Introduction

I came across an interesting study today from the Journal of the American Diabetes Association by Sung et al [1] that looks at the potential effects of resveratrol in diabetes and obesity in mice.

I have previously posted on how autism could be treated by modifying gut bacteria and how the growing role that they seem to play in a host of diseases.

This study is interesting because it suggests that at least part of the activity on glucose (blood sugar) control by resveratrol may be related to changes in the gut bacteria.

(NB - I am trying some experimentation with formatting here. Let me know if you prefer this or my usual method.)

Resveratrol - What is it?

Resveratrol

Resveratrol is a type of compound called a polyphenol that is found in certain plant sources, particularly certain types of berries and grapes.

It is most commonly associated with red wine and the mediterranean diet.

It came to prominence in research around the turn of the century as a potential life-extension supplement.

As someone who is particularly interested in the anti-ageing field it is something that I have followed for some time.

The overall research as it applies to ageing has been mixed and at times inconsistent.

More recent research like today's study has started to examine the effects of resveratrol on type II diabetes and obesity.

It suggests that one of the reasons for previously inconsistent results may be that a large part of the effect of resveratrol comes from changes in the gut bacteria.

For practical reasons these may be more difficult to modify in the human population and this might explain why previous studies have shown mixed results.

Design/Methods

There were 3 main components of the study:

Testing the effects of different diets (see below) on glucose metabolism (see glucose tolerance test below) in mice.
Testing the effects of the different diets on the microbiome (combination of bacteria in the gut) of the mice.
Testing to see if the effects of resveratrol supplementation could be duplicated by faecal transfer of the microbiome between groups alone.

Initial Sample

The sample consisted of 40 male mice aged 8 weeks of age. These were split into four groups according to diet:

Fed chow (the name for a standard generic type of feed used in research).
Fed chow and 0.4% resveratrol.
Fed a high fat and high sugar diet (HFHS) alone.
Fed a HFHS diet and 0.4% resveratrol.

Each diet was given for 8 weeks.

Glucose Tolerance Test

The mice were tested for glucose (blood sugar) control using something called a glucose tolerance test (GTT).

GTT is a common test to see the body's response to sugar.

If you have ever been tested for diabetes or pre-diabetes you may have received this test.

In this case the mice were injected with glucose and their blood was collected at a variety of intervals for up to 120 minutes after administration, to test how quickly the levels went up and down.

In the case of diabetes, or pre-diabetes the blood glucose stays raised for longer than in people who do not have these conditions due to either a lack of insulin or inability/reduced ability of the body to respond to insulin.

This is called impaired glucose tolerance.

WebMD has a nice summary of the human version of the test if you would like to read more.

Second Sample - Mice Used for Faecal Microbial Transfer (FMT)

The aim with this group was to study if simply transplanting the gut bacteria from the resveratrol treated mice in the earlier groups could replicate the effects of resveratrol supplementation.

Twenty mice were fed a HFHS diet for six weeks but were NOT given any resveratrol (for obvious reasons).

They were fasted overnight before being given standardised faecal microbial transfer pellets (FMT) prepared from stool samples of donor mice (fed chow and resveratrol).

A further 2 FMTs occurred with 48 hour gaps in between, the last two being unfasted.

The mice continued their HFHS diet and were administered GTTs to see what the effects were.

Microbiome Profiling

Samples were collected from a particular part of the mice guts (cecum) following a 5-6 hour fasting period.

DNA was extracted for computer data analysis and classification.

The exact methods are described in some detail in the paper and are beyond my area of expertise.

Results

As expected the HFHS diet mice had a poorer ability to clear glucose compared to the chow fed mice as shown by glucose tolerance tests.
The HFHS mice were also more likely to be obese, with significantly higher body weight and higher amount of body fat.
Obese mice who were given resveratrol had significantly better glucose tolerance tests than those that weren't.
Resveratrol was found to alter the microbiome (community of bacteria in the guts) of obese and non obese mice.
Transplanting the altered microbiome from resveratrol fed mice to non resveratrol mice seemed to replicate the improvements in glucose control.
This suggests that a significant mechanism for how resveratrol works is by altering the microbiome.
Further in obese mice the changes in glucose metabolism did not seem to be associated with weight loss.

