Prof. Patrice Cani, of Belgium’s Université catholique de Louvain, is involved in the Metabolism and Nutrition research group of the Louvain Drug Research Institute. He investigates the role of the gut microbiota in the development of metabolic disorders: obesity, type 2 diabetes and low-grade inflammation. He aims to uncover the mechanisms involved in the gut-to-liver and in the gut-to-adipose tissue axis. Dr. Cani is the Gut Microbiota for Health’s expert in metabolic conditions.
You started out as a dietitian and you now study metabolism and nutrition. What led you to connect the gut microbiota to these things?
I [was] ‘scientifically born’ in a laboratory where the concept of a prebiotic was initially created. [Dr.] Marcel Roberfroid… was a professor here at the Université catholique de Louvain, and in the 90s he had the opportunity to work on several dietary fibres: non-digestible carbohydrates, mainly. He discovered that when he fed rats with non-digestible carbohydrates, and it was in fact inulin-type fructans…they found an increase in the cecal weight… the prebiotic concept was born at that time because they decided to analyze the microbial composition in the cecum, which was in fact associated with an increase in Bifidobacterium following the administration of inulin, an effect reproduced in humans.
When I started in the lab they found that rats that were fed with these specific inulin-type fructans had a reduced fat mass. And they were not specifically investigating metabolism or energy homeostasis because it was a lab involved in investigating toxicology and cancer, so far away from metabolic diseases.
And with [Dr.] Nathalie Delzenne we decided to investigate the role of these specific prebiotics on food intake behaviour because we thought that the reduced fat mass was mainly associated with changes in food intake. And indeed we found the changes in food intake: the rats that were fed with oligofructose and inulin had a reduced energy intake and a reduced fat mass also. And during my PhD thesis we investigated the link between the gut microbes and the food intake behaviour and we came into the role of the GI peptides such as GLP-1 and PYY… later on we found that ghrelin, so this orexigenic peptide ghrelin, was in fact decreased following the oligofructose treatments.
So we finally observed the link between the gut microbes and energy intake and food intake behaviour by linking events occuring in the colon with the brain. So this gut-to-brain axis via the PYY, GLP-1 and ghrelin was the first work of my scientific career on the theme of gut microbes and metabolic diseases.
When we found that the prebiotics were able to change food intake and fat mass development, we decided to investigate the role of these specific prebiotics in obese and type 2 diabetic and also type 1 diabetic animals.
Can you tell us about your current studies on metabolic conditions?
We decided to pursue our work on the link between these gut microbes and energy metabolism, knowing that low-grade inflammatory tone is associated with these conditions of obesity and type two diabetes… And [while] searching for some specific reasons for this low-grade inflammatory tone, we investigated the gut microbes and we finally found a link between the gut microbes and inflammation via the concept that we developed, which was ‘metabolic endotoxemia’.
The current projects we are investigating in the lab are mainly basic science projects. We are mostly investigating key mechanisms at the level of different targets. One of the targets we [have been] investigating for a couple of years now is the role of specific microbes such as Akkermansia muciniphila.
Another project we have deals with the role of the innate immune system and the endocannabinoid system. So we discovered and published about five years ago that there are links between the gut microbes and the endocannabinoid system. We found that a specific microbial composition in the gut was associated with specific endocannabinoids… not only in the adipose tissue but also in the intestine… And we found a link between some endocannabinoids and the regulation of the innate immune system.
We are pretty convinced that the gut plays a central role interacting with the different organs at a distance.
If I can summarize, the different models we are investigating now are targeting the innate immune system and the endocannabinoid system in different organs in order to investigate the crosstalk between microbes and host or host and microbes.
What are the biggest challenges you face in your research?
One of the challenges is to prove the causality between different microbes and host metabolism. When we are targeting one specific microbe, for instance Akkermansia in my research, we do observe an interesting impact on metabolism at different levels. But as a scientist I have to acknowledge that there is the possibility that there are different mechanisms in between. And this is a challenge constantly: the different interactions and the different effects… between microbes and host. The key challenge is to translate these data into human data.
You mention the problem of establishing causality. In an ideal world, what combination of studies would you like to see in order to feel confident making causal links between the gut microbiota and various conditions?
For me the challenge is not so simple because they are complex organisms. They are living cells. And it’s really challenging to demonstrate that one specific bug or one specific cell included in a very complex microbial community can impact on all these metabolic features. So it’s really difficult to design, for me, a very key experiment which will be able to demonstrate the causality.
You do basic research in your lab. But how do you see your research having possible clinical applications?
For instance, if we move back to the story on the prebiotics, they are now used everywhere and I’m pretty sure around the world nobody knows that it was coming from Marcel Roberfroid and my lab… and we did find of course that prebiotics not only change the gut microbes in rodents but also in humans. And it’s pretty well accepted now, so we can say that prebiotics improve the gut microbiota composition in humans. If we move specifically to my work, regarding the role of prebiotics on GI peptides… we have translated the data from rodents into humans, showing that indeed if we fed humans with prebiotics we found an increase in GLP-1 and in PYY, and a reduction in ghrelin. So we can indeed observe a reduction of appetite and an increase in satiety in healthy subjects but also in obese patients when they are fed these prebiotics.
But although we have found this relationship – we and others now, because that’s been also confirmed by several other groups over the last five years – although it’s a very interesting translation from the rodents to the human side, we didn’t find so far in humans …a study showing that prebiotics can decrease fat mass to a similar extent as the one we observed in rodents. So I’m not saying that we failed to replicate the data, but I think that it’s so complex that it’s difficult to observe all the different and beneficial effects of prebiotics in humans.
Also, we observed in rodents and we published in 2007 that high-fat diet feeding or genetic obesity was associated with an increase in plasma LPS levels, so this ‘metabolic endotoxemia’. Then we demonstrated that in humans it was also the case. We observed in overweight, in type 2 diabetic patients, and in obese patients, an increase in plasma LPS. And now it’s been published by several other groups in thousands and thousands of patients that indeed the low-grade inflammatory tone observed in obesity and type 2 diabetes is indeed correlated and associated with higher plasma LPS levels.
So I think there are some specific discoveries that we observed in the rodents that have been finally translated into humans. Now the next challenge will be for me to verify whether the strong impact of Akkermansia that we observed in the rodents may or may not be translated into humans.
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