Probiotics as Complementary Treatment for Metabolic Disorders

Abstract

Over the past decade, growing evidence has established the gut microbiota as one of the most important determinants of metabolic disorders such as obesity and type 2 diabetes. Indeed, obesogenic diet can drastically alter bacterial populations (i.e., dysbiosis) leading to activation of pro-inflammatory mechanisms and metabolic endotoxemia, therefore promoting insulin resistance and cardiometabolic disorders. To counteract these deleterious effects, probiotic strains have been developed with the aim of reshaping the microbiome to improve gut health. In this review, we focus on benefits of widely used probiotics describing their potential mechanisms of action, especially their ability to decrease metabolic endotoxemia by restoring the disrupted intestinal mucosal barrier. We also discuss the perspective of using new bacterial strains such as butyrate-producing bacteria and the mucolytic Akkermansia muciniphila, as well as the use of prebiotics to enhance the functionality of probiotics. Finally, this review introduces the notion of genetically engineered bacterial strains specifically developed to deliver anti-inflammatory molecules to the gut.

Keywords: Gut permeability; Insulin resistance; Metabolic disorders; Mucosal barrier; Obesity; Probiotics.

Fig. 1. Potential beneficial effects of probiotic supplementation against metabolic disorders. GPR, G protein-coupled receptor; SCFA, short-chain fatty acid; ChREBP, carbohydrate-responsive element-binding protein; SREBP, sterol regulatory element-binding protein; AMPK, AMP-activated protein kinase; ANGPTL4, angiopoietin-like protein 4; TJ, tight junction; AJ, adherens junction.

Fig. 2. Potential direct effects of probiotics to protect gut microbiota and intestinal barrier integrity. Obesogenic diet or "Western diet" alter gut microbiota population diversity and intestinal barrier integrity. Cross-talk between ingested probiotics, gut microbiota (commensal bacteria) and epithelial cells (1). Probiotics produce metabolites that could serve to increase both the diversity of commensal bacteria and the availability of nutrients used by intestinal epithelial cells (IEC). Commensal bacteria multiply and in turn, also produce metabolites that could be used by surrounding cells. In patients suffering from metabolic disorders, intestinal permeability is altered leading to an increase of low-grade inflammation and metabolic endotoxemia (2). Probiotics can increase production of tight- and adherens junction (TJ and AJ) proteins (3), improving gut permeability and inhibiting the passage of lipopolysaccharides (LPS) into systemic circulation that decreases metabolic endotoxemia. Moreover, probiotics express microorganism-associated molecular patterns (MAMPs) that could bind to host pattern recognition receptors (PRRs) located at cell surface of IEC (1) and dendritic cells (4), and induce the activation/inhibition of signaling pathways. For example (5), probiotics can stimulate dendritic cells leading to inhibition of pro-inflammatory CD4+ cell proliferation and activation of anti-inflammatory pathways (Treg and plasma cell proliferation, resulting in production of anti-inflammatory cytokines and IgA immunoglobulins (6), respectively). Mainly present in the mucus layer, IgA reinforce the protective role of mucosal barrier. Mucus production can also be increased by probiotics that stimulate goblet cells leading to activation of mucin gene expression and therefore production of mucin glycoproteins (7). Once assembled, these proteins are excreted and form the mucus layer, which acts as barrier against pathogen colonization. However, probiotics can also induce physical barrier against pathogens or produce bacteriocins that inhibits undesirable microorganism invasion (8). TLR, Toll-like receptor; NLR, NOD-like receptor; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; TGF-β, transforming growth factor β; IL-10, interleukin 10.