Discussion and Limitations

Lots of Material and Data

This study comes with a lot of supplemental material and data which is normally a good thing because it allows a more detailed review of the results and methods.

However, I wasn't able to find the raw figures which comprised some of the graphs. This may simply be because of the sheer amount of material presented making it hard to find.

Some of the graphs were also quite small and hard to read.

A simple table summary of the GTT figures for each group would have been useful.

Genetic and Microbiological Tests

In addition I am not a microbiologist or geneticist so can't really speak to the methods used in some cases e.g. in identifying bacterial types and the laboratory based analyses involved here.

I will therefore leave that up to those with the pre-requisite expertise to do and concentrate on the things I am familiar with.

Bacteroides : Firmicutes Ratio

One interesting point that did come up and that I have read of previously is the changes in relative ratio of certain bacterial types.

A quick search on Medline brings up a number of papers suggesting the link between poor diet/obesity and a lower ratio of Bacteroides to Firmicutes (as found here) both in humans and animals.

It seems that at least part of the way that resveratrol may work is by correcting such differences.

Resveratrol May Act Via Multiple Mechanisms

That does not mean it is the only way though.

It is entirely possible that there are a combination of mechanisms only one of which involves the microbiome.

It is also possible that it was not necessarily the bacteria themselves being transferred that induced the change.

It could be some unidentified metabolite (either of resveratrol or produced by the bacteria) that brought about the differences.

This could be determined more accurately using further research - for example using heat destroyed bacteria for transplantation (described at the end of the paper).

Mice Are Not Humans

Although this research is promising there is no guarantee that we would see the same results in humans.

The human and mouse gut are similar but they are not identical.

Previous studies in mice (e.g. with leptin) and other studies with resveratrol have shown that extrapolating mouse models to the human situation does not always work.

Further humans do not behave like laboratory mice.

You can't control what they eat and you also can't control their exposure to other humans (and potentially other bacteria/micro-organisms).

This may, however, provide a further avenue for exploration.

I mentioned earlier how previous research in animal models of resveratrol did not always seem to apply to humans.

It is possible that this microbiome related mechanism may be one of the hindrances to resveratrol working as effectively in human studies.

Further if this is confirmed by future research it may be possible to develop (accessory) agents which might facilitate microbiome change and allow the animal results to be replicated in humans.

Very Small Sample Size

The sample sizes used here of 40 (and 20) are tiny, particularly when you break the main group down into its subgroups of 10.

We need conformation from larger studies and repetition to establish that these results aren't the result of some sort of anomaly.

Conclusion/TLDR

Overall this study is an interesting starting point for further research into the how resveratrol might have an effect on glucose clearance/metabolism.

It confirms that (in mice at least) supplementation of the diet with resveratrol has significant benefits for glucose clearance particularly in mice who are obese and/fed a high fat high sugar diet.

This adds further evidence to support the potential use of resveratrol in treating type II diabetes and obesity.

This study also shows that at least some of the effects of resveratrol seems to relate to alterations in gut bacteria.

This is only preliminary research though.

Further research is required to replicate these results in larger sample sizes, to confirm that it is bacterial transference and not a metabolite that is responsible and also to investigate how well these findings translate to humans.

Thank you for reading

References

Sung, Miranda M., Ty T. Kim, Emmanuel Denou, Carrie-Lynn M. Soltys, Shereen M. Hamza, Nikole J. Byrne, Grant Masson, et al. 2017. “Improved Glucose Homeostasis in Obese Mice Treated With Resveratrol Is Associated With Alterations in the Gut Microbiome.” Diabetes 66 (2): 418–25.
Wikipedia contributors. 2017. “Phylum.” Wikipedia, The Free Encyclopedia. January 25. https://en.wikipedia.org/w/index.php?title=Phylum&oldid=761881252.

Resveratrol May Treat Obesity and Diabetes By Altering Gut Bacteria