporting gut flora?→

Diet, above all through fibre and plant diversity. Fibre is the substrate from which gut bacteria produce short-chain fatty acids such as butyrate that nourish the mucosa. A broad selection of different plant foods is consistently associated with higher diversity in observational studies. The Irish comparison between people in long-term care and independently living peers showed that differences in the microbiome could largely be explained by diet. Further factors with a plausible link are physical activity, sleep and restrained use of antibiotics and proton pump inhibitors, where medically defensible.

Sources

Wilmanski T, Diener C, Rappaport N, et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nature Metabolism. 2021;3(2):274–286.
Ghosh TS, Shanahan F, O’Toole PW. The gut microbiome as a modulator of healthy ageing. Nature Reviews Gastroenterology & Hepatology. 2022;19(9):565–584.
Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488(7410):178–184.
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278.

Related hallmarks

Hallmark 11 of 12