Probiotic does not restore gut microbiota function in patients with metabolic syndrome

Insulin resistance may increase the risk for metabolic syndrome

Metabolic syndrome is a condition that often leads to diabetes, heart disease, and even stroke and obesity, a chronic worldwide epidemic is a leading cause of metabolic syndrome (MetS).  It has also been shown that the microbiome may be an important factor in the development of obesity and subsequently, MetS, possibly due to its impact on gut barrier integrity and inflammation. While probiotics have been used as an intervention in several animal studies on obesity and MetS, there have not been sufficient results in humans to show it is having a positive effect.

Despite significant amounts of research, the question still remains if probiotics are having a lasting effect on the gut when administered. It is not clear if taking a probiotic is colonizing in the gut or if it is only providing an acute response during the timeframe it is being administered. A team of scientists published their work showing the effect that Lactobacillus casei Shirota (LcS) had on patients with MetS. The researchers administered LcS to 13 patients with MetS and 15 individuals received no LcS. They sequenced their microbiota composition from stool samples and compared it to healthy controls.

They found that LcS did not have an impact on Bacteroidetes/Firmicutes ratio and that it was slightly higher in the healthy controls. Serum bile acids were similarly not affected by LcS administration. While they did see small microbiota changes, LcS was not able to change the Bacteroidetes/Firmicutes ratio or gut barrier dysfunction, two important staples of metabolic syndrome.

While the small sample size of the patient cohorts may have been a factor in the failure to observe microbiota changes after probiotic administration, it was still important to see that probiotics may not always have the intended consequences we are seeking. In this study, probiotic administration did not provide a benefit to the Metabolic syndrome patients and further studies will be needed to better understand the microbiome implications of probiotics.

There are important differences in the gut mucus of germ free and conventionally raised mice

Mucus is not just produced by snails.

The mucus lining of our intestines are the critical interface between the microbiome and the epithelial cells that make up the intestines.  It provides many essential roles in its interaction with the microbiome, but perhaps most importantly it is a physical barrier that separates microbiome bacteria from the vasculature.  Without it, bacteria can elicit an immune response which results in inflammation that is characteristic of IBDs.  New research out of Sweden shows how mucus changes over time as the result of microbiome colonization.  The results were published in the journal Cell Host and Microbe last week.

The researchers undertook a number of experiments whereby they measured the mucus in germ free and conventionally raised mice.  In general, the conventionally raised mice had thinner, more easily shed mucus in their small intestines that allow for diffusion of nutrients.  This mucus contained antimicrobial peptides that prevented bacteria from passing across it.  The conventional mice’s large intestines’ mucus was thick and stiff and impenetrable to bacteria.  This mucus maintained most of its properties even after the conventionally raised mic were treated with antibiotics.  On the other hand, the germ free mice had thin and stiff mucus in their small intestines, as well as thick, but easily penetrable mucus in their large intestines.  This shows that the conditions under which the mucus develops is important to its eventual structure and function.  After, the scientists inoculated some of the germ free mice with the microbiome of the conventional mice and monitored the mucus over time.  It took an entire 6 weeks for the mucus to finally resemble the mucus of a conventionally raised mice.  In addition, the scientists looked that the glycans that were being formed in the mucus, and also noticed differences between the germ free and conventional mice.  As discussed on this blog previously, these glycans can be important in determining which bacteria colonize the gut.  To that end, the researchers measured the microbiome in the mice and discovered that conventional mice had a higher Firmicutes to Bacteroidetes ratio compared to germ free mice.  In addition, even after the germ free mice had been inoculated with the new bacteria, their microbiomes never truly matched the conventionally raised mice’s.

More than anything, this paper shows us the critical importance that mucus plays in microbiome health, science and research.  It demonstrates the importance of an early life microbiome to the maturation of a healthy mucus that can properly regulate the microbiome.  It also shows a possible negative consequence of antibiotics or dietary compounds can have on the mucus, and by extension the microbiome.  Finally, among many other things, it shows that microbiome research should consider the effect of the mucus on their experiments, especially ones involving germ free mice. 

