Longevity Briefs: Could Poop Transplants Reverse Gut Ageing?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Ageing thins and weakens the lining of the intestine, which relies on intestinal stem cells (ISCs) to renew and repair itself. Over time, age-related DNA damage, changes in gene expression and other age-related changes disrupt key signalling pathways inside stem cells, causing them to become less ‘stem-like’. Aged stem cells decline in number as well as losing their ability to both self-renew and regenerate surrounding tissue. This is known as stem cell exhaustion.

There is no proven way to reverse ageing in human cells (at least not in living humans), but restoring the gut microbiota (the community of microorganisms living within the gut) to a younger state appears to be a lot easier. The gut microbiota becomes less diverse with age: certain species of bacteria that are generally thought to beneficial decline, while other ‘harmful’ species increase in number. These changes correlate with increased risk of age related disease and intestinal ageing, including stem cell exhaustion. But is this relationship causal? In this study, researchers test whether faecal microbiota transplants (stool transplants) from young mice can improve ISC function in older mice. In humans, faecal transplants from younger individuals are currently the only way to restore the gut microbiota to a younger state in a lasting manner.

The discovery:

The study involved young (2–3 month old) and aged (18–22 month old) mice, which in human terms are roughly equivalent to 20 year-olds and 60 year-olds respectively. Researchers used faecal microbiota transplants to transfer the microbiota from young mice to aged mice (YA) and vice versa (AY). They also gave both young and aged mice transplants from the same age group as controls (YY and AA). Each group contained 3-4 mice. 7 days later, researchers analysed the expression of key genes related to stem cell renewal in the mice’s ISCs and in paneth cells. Paneth cells support intestinal stem cells by releasing signalling molecules that promote stem cell renewal.

These graphs show the relative expression levels of 4 genes in each group, with statistically significant differences marked with *. They show that aged mice receiving aged transplants (AA) have significantly less expression of the relevant genes compared to young mice receiving young transplants (YY) for three of the measured genes. However, Ascl2 signalling and Wnt3 signalling in paneth cells was restored in aged mice receiving young transplants (YA), while signalling in young mice receiving aged transplants (AY) was not statistically different from AA. This suggested that having an aged microbiota resulted in reduced regenerative stem cell signalling and that replacing that microbiota with one derived from a young mouse could restore some aspects of this signalling.

Researchers then assessed ISC function by using staining techniques to measure the presence of ISC offspring in the mice’s villi (the structures lining the intestinal walls). As might be expected based on the changes in gene expression, ISCs from AA mice did not function as well as those of YY mice, while improving significantly in aged mice receiving young transplants (YA). Interestingly, function did not seem to be significantly reduced in young mice receiving aged transplants (AY), which could suggest that old ISCs are more vulnerable to microbiota disruptions.

Finally, by looking for bacterial species that were associated with reduced ISC function, and then administering those bacterial species to mice and observing the effect, researchers were able to identify a bacteria called Akkermansia muciniphila as being responsible for some of the changes in stem cell signalling and function. This is slightly surprising as A.muciniphila generally declines with age, while administration of A.muciniphila to aged mice has previously shown beneficial effects including extending their lifespan.

The implications:

This work suggests that restoring a “young” microbiota in aged mice using faecal microbiota transplants (a procedure that also works in humans) can partially rejuvenate aged intestinal stem cells. This doesn’t guarantee that the same treatment would produce the same results in humans, but it’s worthy of further exploration. Improving ISC function could in theory translate to reduced intestinal frailty, improving recovery from injury or infection. Despite their potential, faecal microbiota transplants lack human testing and are only widely used to treat C.difficile infections that resist antibiotics. Maintaining a healthy and diverse diet rich in fibre and plant-based foods, and avoiding unnecessary antibiotics, are sensible ways to help maintain a healthy gut microbiota into old age.

It’s not clear why A.muciniphila appeared to harm ISC function despite previously seeming to be beneficial, but it does highlight an important point. Different types of bacteria are not necessarily inherently ‘good’ or ‘bad’ but may have different effects depending on the context, such as diet, genetics, and which other bacteria are present in the gut. Just because decline in A.muciniphila is a common feature of ageing, this doesn’t necessarily mean that delivering a large quantity of A.muciniphila into the gut will be helpful. This is why adopting a lifestyle that promotes a healthy gut microbiota is probably a safer strategy than trying to ‘fix’ perceived defects by delivering specific bacteria using probiotics. This is not to say that probiotics cannot be helpful in certain diseases, but when it comes to general ageing, we should be cautious about assuming that a ‘good’ bacteria is going to behave as such in all cases.