Gut microbiota, enteroendocrine functions and metabolism

Highlights

• The gut microbiota interacts with enteroendocrine cells.

• SCFAs triggers gut peptide secretion through GPR43-dependent and GPR41-dependent mechanisms.

• The gut microbiota links the endocannabinoid system to L cell functions.

• A. muciniphila interacts with enteroendocrine cells to modulate gut barrier function.

• Several GPCRs expressed on intestinal L cells may constitute putative therapeutic targets.

The gut microbiota affects host metabolism through a number of physiological processes. Emerging evidence suggests that gut microbes interact with the host through several pathways involving enteroendocrine cells (e.g. L cells). The activation of specific G protein coupled receptors expressed on L cells (e.g. GPR41, GPR43, GPR119 and TGR5) triggers the secretion of glucagon-like peptides (GLP-1 and GLP-2) and PYY. These gut peptides are known to control energy homeostasis, glucose metabolism, gut barrier function and metabolic inflammation. Here, we explore how crosstalk between the ligands produced by the gut microbiota (short chain fatty acids, or SCFAs), or produced by the host but influenced by gut microbes (endocannabinoids and bile acids), impact host physiology.

Introduction

Obesity is associated with numerous metabolic comorbidities, such as insulin resistance, diabetes, cardiovascular disease and non-alcoholic fatty liver disease. The reduction of excessive body weight is effective for alleviating many of these metabolic abnormalities; however, the prevention of positive energy balance remains a widely practised cornerstone of obesity-prevention strategies [1]. Therefore, more effective weight loss induction strategies are needed to decrease the incidence and severity of metabolic abnormalities. Alternatively, approaches that can treat obesity-related metabolic abnormalities independent of weight loss are extremely attractive. Recent data indicate that certain microbes may provide templates for the development of such strategies (reviewed in [2, 3]). Over the years, the understanding of the role of these cells (i.e. gut bacteria) has changed, leading to novel and interesting findings. The gut microbiota has profound impacts on host physiology, including in the control of energy homeostasis, the immune system, vitamin synthesis and digestion [4, 5, 6•].

Owing to its huge surface area and multiple functions, the intestine represents one of the most important organs, and it permits vital interactions with the external world, including the gut microbiota. The intestinal epithelium allows the absorption of nutrients and fluids while acting as an efficient barrier against toxins and microorganisms. The gut epithelium is comprised of different cell types, including epithelial absorptive cells, Goblet cells, Paneth cells and enteroendocrine cells. Enteroendocrine cells represent approximately 1% of all epithelial cells in the intestine and are subdivided into more than 10 different cell types based on their major secretory products and their localisation along the gastrointestinal tract. Given that multiple biological functions are physiologically regulated by the gut hormones produced by enteroendocrine cells (e.g. food intake, gastric emptying, gut motility, gut barrier formation, glucose metabolism) (Figure 1), these cells have been positioned at the forefront of research to find novel therapies. The enteroendocrine cells play key roles in the maintenance of gut homeostasis both by enabling nutrient absorption and by preserving the essential function of the gut as a barrier between the external environment (gut lumen) and the host tissues. Because enteroendocrine cells are distributed all along the gastrointestinal tract and are in close proximity to gut bacteria and/or metabolites produced by the metabolic activity of the gut microbiota, it is of utmost interest to unravel the crosstalk between the gut microbiota and these cells and the impact of this crosstalk on host physiology (Figure 1). However, the study of the gut microbiota and its relationship with the host represents a real challenge. Among the enteroendocrine cells, L cells have attracted particular interest because of the pleiotropic effects of their secreted peptides [7, 8, 9]. Although these cells are known to respond to nutrients present in the intestinal lumen, they are also able to detect many other luminal compounds. This is especially true in the colon, where the gut microbiota and most of its metabolites are largely present.

In this review, we discuss the body of evidence linking gut microbes (and specific metabolites produced by these bacteria) with enteroendocrine function and thereby host physiology.