Researchers in Denmark have made a groundbreaking discovery: two signal molecules from common gut bacteria act as the body’s own sports hormones. They help to keep weight down, lower blood sugar and strengthen both muscles and bones – and are already on their way into the first human trials.
You are not alone in the art of staying lean. The bacteria in your gut also seem to play a role – and can tip the balance for or against your chances of being as lean as if carved from Greek marble.
Now, researchers at the University of Copenhagen have identified bacteria and their signal molecules that appear to decisively influence blood sugar control and the build-up of fat, bone and muscle.
Certain gut bacteria produce the beneficial molecules. Almost everyone carries some – but some people have many and others almost none. This means that we do not all get the same level of help from gut microbiome in keeping weight and blood sugar in check.
The researchers behind the discovery see the bacteria as a chance to develop probiotics that could help far more people keep their weight down, control blood sugar and build strong bones and muscles – and lower their risk of disease.
“Some media outlets call them the sports hormones of bacteria because they almost work like a trip to the gym – only without you lifting a finger. We imagine that, within 10–15 years, specific bacterial strains could be developed into a probiotic taken daily to strengthen the gut microbiome in a health-promoting direction. Developing a drug directly from the signal molecules secreted by bacteria in the gut may also be possible,” explains the head of the project, Oluf Borbye Pedersen, Professor and Research Director from the University of Copenhagen and the Centre for Clinical Metabolic Research at Herlev and Gentofte Hospital, Denmark.
With support from the University of Copenhagen, Oluf Borbye Pedersen and the first author on the current paper,Assistant Professor Yong Fan, founded a biotech company two years ago to explore how to turn the discovery into practice.
The findings have been published in Nature Microbiology.
How your gut bacteria strengthen your health
When the project began six years ago, the team hypothesised that humans and gut bacteria might share signalling proteins with partly similar structures and functions.
They focused on hormones and hormone-like signalling molecules and identified two candidates in large microbiome databases and named them RUMTOR-derived peptide 1 (RORDEP1) and RORDEP2.
Both substances turned out to have 24 and 25 percent amino acids identity to the body’s own exercise hormone, irisin – a myokine released by muscles during physical activity that helps to regulate fat burning and insulin sensitivity. This structural similarity is likely the reason why RORDEP1 and RORDEP2 can mimic some of the effects of exercise on metabolism.
RORDEP1 and RORDEP2 are secreted in the intestine by specific strains of Ruminococcus torques.
“More than 90% of the people we have studied carry R. torques in their gut but in very different amounts. Individuals can differ by up to 100,000-fold – and those with many R. torques are more likely to be slim,” notes Oluf Borbye Pedersen.
When bacteria trigger the body’s hormone signals
The researchers tested what happens when laboratory animals such as mice and rats are given either the bacteria themselves or the signalling molecules they produce.
Twice a week for two months, mice were given a bacterial strain that produces both RORDEP1 and RORDEP2. The results were striking: compared with control groups, the animals gained 20–30% less weight, burned more fat and had better glucose tolerance, lower levels of proinflammatory cytokines and higher bone density and muscle mass.
In other experiments, the animals received recombinant RORDEP1 or RORDEP2 – either as an infusion into the duodenum or as an injection into the abdominal cavity.
There, RORDEP1 and RORDEP2 activated specific neurons in the intestinal wall, which in turn triggered secretion of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). Both hormones play a central role in regulating appetite and blood sugar: GLP-1 prolongs satiety and lowers blood sugar by stimulating insulin release, and PYY retards gastric emptying and dampens hunger signals to the brain.
GLP-1, in its chemically modified form, is already known as an active ingredient in modern drugs for obesity and type 2 diabetes.
Conversely, treatment with RORDEPs reduced production of the gut hormone gastric inhibitory polypeptide (GIP). GIP influences several centres in the brain and can contribute to weight change in complex ways – sometimes stimulating, sometimes inhibiting.
RORDEP1 and RORDEP2 seem to work only by stimulating neurons in the intestinal wall – and thus the gut’s own nervous system. That is also why they do not work if the molecules are given intravenously or under the skin or are added to cell cultures in the laboratory. RORDEPs send signals to the brain, which then regulate appetite. In addition, RORDEPS send signals to the liver to reduce sugar production. This is our current understanding of RORDEPs’ mode of action on weight and blood sugar control,” says Oluf Borbye Pedersen.
The first studies involving humans are in full swing
The University of Copenhagen patented the discovery of RORDEP1 and RORDEP2 two years ago and, together with Oluf Borbye Pedersen and Yong Fan, has since launched a biotech company called GutCRINE to explore their commercial potential.
In this context, the researchers are now running the first tolerance trials involving humans. For five hours at a time, thin tubes are inserted through the nose, oesophagus and stomach into the duodenum to deliver either bacteria or RORDEP1.
These first studies are designed only to show that it is safe to give people these bacteria and hormone-like signalling molecules – substances most people already have in their intestines.
Measurements show that RORDEP1 and RORDEP2 naturally circulate in human blood at picomolar concentrations – similar to insulin levels in the fasting state. This suggests that the bacterial signalling molecules are not confined to the gut but can also act systemically via the bloodstream.
“The double-blind, placebo-controlled tolerance trials involving humans are now completed, and we have not found any side-effects from short-term infusion of either bacteria or RORDEP1,” explains Oluf Borbye Pedersen.
The next step is randomised clinical trials to show how the bacteria or their signalling molecules affect human weight, blood sugar, bone density and muscle mass.
“RORDEP1 and RORDEP2 may be able to do something different – and perhaps more – than the chemically modified gut hormones currently used for weight loss and blood sugar control. That is why we have hopes that, within 10 to 15 years, products can be developed to help people live healthier lives.”
This could be through a preventive probiotic sold in health food shops that boosts the amount of naturally occurring R. torques permanently colonized in the gut – or as a drug containing chemically modified RORDEP1 or RORDEP2, prescribed for people who have overweight or are living with type 2 diabetes, cardiovascular disease, osteoporosis or sarcopaenia,” says Oluf Borbye Pedersen.
He adds that the great advantage of the bacteria is that, unlike current weight-loss drugs, they have shown no side-effects – which could make them far easier for people to use long term.
“Today, many people who start modern weight-loss drugs stop within a year or two. With gut bacteria signalling molecules, we hope to create a more natural way with fewer side-effects to keep the body healthy and strong – for far more people,” concludes Oluf Borbye Pedersen.
