Microbiota and Diabetes Mellitus: Role of Lipid Mediators

Abstract

Diabetes Mellitus (DM) is an inflammatory clinical entity with different mechanisms involved in its physiopathology. Among these, the dysfunction of the gut microbiota stands out. Currently, it is understood that lipid products derived from the gut microbiota are capable of interacting with cells from the immune system and have an immunomodulatory effect. In the presence of dysbiosis, the concentration of lipopolysaccharides (LPS) increases, favoring damage to the intestinal barrier. Furthermore, a pro-inflammatory environment prevails, and a state of insulin resistance and hyperglycemia is present. Conversely, during eubiosis, the production of short-chain fatty acids (SCFA) is fundamental for the maintenance of the integrity of the intestinal barrier as well as for immunogenic tolerance and appetite/satiety perception, leading to a protective effect. Additionally, it has been demonstrated that alterations or dysregulation of the gut microbiota can be reversed by modifying the eating habits of the patients or with the administration of prebiotics, probiotics, and symbiotics. Similarly, different studies have demonstrated that drugs like Metformin are capable of modifying the composition of the gut microbiota, promoting changes in the biosynthesis of LPS, and the metabolism of SCFA.

Keywords: diabetes; dysbiosis; inflammation; lipopolysaccharides; microbiota; short-chain fatty acids.

Figure 1

Modification of the intestinal barrier permeability. Dysbiosis, as a result of high fat intake, leads to a higher concentration of lipopolysaccharides (LPS). When LPS interacts with toll-like 4 receptors, a signaling cascade is triggered, which results in a decrease of binding proteins and, therefore, an increase in gut permeability. The resulting endotoxemia generates changes in the immune response of the host, favoring a pro-inflammatory state in different organs and tissues, which can lead to the development of metabolic diseases, such as Diabetes Mellitus. Abbreviations: CD14: Cluster of differentiation 14; TIRAP: Toll-Interleukin-1 receptor domain-containing adapter protein; MyR88: Myeloid Differentiation Gene 88; IRAK: Interleukin 1 Receptor Associated Kinase.

Figure 2

Main microorganisms seen in patients with DM2 and their potential role. DM represents a model of the wide heterogeneity of microbiome in humans and the poor role played by the Firmicutes/Bacteroidetes ratio as a gut microbiome homeostasis marker in certain diseases. In this particular case, the Bifidobacterium and Bacteroidetes genres are the main groups of microorganisms present in DM2 patients. Although they have potential antagonist functions, these have not been completely elucidated. Abbreviations: DM: Diabetes mellitus; Treg: Regulatory T Cells; CDs: Dendritic Cells; Th17: T Helper 17 Lymphocytes.

Figure 3

Potential regulation of hunger perception and satiety. In dysbiosis SCFA production, specifically, acetate allows the activation of the parasympathetic nervous system, which increases ghrelin secretion and, therefore, hyperphagia. It also enables the secretion of insulin, favoring the development of obesity, hyperlipidemia, and insulin resistance. Abbreviations: SCFA: short-chain fatty acids; GLP1/2: glucagon-like peptide 1/2; PPY peptide tyrosine.