Microbiota, Obesity and future perspectives

November 2016

The rising prevalence of obesity is becoming a major health problem. It results in an increase in metabolic disorders as type 2 diabetes, insulin resistance, metabolic inflammation, and nonalcoholic liver diseases which are major risk factors for cardiometabolic disorders and various cancers. The main cause of overweight and obesity are inadequate dietary habits and physical inactivity. Besides that several other environmental factors are also becoming recognized as important. During the last 10 years the microbiota has raised substantial attention and was also discussed at the 8th International Yakult Symposium held in Berlin last year.

Prof. Patrice D. Cani is Group Leader in the Metabolism and Nutrition research Group in the Louvain Drug Research Institute, Metabolism and Nutrition at the Université catholique de Louvain in Belgium and one of the leading scientists in the field of microbiota.

What do we know about the significance of the microbiota for obesity?

Prof. Cani: According to many data there is consensus in the scientific community about the fact that the composition and activity of microbes in the gut of patients that are overweight, obese or diabetic seems to be different than the composition and activity of microbiota observed in lean and non-diabetic patients. What is still under debate is the question, if we do have a specific profile of bacteria as a signature of obesity and diabetes.

Depending on the condition – obesity, diabetes, low grade inflammatory tone – it seems that certain bacteria are less abundant. This is an observation / correlation and does not necessarily mean, that this contributes to the development of these conditions. But in animal models a clear correlation has been shown. If we transfer the microbiota from obese mice into germ-free mice we can trigger obesity.

Thinking in the other direction – can obesity be influenced by changing the microbiota?

Prof. Cani: In animal models, there are clear data and well performed experiments coming from different labs including our lab showing that if we change microbiota composition e.g. in obese and diabetic rodents by using pro-, pre- or antibiotics, we can improve the phenotype – that means reduce plasma glucose and decrease obesity for instance. Of course the effect of pro- and prebiotics is more specific than that of antibiotics.

There are also some data suggesting that the use of probiotics can be positive in humans as well. Data suggest that there is an improvement of some parameters that are associated with obesity and diabetes, for example hyperglycemia or cholesterolemia. But the impact seems to be lower than what has been observed in rodents. A recently published meta-analyis is showing that different probiotic strains can indeed reduce the BMI after a certain time of treatment – usually more than 8 weeks. The weight difference was 2 to 5 kg vs placebo. We have to keep in mind that the effects are strain-specific. Different genera as Lactobacilli or Bifidobacteria for instance have been tested. L. acidophilus has problably not the same impact as L. casei or L. plantarum.

Quite recently we have discovered that Akkermansia muciniphila was lower in obese and diabetic patients. If we supplement animals with this bacterium we find a reduction of diet induced obesity, diet induces hepatic steatosis and other parameters as low grade inflammatory tone. But so far this bacterium has not been investigated in humans.

Another candidate could be Faecalibacterium prausnitzii. This bacterium has been found in the context of inflammatory bowel diseases such as colitis and Crohn disease and was associated with improvement of bowel inflammatory tone.

Which mechanisms are involved in the cross-talk between bacteria and host?

Prof. Cani: There are data form different labs including our lab showing the bacteria can dialog with the host cells and can change – for instance in the context of obesity – the energy homeostasis. There are data suggesting that microbes produce short chain fatty acids. These metabolites finally can trigger the secretion of gut hormones as the glucagon-like peptides 1 and 2 (GLP-1, GLP-2) or peptide YY (PYY) and by this way increase satiety and reduce hunger. We have shown in different settings in rodents as well as in humans that changing the microbiota by using prebiotics induces an increase in GLP-1 and PYY. That is associated with a lower food intake. This is one of the mechanisms that can explain a beneficial impact.

BUT there are also data that suggest that microbes can contribute to the onset of low grade inflammatory tone via a small but significant transfer of lipopolysaccharides into the blood. We call that metabolic endotoxemia. Diabetic patients for instance do have higher levels of LPS and we have proposed that this is the case in obesity too.

We have to keep in mind, that this is an association and not THE pathogenic factor. Diabetes and obesity are of multifactorial origin.

The endocannabinoid system is one of your main research interests

Prof. Cani: The endocannaboinoid system encompasses a wide range of lipid mediators, proteins and receptors and is playing a central role in regulation energy metabolism and food intake. These biomolecules are considered as potential therapeutic targets in many areas as appetite regulation, inflammation and cognition.

We were the first to show that microbes can change the endocannabinoid system in the gut as well as the adipose tissue. We found that during obesity and diabetes the microbes are dialoging with host cells and change the production of some endocannabinoids that are anti-inflammatory and that also reduce food intake. This is e.g. the case for bioactive lipids as N-oleoylethanolamine (OEA) or N-palmitoylethanolamine (PEA). In the context of obesity the production of some lipids belonging to the endocannabinoid system is apparently reduced. We are currently investigating this kind of mechanism and how we could improve the sensitivity of the host and the response of the brain to food ingestion.

When we eat lipids, signals in the brain are induced and trigger a reduced food intake. With obese patients this effect is disturbed. We have data suggesting that microbes might be involved in this alteration of the gut-to-brain-axis – maybe via the endocannabinoid production, maybe via a change in the vagus nerve tone.

Data suggest that microbes can send some metabolites via the nerves and by changing the firing of the nerves they can also change the message that is coming from the gut and going to the brain. In Humans there is no proof yet but in rodents it seems to be clear that microbes can really improve or decrease the dialog between the gut and the brain and eventually change the food intake.

We found that Akkermansia can change the endocannabinoid system tone in the gut and improve the endocannabinoid signaling from the gut to the brain. There are very many mechanisms involved in the cross-talk between bacteria and host that have still to be investigated. This is actually a novel field. We have observed some specific effects for some specific strains so far, for instance the reduction of cholesterol.

What do expect for the future?

Prof. Cani: I am personally convinced that in the future we will be able to improve cardiometabolic disorders associated with obesity by targeting bacteria in the gut via specific microbes/probiotics or specific nutrients/prebiotics that can change the microbiota composition. In this way we will probably be able to reduce cholesterol, inflammatory tone, triglycerides or other effectors that contribute to cardiovascular risk factors – but hardly ever obesity per se via the microbiota.

Thank you very much.

K. Gruber

Further Reading:

Geurts L et al., Benef Microbes 2014; 5: 3–17

Cani PD et al., Mol Nutr Food Res 2016; 60: 58–66

Cani PD et al., Nat Rev Endocrinol 2016; 12: 133–143