Inside the human gut is a thriving community of bacteria, many of which provide nutrients in exchange for a safe place to live. But they are not merely passive inhabitants – these microbes can also impact upon our metabolism. GEE researchers in the Institute of Healthy Ageing have been investigating how gut bacteria interact with medicinal drugs to influence lifespan and health.

There are 100 trillion microorganisms inhabiting the human gut – outnumbering human cells ten to one. These microorganisms are generally harmless, and in fact many are beneficial, forming a symbiotic relationship with their host. Occasionally, this relationship is less friendly, however, and gut bacteria can sometimes cause illness. Whether beneficial or harmful, gut bacteria can alter metabolic processes and chemical signalling pathways in the host, and recent research by Filipe Cabreiro, Catherine Au, David Gems and colleagues suggests gut microorganisms may interact with medicines to effect health and ageing.

Metformin: Beneficial Side Effects in Diabetes Treatment
A drug called Metformin is the most commonly prescribed treatment for type 2 diabetes, but it has long been noted that Metformin has some positive effects beyond those it is prescribed for, including reducing the risk of cancer. Metformin has also been found to slow the ageing process in rats and the nematode worm, Caenorhabditis elegans. This is partly mediated through Metformin’s effect on an enzyme, AMP-activated protein kinase (AMPK), which is important in influencing several key signalling pathways which have a knock-on effect on the ageing process. However, this is not the whole story – in nematodes Metformin also influences health and ageing through an interaction with microbes in the gut.

Using a combination of techniques, including liquid-chromatograph mass spectrometry (LCMC) to visualise folate composition, and mutant E.coli strains and nematode worms lacking key metabolic cycles, Cabriero et al showed that E.coli are a critical aspect of the anti-aging properties of Metformin. The nematode, C.elegans, usually feeds on E.coli, but some of their microbial diet manages to avoid digestion and stick around in the nematode’s gut. Although the microbes aren’t really welcome there, and ultimately contribute to the worm’s death, they inadvertently have some beneficial effects during their stay. Worms reared on an E.coli-free diet do not show the usual positive effects of Metformin – in fact, without E.coli, metformin is toxic to the nematode. The researchers were able to track this bacteria-drug interaction to the B-vitamin, folate. Metformin substantially altered the folate content of E.coli, and when the researchers created a mutant strain of E.coli that lacked the ability to metabolise folate, nematode hosts experienced the same toxic effects were seen as when nematodes lacked the gut-bacteria entirely.

Interactions Between Host and Guest
So, metformin alters the folate cycle in the gut bacteria of nematode worms, and this in turn influences ageing in the worm. But how? There were no changes in the folate levels of the nematode worms treated with Metformin, indicating there must be another step in the process. This step appears to be mediated by methionine, an amino acid which is an important part of the nematode’s diet, obtained almost entirely from its gut bacteria. Metformin, by altering the folate cycle, reduces methionine production in E.coli, and this seems to be responsible for the anti-ageing effects on the worm host.

Metformin, Dietary Restriction and Ageing
Metformin, in interaction with the gut-bacteria, seems to mimic the effects of dietary restriction – the well-documented but still relatively poorly understood phenomenon by which reducing food intake increases lifespan. Anti-aging effects of dietary restriction have now been documented in rats, worms, and monkeys, and some people have even made the decision to reduce their food intake in the hopes that it will extend their lives. Research into the mechanisms by which dietary restriction is able to increase lifespan is on-going, and is a major focus of research in UCL’s Institute of Healthy Ageing. It is currently thought that dietary protein (and amino acids) may be important in controlling the effects of dietary restriction on ageing, and several chemical signaling pathways, including those regulated by AMPK, have been implicated in this process.

Thus, the anti-ageing properties of Metformin appear to be two-fold. By activating AMPK, Metformin may mediate life extension through its influences on key signalling pathways, essentially mimicking dietary restriction. Secondly, Metformin alters folate metabolism in microbial symbionts, reducing methionine production and again mimicking a restricted diet. Importantly, in the absence of the gut microbes, the drug showed strongly toxic effects, indicating that in some way, E.coli is able to ameliorate the drug’s toxicity. The effect of the drug Metformin is the result of a complex interplay between both toxic and beneficial effects on the host and the gut microbiota. Finally, all of this appears to interact with the diet of the nematode – feeding nematodes on a high-sugar diet eliminated the positive effects of Metformin.

Our gut bacteria are not passive hitch-hikers, but instead interact with our metabolic processes and dietary intake in complex ways. The effects of medicine can be strongly dependent upon our gut microbiome, and understanding this may help us to understand why the same drugs have different effects on different people. Drugs chosen for one beneficial effect may also have other, unintended effects (both positive and negative), but the extent and type of these may be heavily dependent upon our diet and gut bacteria. By viewing our bodies as a complex ecosystem of human cells interacting with a large and varied microbial population, we can gain greater insights into the workings of our bodies, and how to improve our health and lifespan.

Original Article:

This research was made possible by funding from the Wellcome Trust, The European Union and the Medical Research Council.

Filed under Biology of Ageing, Institute of Healthy Ageing, Research

Tags: Ageing, Dietary Restriction, Gut Microbiota, Health, Nematode

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