Leading researchers in the field of gut microbiota and metabolic health are set to discuss new insights at an upcoming symposium in Denmark, organized by The Gut, Grain and Greens (3G) Center and the Danish Diabetes Academy. Among the scheduled speakers for this event is Yolanda Sanz, Professor of Research at the Institute of Agrochemistry and Food Technology (IATA) of the Spanish National Research Council (CSIC) and co-ordinator of the MyNewGut gut microbiome research initiative.
Sanz, who plans to present unpublished data from MyNewGut at the symposium (November 24th and 25th), spoke with GMFH editors to share a broad perspective on how research on gut microbiota and metabolic health is poised to affect lifestyle and medical interventions in the years ahead.
We already know metabolic syndrome and diabetes are related to diet. How does gut microbiota add to this knowledge?
What we now know, with evidence available, is that the microbiota can be one of the factors that mediates the effects attributed to the diet for metabolic health. This means it at least can be considered a secondary consequence of the diet, although a primary role cannot be completely disregarded yet.
Researchers once thought the ratio of Firmicutes to Bacteroidetes was important in obesity, but recent data cast doubt on this idea. What are the next steps?
The relationship of [the] ratio of Firmicutes and Bacteroidetes with obesity initially was an interesting concept, because it was a way to propose a first hypothesis. But we know that these phyla are very broad, and include many different species. This means that the functional properties of these species may vary tremendously, so we cannot expect that this could be a good indicator for predicting a disease.
The way to progress from this general concept into a more refined hypothesis, which could be the markers of development of obesity, is to evaluate the role of each of the bacterial species or consortia of bacteria (groups of species)—what they are doing in rodents, in models of metabolic disease, and later on if possible, to prove and to test the effects in humans.
This is also what we are doing in MyNewGut: those bacteria that we associate with obesity or with metabolic syndrome in humans will be tested in animal models to see specifically which ones play a role and which associations are meaningless.
What avenues of research are most promising for figuring out the role of gut microbiota in obesity & metabolic syndrome?
One of the challenges we are facing is that it’s very difficult to differentiate the effects of the diet from the effects of the microbiota, because in fact, diet and microbiota have reciprocal interactions.
At least, we know that via these interactions the microbiota exerts effects on metabolic health, and this has been proven in rodents via mechanistic studies. For example, it’s known that the microbiota that is altered by the diet could increase the inflammatory tone that also leads to metabolic syndrome and diabetes; and for example, it has been proven that diets rich in saturated fat increase the abundance of some pathobionts that are pro-inflammatory, such as Bilophila wadsworthia or other gram-negative bacteria that provide LPS (which is an inflammatory bacterial component). Very recently it has also been described that insulin resistance and the possible development of diabetes is related to some alterations in the microbiota and its metabolic activities (e.g. synthesis of branched-chain amino acids in particular).
These correlations were shown in humans, and have been proven later on in a more specific way in animal models, by feeding animals with the specific bacteria that were increased in humans with insulin resistance.
The causality has also been proven in the study in humans that involved a fecal transplant of the healthy microbiota into subjects with metabolic syndrome, and it was proven that the glucose tolerance was also improved. So this study did not point to the role of specific bacteria in the process but, at least, demonstrated the concept that the microbiota matter for metabolic health in humans.
The triggering role of the gut microbiota alterations in the onset of metabolic disease is less well documented, because for finding this out we have to conduct long-term longitudinal studies and track the progression of metabolic disease in subjects that initially are healthy.
Some studies are in progress… We have to bear in mind, however, that these disorders are multi-factorial, so we cannot expect that only the microbiota plays a key role. These roles and these effects, adverse or beneficial, will be played by many factors, many variables, that are interacting together. We do know that some of the key factors are the gut microbes and the diet.
How much will we have to account for personalization in diet-microbiome interactions?
In this field we are just getting started so it’s very difficult to quantify what is going to be developed regarding diet-microbe interactions in personalization of treatments or prevention. But the results that we have got so far point to the idea that these interactions will play a role.
In fact, it was recently published that the gut microbiome, together with some other host factors such as body mass index and other physiological parameters, influence the response to different diets in terms of the glucose levels you reach in blood after the meal. And… the glucose levels in blood can indicate also the risk you have to develop insulin resistance and type 2 diabetes.
So we think that there is enough evidence so far to start forseeing that gut microbe interactions with the diet will play a role in the personalization of dietary strategies, but still we don’t have very clear ideas about the way we are going to stratify the population as a function of the microbiota. Probably, this will depend on the effect we want to investigate or the effect we want to prevent. For example, it will be different if you are planning an intervention with fibre to look at the response and to reduce glucose response than if you are trying to stratify people for assessing the efficacy of a drug treatment. Because the metabolic activities and the bacteria that could play a role will be different.
What is the promise of new diagnostics based on the gut microbiota?
The role of the gut microbiota in diagnosis still has to be proven, because for doing so we need longitudinal studies looking at the progression from health to disease. The limitations of defining a biomarker for use as a diagnostic tool based on the gut microbiota would be related to the fact that there are many, many different factors that can influence the microbiome and the microbiota, so this could reduce the predictive value of these biomarkers or diagnostic tools. But on the other hand, the advantage of these potential early diagnosis tools could be that these biomarkers could be partially modified by interventions. This means there could be early predictors of development of disease (or the risk of developing disease) that we can modify to prevent disease, and this is the most attractive part of this new vision and these new diagnostic tools.