Perspectives for Novel Therapies to Control Diabetes.

In 2016, obesity and related diabetes caused 1.6 million deaths worldwide. Nine percent of adults globally have diabetes (IDF Diabetes Atlas 2019) and the premature mortality rate has steadily been increasing (WHO Diabetes Report, online). Type 2 diabetes mellitus (T2DM), represents more than 90% of total cases and is widely recognized as a multifactorial disease, where endogenous and environmental factors interact. With a focus on gut microbiota, this article examines why a deeper understanding of factors influencing obesity and diabetes is needed to create, and implement, therapeutic strategies that improve patient outcomes.

Amongst the endogenous factors influencing human physiology and metabolism, gut microbiota has a profound affect on host physiological and pathophysiological processes.

Gut microbiota plays a crucial role in metabolic diseases, such as obesity, impaired glycemic control and diabetes (Aydin 2018, Harsch 2018) with some studies correlating glycemic control impairment and insulin resistance to specific gut microbiota composition. Bacteroidetes and Firmicutes, including species of the Ruminococcus, Lactobacillus, and Clostridium genera, constitute over 90% of the known phylogenetic categories and dominate the healthy intestinal microbiota (Eckburg 2005). Alterations of both composition and function of the microbiota, called “dysbiosis”, are common features of obesity and T2DM. In particular, obesity is related to lower microbial diversity and taxon depletion (Cotillard 2013, Le Chatelier 2013).

Several key molecular mechanisms that link gut bacterial populations and host glucose homeostasis, have been identified, including intestinal incretin secretion, short chain fatty acids (SCFA) production, bile acid metabolism, and adipose tissue regulation (Gérard 2019).

Incretins, a group of metabolic hormones principally represented by glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), play a pivotal role in glucose homeostasis, since they stimulate immediate insulin secretion from β-cells in response to nutrients, in order to control meal-related glycemic excursions (Drucker 2018).

Incretin secretion is compromised in individuals with obesity and T2DM. Some bacteria of the gut microflora can directly regulate incretin secretion by producing active metabolic compounds. For instance, recent studies identified that hydrogen sulfide, a bioactive gas metabolite, abundantly produced in the colon by sulfate-reducing bacteria, can stimulate intestinal GLP-1 response (Pichette 2017). Evidence suggests that the daily administration of probiotics can ameliorate glucose control, and attenuate T2DM state, by increasing incretin production. This implies that gut microbiota is essential to glycemic control via the regulation of insulin secretion (Gérard 2019).

Gut microbiota is also integral to SCFA production. SCFA are organic fatty acids produced in the colon and the caecum by saccharolytic bacteria, as a result of anaerobic fermentation of non-digestible dietary fibers. Once in circulation, SCFA are substrates for de novo lipid or glucose synthesis, thus participating to host glycemic control (Puddu 2014).

Deficiency in SCFA synthesis has been associated with diabetes pathophysiology and a study involving metagenomic analysis described a unified profile of gut microbiome dysbiosis in T2DM patients, with a notable depletion of butyrate-producing bacteria (Forslund 2015). Propionate and butyrate, two main products of the gut microbiota, have a crucial role in host glycemic control, by stimulating intestinal gluconeogenesis, a mucosal process exerting anti-diabetic and anti-obesity effects via the activation of gut-brain neural circuits improving glucose and energy homeostasis (Mithieux 2014).

Healthy gut microbiota is crucial in regulating bile acids metabolism in the host. Bile acids are powerful surface-active digestive agents that, acting as emulsifier, are essential for the digestion and absorption of lipids and fat-soluble vitamins. In addition to this, bile acids are also potent signaling molecules - mainly through their interaction with nuclear receptors and membrane G-protein coupled receptors - regulating biomolecular pathways involved in pathogenetic processes, including obesity and T2DM.

Consequently, dysregulation of bile acids metabolism could lead to biochemical dysregulations involved in diabetes pathogenesis. Bile acids are produced exclusively in the liver, secreted in the intestinal lumen, then efficiently reabsorbed by the small intestine. They are eventually returned to the liver via the portal circulation. Bile acids that are not reabsorbed enter the colon, to be transformed into secondary bile acids by the resident gut microbiota. The enzymatic activity of gut microflora makes an important contribution to the chemical diversity and heterogeneity of bile acid pool (Ramírez-Pérez 2017) and increasing evidence points to the involvement of enzymes in bile acids metabolism, such as cholesterol 7 alpha-hydroxylase, in regulating body weight, glucose tolerance and insulin resistance. Research and clinical evidence suggest that manipulation of the bile acid pool could represent a novel route to managing metabolic diseases (Li 2010).

The gut microflora is crucial in host metabolism as it affects the energy harvest from the diet and energy store, through adipose tissue regulation. In excess nutrient conditions surplus nutrients are stored as neutral lipids in adipose tissue, causing the overgrowth of adipose white mass, hyperplasia and hypertrophy, leading to a tissue stress that triggers cytokines response and inflammation. This process of chronic low-grade inflammation - denominated “metabolic endotoxemia” - actively participates in obesity, impaired glucose control, insulin resistance and ultimately leads toT2DM (Hotamisligil 2006).

Gut microbiota is important to the regulation of metabolic endotoxemia which is mediated by the inflammatory effect of bacterial lipopolysaccharide (LPS). Therapeutic strategies aimed to lower plasma LPS may be effective in controlling T2DM (Cani 2008). The supplementation of several probiotic bacterial strains, such as some species of Lactobacillus, is able to reduce metabolic endotoxemia, through the increase of anti-inflammatory molecules and inhibition of pro-inflammatory markers, such as LPS, and the promotion of white-brown adipose tissue transition. The decrease of inflammation in adipose tissues leads to attenuation of insulin resistance and hyperglycemia, that significantly improve metabolic control and attenuate diabetes (Gérard 2019).

It is clear that healthy gut microbiota is essential for the host physiology, both as support for the intestinal epithelial barrier and as a leading factor in metabolic control, critically regulating energy metabolism and inflammation.

A greater understanding of the impact of gut microbiota on host physiology, together with further clarification of the molecular mechanisms involved is needed to assist in identifying probiotic strains with specific antidiabetic activities. Improving knowledge in these areas would help prevent diabetes progression and support standard of care therapies.