Professor of Nutrition, Director of the Institute of Cardiometabolism and Nutrition (ICAN) linked to the University of Pierre and Marie Curie in Paris and head of a research group at INSERM; it is no surprise that Karine Clément is a well-known expert in metabolic diseases, nutrition and the role the gut microbiota plays in these conditions. Last year, she received an award from La Recherche for her contribution to understanding the role of the 100 trillion microbes that inhabit the colon. She also coordinates the European international project Metacardis, which was launched in 2012 with the aim of better understanding how gut microbiota influences cardiometabolic diseases in a cohort of nearly 2000 patients. Clément was one of the main speakers at the Bdebate conference, held at the beginning of July at the Cosmocaixa science museum in Barcelona, where she kindly agreed to be interviewed by Gutmicrobiotawatch.org.
When did we start connecting the gut microbiota to obesity, diabetes and other metabolic diseases?
Only relatively recently – the first publication was less than 10 years ago and I remember that, for me, as a clinician that visits obese patients – people with diabetes and cardiovascular disease – it was very surprising to learn that when you take gut microbiota from obese rodents and transfer it to germ-free mice you can actually induce obesity and increase some risk markers such as metabolic factors for diabetes or cardiovascular disease. Furthermore, there have been some very interesting subsequent publications, such as the one showing that if you compare lean and obese subjects – people at risk of metabolic diseases and so on – you find differences in their gut microbiota. These differences are found mostly in the more abundant bacteria: certain microbial groups – for example, Bacteroides – were down and others – such as Firmicutes – went up.
Those are animal model-based studies. What about humans?
At the French National Institute for Agricultural Research (INRA), for instance, we have undertaken several types of interventions, addressing the diet of obese and overweight patients in order to see whether these results in rodents can be translated to humans. But one of the main problems is that in people we only make observations and you only get a picture of the gut microbiota in different conditions. It is very difficult to know whether it is just a picture or if it has had a real impact on the metabolism. So, that is why we decided to perform several types of interventions.
Can you explain what these interventions consist of in humans?
One of our studies, published in Nature, was on overweight and obese subjects. The aim was to find out whether we could regulate the gut microbiota through a weight loss programme. So the first observation we made was in 50 subjects who were overweight and obese. We looked at their gut microbiota and saw that it differed from one subject to another: 30% of the subjects had a low abundance of bacterial genes, meaning those subjects had poor gut microbiota. Then we ran a dietary intervention consisting of a diet rich in protein, fibre and carbohydrates with a low glycaemic index. Through this we observed an increase in gene abundance of about 30% in the subjects with poor gut microbiota. So they not only improved gene richness, but also reduced their cardiometabolic risk through an improvement in their scores for glycaemia, triglycerides and rate of inflammation. Nevertheless, the gut microbiota improvement in terms of richness remained inadequate when compared to the subjects with a high gene count (i.e. rich microbiota).
What about the second intervention you carried out?
As a follow-up study we studied a bacterium called Akkermansia muciniphila, which makes up 3% to 5 % of the gut bacteria. The strain is linked with a fibre-rich diet. It’s also associated with lower levels of blood sugar, insulin and fats, which help ward off obesity, diabetes and heart disease. So in this experiment we had subjects with low and high rates of this microbe. The ones with low rates were also the ones with higher glycaemia and cell adiposity, which is more proinflammatory. We also observed that they had a reduced response to the dietary interventions made in the study, leading to less improvement. So probably the overall abundance of gut microbiota matters, but specific bacterial strains are particularly important. In that experiment, the individuals with a higher abundance of A. muciniphila and greater gut microbiota richness were also the ones with better metabolic profiles.
Is gut microbiota a key factor in the induction of metabolic diseases or are metabolic diseases altering the profile of gut microbes?
I think that it is a multi-directional dialogue. You cannot consider changes of environment – either in the gut microbiota or in the metabolism – in isolation. In fact, metabolism per se probably has an impact in the gut microbiota; cardio-metabolic diseases, such as obesity, diabetes and cardiovascular disease, are linked together in subjects who have low-grade inflammation, that is, an increased rate of inflammation in the blood over a long period of time. We also see that inflammation in itself could contribute to shaping the gut microbiota.
The other interesting thing is that these diseases are chronic, so it could be that changes in gut microbiota also play a contributory role. It is part of a vicious cycle that contributes to chronification. There are some studies, for instance, showing that in certain populations – for example the US – a decrease in gut microbiota richness can be observed even at an early stage of life, such as in children under three. And that is a potent indicator that some changes occur very early in life due to lifestyle, environmental changes and so on. So, it is likely that gut microbiota richness is of great importance.
Could modifications in the gut microbiota profile be considered an early biomarker for metabolic disease risk?
That is one of our hopes. But we have to keep in mind that we have been applying this approach to our genome for 15 years. We thought that being able to sequence the genome would reveal early markers and predictors for diseases. But what we have learnt from the sequencing of our genome is that there are many risk factors in general, but when you try to apply them to a concrete person – and I am very sensitive to that as a clinician – it is very difficult to predict. It is true that now we have new targets, the gut microbiota, and we also have the necessary tools for testing. The question now is whether we can see differences at the population level that can help us make predictions for one given individual, taking into account our complexity – our environment, our biology, our own immunity and so on. So, for now, we must exercise caution.
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