There are more than 2 billion overweight and obese individuals worldwide, surpassing for the first time, the number of people affected by undernutrition. Obesity and its comorbidities inflict a heavy burden on the global economies and have become a serious threat to individuals' wellbeing with no immediate cure available. The causes of obesity are manifold, involving several factors including physiological, metabolic, neural, psychosocial, economic, genetics and the environment, among others. Recent advances in genome sequencing and metagenomic profiling have added another dimension to this complexity by implicating the gut microbiota as an important player in energy regulation and the development of obesity. As such, accumulating evidence demonstrate the impact of the gut microbiota on body weight, adiposity, glucose, lipid metabolism, and metabolic syndrome. This also includes the role of microbiota as a modulatory signal either directly or through its bioactive metabolites on intestinal lumen by releasing chemosensing factors known to have a major role in controlling food intake and regulating body weight. The importance of gut signaling by microbiota signaling is further highlighted by the presence of taste and nutrient receptors on the intestinal epithelium activated by the microbial degradation products as well as their role in release of peptides hormones controlling appetite and energy homeostasis. This review present evidence on how gut microbiota interacts with intestinal chemosensing and modulates the release and activity of gut peptides, particularly GLP-1 and PYY.
The human body has been coined a superorganism for it is the host of a complex consortia of commensal microbes that contain 10-fold more cells and 150 times more genes. These trillions of microorganisms with thousands of bacterial phylotypes reside mainly in the gastrointestinal tract and are collectively termed the gut microbiota. Although its existence and importance has long been recognized, recent advancements in identification, quantification and functional properties of the gut microbes highlights its role in protection against enteropathogens, extraction of nutrients and energy from our diets, and contribution to normal immune functions. More importantly, increasing evidence suggests that the cross talk between bacteria and the host is critical in maintaining health and an imbalance (i.e., dysbiosis) has been associated with chronic disorders including obesity, diabetes, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease, malnutrition, cancer, and psychiatric disorders.
Although our understanding of how gut microbiota impacts health and disease is still evolving, the development of quantitative and functional metagenomics offers insights into the mechanisms by which bacteria affects the host in both health and disease. For example, the discovery of novel bacterial metabolites and their activities such as β-D-glucuronidases, neurotransmitters (e.g., cathecolamines) or the new roles of short chain fatty acids (SCFA) in energy balance via gut satiation peptides such as CCK, GLP-1, and PYY underscore the importance of gut bacteria in host metabolism.
In this review, we will summarize the most recent findings on the role of gut microbiota in obesity-induced microbiota imbalance. The bidirectional communication between the host and microbes influencing gut chemosensory and metabolic signaling pathways, the current challenges and emerging ideas on using bacteria to change behavior and phenotype will also be discussed.
The link between gut microbiota and production of gut peptides by enteroendocrine cells has been well documented. Enteroendocrine cells (EEC) have been widely studied for their critical role in regulating gut motility, secretion, and production of peptide hormones that control food intake as well as insulin release. Intestinal enteroendocrine cells such as L-cells are strategically positioned to detect the presence of nutrients, microbiota and their metabolites. They act via G-protein coupled receptors (GPCRs) and transporters that activate different pathways known to regulate gene expression and/or to promote exocytosis by raising intracellular Ca 2+ levels. These open-type enteroendocrine cells are present in high density in the ileum and colon, areas where the majority of bacteria reside. Therefore, there is an intimate relationship between bacteria and eneteroendocrine cells. Not surprisingly, microbiota controls enteroendocrine cells differentiation and the number of GLP- and PYY-secreting L-cells. As a result, consumption of non-digestible carbohydrates, prebiotics, direct administration of SCFAs or specific bacteria (e.g., A. muciniphila) increases L-cell numbers as well as intestinal expression and release of GLP-2 and PYY, demonstrating a role of bacteria in gene regulation and signaling. For example, ingestion of fructooligosaccharides that results in subsequent high production of luminal SCFAs increases proliferation of L-cells that express FFRA2 and GLP-1. This effect involves upregulation of Neurogenin3 (NGN3) and NeuroD, two transcription factors required for enteroendocrine cell differentiation. The interactions between microbial metabolites and specialized enteroendocrine cells have an organic, physiological, and behavioral correspondent. For example, decrease in abundance of specific bacteria such as A. muciniphila that produce bioactive metabolites with an effect on gut hormones is associated with increased gut permeability, obesity and type 2 diabetes whereas restoration of this bacteria levels reverses such effects. Further, blockade of GLP-2 receptors abrogates prebiotic-induced improvements in gut barrier functions demonstrating a causal relationship between microbiota and hormone secretion. GLP-2 receptor has been implicated in regulating intestinal epithelium integrity, and bacteria-induced increase in GLP-2 levels can protect against inflammation. Notwithstanding the absence of precise regulatory mechanisms, it is clear that bacterial metabolites are active participants in the connection between the enteroendocrine cells secretory milieu and overall host metabolic functions.
The interaction of gut microbiota is not limited to L-cells and their products. Numerous bacteria such as Lactobacillus, Bifidobacterium, Escherichia, Enterococcus, and Truchuris among others, interact with other enteroendocrine products such as serotonin and/or produce a large repertoire of their own bioactive molecules including serotonin, dopamine, gamma-aminobutyric acid (GABA), brain derived neurotrophic factor (BDNF), and norepinephrine. In fact, the enterochromaffin cells (EC) which are the most numerous cell type among the enteroendocrine cells, are the main source of serotonin. They are directly exposed to microbial products and express chemosensory receptors for a variety of microbial metabolites, including short chain fatty acids. Recent studies in humans and mice demonstrated that gut microbiota promote colonic Tph1 (tryptophan hydrolase 1, the rate limiting enzyme for 5-HT biosynthesis) expression and 5-HT production following stimulation of EC cells by SCFA, such as butyrate and acetate. Although it seems that EC cells do not express GPR41 and GPR43 receptors, treatment of human BON cells, a EC model of 5-HT synthesis, with butyrate enhanced Tph1 transcription in mice via a ZBP-89 zinc finger transcription factor involved in the secretion of antimicrobial peptides. Furthermore, it was recently reported that GLP-1 receptor is highly expressed in EC cells and stimulates 5-HT release. Along with this, colonic EC cells express increased expression of a host of other receptors sensing microbial metabolites such as FFAR2 and OLFR78 for SCFA, in line with their stimulatory effects on Tph1 expression and 5-HT synthesis; OLFR558, receptor for branched SCFA; GPBARR1/TGR5 for secondary bile acids; GPR35 for small aromatic acids, and GPR132 for lactate and acyl amides. Not surprisingly, the expression of these receptor sensing microbial metabolites were much lower in the EC cells of the small intestine where microbial flora is less abundant. As such, dietary supplementation with insoluble fiber like cellulose, significantly increased the density of EC cells as well as fecal content. Together, this data demonstrate that colonic EC cells represent a rich reservoir of specialized receptors and are well equipped to directly sense the microbiota-derived biomolecules. This could well explain why disruptions of gut microbiota have been associated with intestinal pathologies including irritable bowel syndrome and other systemic disorders. Figure 1 depicts the different known pathways implicated in PYY/GLP-1 expression and secretion in L-cells in response to luminal molecules.
It has been well established that SCFAs are the primary candidates in the crosstalk between bacteria and the host. The major SCFAs produced as a result of anaerobic bacterial fermentation of carbohydrates and proteins are acetate, propionate and butyrate. However, other SCFAs, albeit in smaller quantities, such as formate, valerate, caproate, isobutyrate, 2-methyl-butyrate, and isovalerate are also produced from the breakdown of branched-chain amino acids.