Eating more vegetables appears to improve microbiome-mediated health indicators

There are many diets that have been rigorously shown to decrease metabolic syndrome (obesity, diabetes, etc.) and are generally associated with a healthy lifestyle, such as vegetarian, vegan, and Mediterranean diets.  The one thing they share in common is a high consumption of plant material, and a low consumption of meat.  There are mechanistic reasons for why high veggie - low fat diets should improve health, and many researchers now believe this is partly due to the gut microbiome that these diets create.  In order to help demonstrate the microbiome-mediated health benefits of a high vegetable – low meat diet, a team of researchers from Italy recently measured the microbiome and specific metabolites produced by the microbiome in 153 individuals.  They then compared these results with the diet that the individual had consumed prior to the measurements, and confirmed that these ‘healthy’ diets were creating ‘healthy’ microbiomes.  They published their results in the journal Gut.

The scientists asked 51 vegans, 51 vegetarians, and 51 ominivores individuals to self-declare their eating habits over the past seven days, and then sampled their stool and urine for bacteria and metabolites.  They learned that amongst the different types of diet the individuals’ overall microbiome diversities were relatively similar.  However, they did show that Bacteroidetes were more prevalent in vegetarians and vegans than in ominvores, and that a higher Firmicutes to Bacteroidetes ratio existed in the guts of ominvores than in vegans and vegetarians.  In addition, the abundance of Prevotella, which is normally associated with health, was positively correlated with overall vegetable intake, and on the contrary Ruminococcus was negatively associated with a high vegetable diet.

The scientists also measured specific metabolites in the individuals.  They discovered that short chained fatty acids (SCFAs), which are normally implicated with health, were associated with the consumption of fruits, vegetables, and legumes.  In addition, there were positive associations between SCFAs and specific populations of bacteria, such as Prevotella.  On the other hand, the metabolite trimethylamine oxide (TMAO), which is a microbiome metabolite whose concentration is directly related to atherosclerosis and other diseases, was significantly lower in vegetarian and vegan diets compared to omnivore diets. It was also directly associated with the abundance of the aforementioned Ruminococcus. 

These relationships between SCFAs and veggies are unsurprising, because SCFAs are the byproducts of bacteria breaking down the complex glycans found in fiber.  In addition, the TMAO is produced by gut bacteria from carnitine and choline, two molecules that exist in red meat and eggs, among other things.  Regardless though, this study should remind us that our diet can shape our microbiome and have lasting health effects.  This study only reinforces that a diet high in veggies that feeds the microbiome is probably a healthy choice.

Fish oil may be important to altering the microbiome, reducing anxiety

Last week we published a blog on the gut-brain axis, and the various associations between brain health and the gut microbiome.  One of the ailments we discussed was depression, which is often studied in mice by inducing early life stress on the mice.  One way to do this is by separating mice from their mothers for hours at a time at a young age.  The Maternal Separation model, as it is known, causes stress and anxiety in these mice, but more importantly, research has shown that it creates a dysbiosis of their gut microbiomes as well.  Many scientists believe the dysbiosis may be implicated in causing some of the stress phenotypes, and so reversing this dysbiosis could have therapeutic value.  Researchers from the University College Cork, in Cork Ireland, experimented with N-3 polyunsaturated fatty acids (PUFAs), like those found in fish oil, in these maternally separated mice, and found they may be important to preventing the dysbiosis.  They published their findings in the journal PLoS ONE.

In the study, the researchers separated mice into two groups, one underwent maternal separation, and the other had a normal upbringing.  Within each group the mice were separated into two more groups, one that received fish oil supplements and the other that didn’t.  Over the course of 17 weeks each groups’ feces were sampled for their microbiomes.  The Maternal separation tended to decrease the bacteroidetes to firmicutes ratio of the mice’s microbiome, which has previously been linked to depression in humans.  Interestingly, supplementation with the fish oil increased this ratio in those maternally separated mice.  In addition, the fish oil also increased the concentration of bacteria that were higher in non-separated mice, such as populations of Rikenella.  Finally, the fish oil increased the amount of butyrate producing bacteria, and as we have seen many times before, butyrate and other short chained fatty acids (SCFAs) are often associated with health.

Overall this study showed that fish oil shifted stressed mice’s microbiome to a more natural state, presumably helping them in the process.  While the scientists did not directly measure stress levels in these mice to support the microbiome connection, hopefully that will be part of a follow up study.  The scientists noted that fish oil is clinically shown to reduce inflammation, and made it a point to connect the stress in the mice to systemic inflammation.  Systemic inflammation is also mediated by the microbiome.  Indeed, people that have inflammation from IBD, for example, do tend to have more stress and anxiety.  In the end, fish oil could make for an interesting prebiotic to shift the microbiome, counteract inflammation, and improve mental health.