Gut bacteria the missing link in Insulin Resistance

New research discovering the gut microbiome’s role

Insulin resistance is a key factor in the development of metabolic syndrome and type 2 diabetes. While the connection between gut microbiota and metabolic health has been established through previous studies, the specific mechanisms linking gut microbial activity to insulin resistance have remained unclear. Research from Japan employs a multi-omics approach, combining faecal metabolomics, metagenomics, host metabolomics, and transcriptomics, to provide a more comprehensive and transformative understanding of this relationship.

This recent groundbreaking study has uncovered fascinating links between the levels of specific faecal carbohydrates and insulin resistance. This research delves into the dynamics of how these carbohydrates, particularly monosaccharides, not only are absorbed by the host but also how they intertwine with the metabolic processes of gut microbiota and the triggering of inflammatory cytokines.

The study goes a step further, identifying specific gut bacteria that have distinct associations with either insulin resistance or sensitivity. Each of these bacterial groups showcases unique carbohydrate metabolic patterns, offering a window into a complex microbial world that could be key in understanding and managing insulin resistance. Perhaps most compelling is the revelation that certain bacteria, which are linked to insulin sensitivity, may actually hold the potential to mitigate insulin resistance phenotypes. Could the manipulation of the microbiome’s carbohydrate metabolism be a novel pathway to treating or even preventing insulin resistance?

Links established

A study conducted by the RIKEN Center for Integrative Medical Sciences (IMS) in Japan has provided new insights into the relationship between the gut microbiome and insulin resistance (IR). This comprehensive research combined multiple omics strategies to investigate how the metabolism of faecal carbohydrates by gut bacteria is linked to IR.

The study found a strong association between faecal carbohydrates and inflammatory responses in individuals with IR. Specifically, it observed that certain cytokines, such as IL-10, which have been shown to paradoxically contribute to IR, were closely associated with the presence of faecal carbohydrates. This suggests that these carbohydrates, produced by gut microbiota, could be key players in the inflammation seen in IR. The researchers noted that while faecal carbohydrates accounted for a smaller proportion of the variance in these cytokines compared to plasma metabolites, their impact was significant, highlighting the importance of gut-derived metabolites in the body’s inflammatory response.

Faecal carbohydrates and inflammation in IR

To explore the causal relationships between gut microbiota, faecal carbohydrates, and metabolic diseases more deeply, the RIKEN IMS team analysed metabolites in bacterial cultures from human faeces. They specifically looked at bacteria associated with insulin sensitivity (IS) and IR. They found that Bacteroidales, a bacterial order associated with IS, showed a distinct metabolic profile, characterised by the consumption of various carbohydrates and the production of certain fermentation products. This contrasted with other bacterial orders, revealing how different gut bacteria could influence host metabolism and IR.

Further, the study tested the therapeutic potential of several bacterial strains associated with IS in a mouse model. Mice administered with strains such as Alistipes indistinctus, Alistipes finegoldii, and Bacteroides thetaiotaomicron showed reduced postprandial blood glucose levels and improved IR, particularly with A. indistinctus administration. This strain also led to reduced body mass gain, lower ectopic triglyceride accumulation in the liver, and improved levels of HDL-C, adiponectin, and triglycerides. These changes were accompanied by enhanced insulin signalling in the liver and adipose tissue.

Mechanistic insights

Mechanistically, the study observed that carbohydrate oxidation was significantly reduced in mice treated with A. indistinctus, suggesting a limitation in carbohydrate usage by the host. This was associated with a substantial alteration in caecal metabolites, including a reduction in monosaccharides like fructose, which is known to be lipogenic. This reduction in caecal and serum fructose correlated with improved insulin tolerance.

By showing how specific gut bacteria and their metabolic activities can influence host metabolism and inflammatory responses, this research opens new possibilities for targeted therapeutic strategies to combat insulin resistance and related metabolic disorders.

A future of microbiome interventions

The study from Japan provides crucial insights for clinicians regarding the role of the gut microbiome in insulin resistance (IR). By employing faecal metabolomics, the research identified specific faecal carbohydrates linked to IR and low-grade inflammation. This highlights the impact of gut microbial carbohydrate metabolism, particularly excessive monosaccharides like fructose, on the development of IR through mechanisms such as lipid accumulation and immune activation.

A significant finding for clinical practice is the potential therapeutic role of specific gut bacteria, especially Alistipes strains like A. indistinctus. In mouse models, administration of these bacteria showed a reduction in lipid accumulation and improved insulin sensitivity, along with decreased intestinal monosaccharide levels. This suggests a promising avenue for novel treatments targeting the microbiome in IR.

The study, while comprehensive, acknowledges the need for further research to fully understand the mechanisms involved and the broader implications for insulin signalling in various tissues. It also underlines the importance of controlled longitudinal studies to evaluate the long-term impact of microbial metabolism on diabetes and its complications.

For clinicians, this research underscores the importance of considering the gut microbiome in the management of IR and related metabolic disorders, potentially leading to more effective and targeted therapies.

Find the full publication here: https://www.nature.com/articles/s41586-023-06466-x

akeuchi, T., Kubota, T., Nakanishi, Y. et al. Gut microbial carbohydrate metabolism contributes to insulin resistance. Nature 621, 389–395 (2023). https://doi.org/10.1038/s41586-023-06466-x