Golden Brown

When, in 1747, Julien Offray de La Mettrie described human bodies as machines "which wind up their own springs", he expressed something that became a dominant metaphor throughout science and culture: that bodies are essentially mechanical, and by extension, medicine a kind of mechanical repair. Many may find support for his position in the restorative "oil-change" offered by in the rejuvenating effects of young blood. However, while the science of such transfusions continues to be explored, including with research around Alzheimer's disease in humans, there is a major problem: a substance vital to the life and well-being of the donor could never be treated as a simple spare part available on demand. Machine repair, largely, doesn't land us in such deep ethical and legal quagmires.

It would be better, of course, for human treatments to use substances that donors didn't need and were actively keen to get rid of. What might the world be be like if the first flushes of youth were not flushed at all, and instead repurposed as a health-giving elixir to the elderly and infirm? It should come as no surprise that research of that kind has been in motion (ahem) for some time.

We've known for a while that overuse of antibiotics in agriculture and medicine is a bad idea. The sufferers of recurrent C. difficile infection (CDI) are only one set of victims. C. difficile is a quorum-sensing microbe; while it behaves itself in a diverse environment, it exhibits bacterial mob-mentality when there is too much of it around. Thus, should a course of antibiotics wipe out too many good bugs, the human gut can become over-colonised by C. difficile, with effects ranging from gastric distress to life-threatening toxic megacolon and sepsis. There weren't many good treatments for this until we understood that the best way to repopulate an unhealthy colon was to introduce the contents of a healthy one. Roll forward to April of this year when the FDA authorised the first oral fecal microbiota treatment for recurrent C. difficile infection. While a pill derived from fecal matter might sound icky, it is obviously better than the potentially deadly condition it helps control. But do similar treatments have anything to offer outside such urgent risk to life?

Relevance encourages me to sidestep my partial embargo on rodent research and lead with a 2019 study from Ireland where microbiota treatments improved brain health in old mice. The team's prior work had shown supplementing a specific bacterial strain could reduce stress hormones and consequent behaviours related to anxiety and depression. The later paper advanced on this to show how fecal transplants from young (but not old) mice could reverse brain aging and improve learning and memory. Aging treatments for mice are, as always, some distance from a clinically useful human therapy, but perhaps there is more cause for optimism here than usual: after all,  the composition of the microbiome is recognised as of common importance across many mammals. Indeed, our optimism can only be reinforced by emerging human evidence that microbiota treatments are pertinent to multiple diseases of aging.

The human microbiome has become a key focus in current research. This arose from the realisation that humans are not literal meat-machines driven by selfish genes, but more holobionts, organisms comprised of a cooperative set of species that evolved together and exist in symbiosis. While antibiotics were a massive breakthrough for human health, the next level of understanding acknowledges many microbes are a vital part of our healthy functioning. For this reason the impact of microbiota treatments isn't felt only in our gut, but beyond, extending into many areas of human health.

As one example, we've previously discussed the cancer-fighting capabilities of immunotherapy. Sadly however, while these treatments might save one life, another patient may not respond at all. It transpires that one driver of this difference is the presence (or lack) of a receptive microbiome. A recent study in Nature Medicine showed that combining fecal transplant capsules with immunotherapy increased the response rate for melanoma immunotherapy from an expected 40-50% to 65%. This was a small phase 1 trial, but the results are promising, and more work will follow with other cancers.

Research proceeds not just for cancer, but also in another primary cause of aging mortality - cardiovascular disease. A review in Nature's Journal of Hypertension from 2022 discussed links between the gut microbiota and atherosclerosis, hypertension and heart failure. Degenerative brain disease is also under scrutiny. For Parkinson's disease, a metanalysis from 2021 found microbiome differences between patients and healthy controls, suggesting a role for intestinal inflammation in the condition. A similar finding could well be emerging for Alzheimer's disease.

If we view the history of modern medicine as a timeline of increasing complexity, it may be that we've now breached the outer limits of La Mettrie's metaphor. Human bodies, apparently, are not solitary machines with rusting springs, but entire gardens that must be fertilised. It is a happy accident that here we return to the familiar soil of our primary subject; after all, we know what best fertilises a garden...