The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities

Abstract

The totality of microbial genomes in the gut exceeds the size of the human genome, having around 500-fold more genes that importantly complement our coding potential. Microbial genes are essential for key metabolic processes, such as the breakdown of indigestible dietary fibres to short-chain fatty acids, biosynthesis of amino acids and vitamins, and production of neurotransmitters and hormones. During the last decade, evidence has accumulated to support a role for gut microbiota (analysed from faecal samples) in glycaemic control and type 2 diabetes. Mechanistic studies in mice support a causal role for gut microbiota in metabolic diseases, although human data favouring causality is insufficient. As it may be challenging to sort the human evidence from the large number of animal studies in the field, there is a need to provide a review of human studies. Thus, the aim of this review is to cover the current and future possibilities and challenges of using the gut microbiota, with its capacity to be modified, in the development of preventive and treatment strategies for hyperglycaemia and type 2 diabetes in humans. We discuss what is known about the composition and functionality of human gut microbiota in type 2 diabetes and summarise recent evidence of current treatment strategies that involve, or are based on, modification of gut microbiota (diet, probiotics, metformin and bariatric surgery). We go on to review some potential future gut-based glucose-lowering approaches involving microbiota, including the development of personalised nutrition and probiotic approaches, identification of therapeutic components of probiotics, targeted delivery of propionate in the proximal colon, targeted delivery of metformin in the lower gut, faecal microbiota transplantation, and the incorporation of genetically modified bacteria that express therapeutic factors into microbiota. Finally, future avenues and challenges for understanding the interplay between human nutrition, genetics and microbial genetics, and the need for integration of human multi-omic data (such as genetics, transcriptomics, epigenetics, proteomics and metabolomics) with microbiome data (such as strain-level variation, transcriptomics, proteomics and metabolomics) to make personalised treatments a successful future reality are discussed.

Keywords: 16S sequencing; Faecal microbiome; Genetics; Glycaemic control; Gut microbiome; Metagenomics; Metformin; Personalised nutrition; Probiotics; Review; Type 2 diabetes.

Fig. 1

The gut microbiome as a prevention and treatment target for hyperglycaemia in type 2 diabetes: current evidence from human studies and future possibilities. Research has aimed to investigate how host genetics and internal and external environmental exposures (e.g. diet, medication, surgery) affect the gut microbiota, and how this information, along with information on gut bacterial composition, may be used to develop prevention and treatment strategies for personalised medicine in type 2 diabetes. Current human evidence has revealed that individuals with type 2 diabetes have a slightly altered overall bacterial composition, including decreased abundance of butyrate-producing bacteria and those with prediabetes/type 2 diabetes have a decreased abundance of A. muciniphila. Furthermore, in individuals with insulin resistance, serum BCAAs are shown to be elevated in insulin resistance and gut microbiota are thought to be a significant contributor, with P. copri and B. vulgatus being the main producers of BCAAs. Interestingly, glucose-lowering treatments, such as metformin, can alter overall bacterial composition e.g. by increasing abundance of Lactobacillus and Escherichia species. Diet has also been shown to cause short- and long-term alteration in gut microbial richness and composition. For example, high fibre intake increases Prevotella abundance. However, response to diet is varied, with some individuals being non-responders to dietary interventions. In line with this, gut microbial composition may provide a tool for the identification of individuals who are expected to benefit from dietary interventions. Further, evidence from bariatric surgery suggests that its effects on bacterial composition in the gut may contribute to the BMI-independent effects on glucose metabolism after surgery. Together, these findings open doors for novel future possibilities for the prevention and treatment of type 2 diabetes; however, the implementation of these is associated with many challenges. For example, a personalised nutrition approach (a synergistic approach involving diet, probiotics and microbiota) may be developed to improve glycaemic control. However, prior to implementing this strategy, there is a need for prospective follow-up studies, studies investigating the influence of habitual dietary intake on responsiveness to personalised nutrition, and large long-term randomised controlled trials (RCTs) to investigate single vs multiple probiotic strain effects and the use of probiotics as adjuncts to glucose-lowering drugs. Targeted colonic delivery of SCFAs may also be used to beneficially alter glycaemic control, without the need for high consumption of indigestible fibres (and for responsive gut microbiota, which may not be available in diabetes). In line with this, targeted delivery of propionate has been shown to decrease energy intake and improve glucose metabolism, making this a promising approach. Pasteurised probiotics provide another potential therapy in diabetes; these enable use of oxygen-sensitive anaerobic bacteria in diabetes treatment. For example, pasteurised A. muciniphila has been shown to improve glucose metabolism in mice. However, human studies are needed. Likewise, genetically modified bacteria can be designed to express therapeutic factors and incorporated into the microbiota. For example, L. Lactis (a ‘safe’ bacteria) has been genetically modified to produce GLP-1 and, hence, improve glucose metabolism in mice; however, human studies are lacking. Finally, FMT has been shown to be effective in the treatment of severe forms of C. difficile infection (for which there are high mortality rates if not treated). However, evidence is required to ensure that it can be used to improve glycaemic control in diabetes and that the potential risks of this therapeutic approach can be eliminated