Using Gut Bacteria To Treat Diabetes

Type 2 diabetes currently affects about 462 million individuals worldwide. A multi-institutional study led by Dr. Tadashi Takeuchi at Stanford University and published in Nature, demonstrates the specific role that various species within the gut microbiota play in carbohydrate metabolism, suggesting the potential for insulin-sensitive (IS) gut bacteria to combat insulin resistance (IR) and serve as a treatment for individuals with Type 2 diabetes.

Targeting insulin resistance

IR, which is when cells are unable to respond to insulin and extract glucose from the blood, is one of the key factors responsible for the development of Type 2 diabetes. Previous studies have indicated that many species in the gut microbiota are involved in carbohydrate metabolism, which can contribute to insulin resistance when unregulated. However, Takeuchi et al. wanted to improve understanding of the roles of specific species within the gut microbiota, because, while there are IR-associated bacteria in the gut, there are also understudied IS-associated bacteria that could play a role in combating insulin resistance.

Identification of gut bacteria associated with insulin resistance and insulin sensitivity

The researchers combined unbiased fecal metabolomics with metagenomics, host metabolomics and transcriptomics data to determine the role of the microbiome in insulin resistance. They recruited 306 individuals (71% male) without diabetes, between the ages of 20 to 75 years. They were assessed for insulin resistance, which was defined as a homeostatic model assessment of IR (HOMA-IR) of at least 2.5. They analyzed metabolites in 22 human fecal IS- and IR-associated bacteria to understand which carbohydrates were consumed by each type of bacteria. They also looked for the presence of associations between fecal metabolites and metabolic syndrome (MetS), an IR-related pathology, and used two mass spectrometry (MS)-based analytical platforms to conduct untargeted metabolomics analysis. After these various tests were conducted on human-derived samples, Takeuchi et al. administered seven IS-associated bacterial strains in mice to assess their role in potentially combating IR.

The key findings from this study were that:

• Fecal metabolomics could be used to study IR pathogenesis, as many features of fecal metabolomic data were more efficient at predicting IR compared to 16S rRNA sequencing and metagenomics
• Fecal carbohydrates are increased in IR, as monosaccharides were increased in the feces of individuals with IR and MetS
• When administered to mice, Alistipes indistinctus (A. indistinctus) was able to reduce diet-induced obesity and IR, through ameliorating ectopic triglyceride accumulation in the liver and glucose intolerance

A. indistinctus as a treatment for insulin resistance

Although carbohydrate metabolism has been implicated in obesity and prediabetes before, the actual biological link has not been thoroughly studied, and Takeuchi et al.’s findings suggest that fecal metabolomics may be an efficient way to study IR pathogenesis, compared to other methods such as 16S rRNA sequencing and metagenomics. Through using metabolomics, they were able to identify fecal metabolites involved in IR. They found that excessive monosaccharides can further ectopic lipid accumulation and activate immune cells, leading to a host inflammatory response and increased IR. However, the team found that A. indistinctus administration in mice was able to improve lipid accumulation and alleviate IR, thereby suggesting the role that IS-associated bacteria could play in treating IR.

In order to improve understanding of how to treat patients with IR, it is important to understand the interactions that occur between the gut microbiome, the immune system and nutrients that are fed to the body on a daily basis. By utilizing metabolomics, Takeuchi et al. were better able to understand the role that fecal carbohydrates play in the development of IR. Additionally, they realized the role that gut bacteria could hold in reducing IR, which suggests the potential for probiotics to be a therapy for patients with Type 2 diabetes.

Further experimentation is required to understand the mechanisms of A. indistinctus absorption and the specific ways in which it affects host metabolism, such as further examining how they suppress carbohydrate metabolism. Additionally, it would be important to assess how insulin signaling occurs in not only the liver, but also peripheral tissues, such as skeletal tissue and adipose tissue, to improve understanding of the whole-body impact of therapeutics that could potentially treat IR.

The need for longitudinal studies

This study shows promise in better understanding the role that microbial metabolism plays in the development and course of insulin resistance in patients with Type 2 diabetes. Not only does it reveal new ways to study insulin resistance, but it also demonstrates the potential that IS-associated probiotics could have in treating people with diabetes. However, the next step is to conduct a longitudinal study in order to determine the role of microbial metabolism in patients with diabetes in the long-term and thereby inform scientists on the development of long-lasting therapies to combat insulin resistance.

Reference: Takeuchi T, Kubota T, Nakanishi Y, et al. Gut microbial carbohydrate metabolism contributes to insulin resistance [published online ahead of print, 2023 Aug 30]. Nature. 2023. doi:10.1038/s41586-023-06466-x

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