Therapeutic Potential of Butyrate for Treatment of Type 2 Diabetes

Abstract

Metagenomics studies have shown that type 2 diabetes (T2D) is associated with an altered gut microbiota. Whereas different microbiota patterns have been observed in independent human cohorts, reduction of butyrate-producing bacteria has consistently been found in individuals with T2D, as well as in those with prediabetes. Butyrate is produced in the large intestine by microbial fermentations, particularly of dietary fiber, and serves as primary fuel for colonocytes. It also acts as histone deacetylase inhibitor and ligand to G-protein coupled receptors, affecting cellular signaling in target cells, such as enteroendocrine cells. Therefore, butyrate has become an attractive drug target for T2D, and treatment strategies have been devised to increase its intestinal levels, for example by supplementation of butyrate-producing bacteria and dietary fiber, or through fecal microbiota transplant (FMT). In this review, we provide an overview of current literature indicating that these strategies have yielded encouraging results and short-term benefits in humans, but long-term improvements of glycemic control have not been reported so far. Further studies are required to find effective approaches to restore butyrate-producing bacteria and butyrate levels in the human gut, and to investigate their impact on glucose regulation in T2D.

Keywords: butyrate; metabolic disease; microbiota; short chain fatty acids (SCFAs); type 2 diabetes (T2D).

Figure 1

Several independent metagenomics studies have detected a decrease of butyrate producers in stools from individuals with prediabetes and type 2 diabetes (T2D) compared to individuals with normal glucose tolerance (NGT). While the loss of butyrate producers is robust and associated also with obesity and other cardiometabolic comorbidities (18), consistent patterns for increased microbial features have not been found, possibly due to the redundancy of the gut microbiota and stochasticity in gut microbiota alterations (30); only few gut microbiota species (mostly opportunistic pathogens) have been observed as increased in a limited number of studies. Thus, butyrate and butyrate producers have been selected as potential targets for the development of novel therapeutic strategies for T2D, such as direct butyrate administration, administration of butyrate producers and/or bacteria able to promote intestinal butyrate production [probiotics and next-generation probiotics (NGPs)], interventions with dietary fibers and fecal microbiota transplant (FMT).

Figure 2

Dietary fiber is fermented by the gut microbiota to produce short chain fatty acids, including butyrate. Butyrate is efficiently absorbed by colonocytes and is utilized as energy source. Butyrate-mediated activation of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) induces β-oxidation and consumption of oxygen, thus facilitating the establishment of anaerobic conditions that are required for the growth and function of several anaerobic gut commensals (57). In the specialized enteroendocrine cell (EEC), butyrate binds free fatty acid receptors (FFAR) FFAR2 and FFAR3 and regulates gut hormone release (73). Butyrate also acts as histone deacetylase (HDAC) inhibitor to regulate gene expression in EEC (76) and enterocytes (63). After absorption and utilization by colonocytes, the residual butyrate is first drained into the portal circulation, and then into the peripheral systemic circulation (29). In the systemic circulation, butyrate may regulate thermogenesis in brown adipose tissue (66) and β-cell function in pancreas (82).