Multiomics Peers into Gut Microbiome, IDs Bacteria with Role in Insulin Resistance

It is widely adopted that tweaking the composition of our gut microbiomes provides health benefits. Indeed, this is the idea driving the (multi-billion-dollar) probiotic industry. However, identifying which bacteria may alleviate which ailment is research that is still in its infancy.

Now, researchers from the RIKEN Center for Integrative Medical Sciences (IMS) in Japan have identified gut bacteria that might help improve insulin resistance, and thus protect against the development of obesity and type 2 diabetes. To do this, they took a comprehensive multi-omics approach using human fecal microbiomes.

This work is published in Nature in the paper, “Gut microbial carbohydrate metabolism contributes to insulin resistance.”

What role do bacteria play in insulin resistance? Our gut microbiome breaks down the carbohydrates from food, creating a link between this process and obesity and pre-diabetes. However, the association has remained unclear because of the diversity of bacteria in the gut microbiome and lack of metabolic data.

Now, Hiroshi Ohno, MD, PhD, team leader at RIKEN and his team have filled in some of the gaps with this new study which takes an unbiased approach—combining the analysis of fecal metabolomics with metagenomics, host metabolomics, and transcriptomics data to profile the involvement of the microbiome in insulin resistance. Their method led to the discovery of a type of bacteria that might help reduce insulin resistance.

First, they examined metabolites in the feces of over 300 adults at their regular health checkups. They compared this metabolome with the insulin resistance levels obtained from the same people. “We found that higher insulin resistance was associated with excessive carbohydrates in the fecal matter,” said Ohno, “especially monosaccharides like glucose, fructose, galactose, and mannose.”

More specifically, they found that fecal carbohydrates, particularly host-accessible monosaccharides, “are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines.”

People with higher insulin resistance contained more bacteria from the taxonomic order Lachnospiraceae than from other orders. Additionally, microbiomes that included Lachnospiraceae were associated with excess fecal carbohydrates. Thus, a gut microbiota dominated by Lachnospiraceae was related to both insulin resistance and feces with excessive monosaccharides. At the same time, insulin resistance and monosaccharide levels were lower in participants whose guts contained more Bacteroidales-type bacteria than other types.

In characterizing the gut microbiota of the study participants and their relationship with insulin resistance and fecal carbohydrates, they “show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model.”

They then set out to see the direct effect of bacteria on metabolism in culture and then in mice. In culture, Bacteroidales bacteria consumed the same kinds of monosaccharides that were found in the feces of people with high insulin resistance, with the species Alistipes indistinctus consuming the greatest variety. In obese mice, the team looked at how treatment with different bacteria affected blood sugar levels. They found that A. indistinctus lowered blood sugar and reduced insulin resistance and the amount of carbohydrates available to the mice.

These results were compatible with the findings from human patients and have implications for diagnosis and treatment. As Ohno explained, “Because of its association with insulin resistance, the presence of gut Lachnospiraceae bacteria could be a good biomarker for pre-diabetes. Likewise, treatment with probiotics containing A. indistinctus might improve glucose intolerance in those with pre-diabetes.”

Although most over-the-counter probiotics do not currently contain the bacteria identified in this study, Ohno urges caution should they become available. “These findings need to be verified in human clinical trials before we can recommend any probiotic as treatment for insulin resistance.”