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