Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota

Abstract

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut-brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.

Keywords: CCK; GLP-1; Gut microbiome; PYY; Satiation; Satiety; Short-chain fatty acid; Small intestine.

Fig. 1

Gut–brain communication through gut peptides. Gut peptides are released from enteroendocrine cells in response to preabsorptive nutrients and act to relay information regarding incoming energy to the brain. Once released into the subcellular space, gut peptides can act locally on gut peptide receptors expressed on vagal or spinal afferent nerve terminals innervating the gut to activate gut–brain neuronal signaling. Gut peptides might also act indirectly via receptors on intrinsic neurons of the enteric nervous system to relay neuronal signaling to afferent nerves. In contrast, gut peptides can diffuse into the systemic circulation or lymphatics to eventually reach the brain and act on central receptors in an endocrine fashion

Fig. 2

Potential influences of the gut microbiota on host gut–brain axis. The gut microbiota has been associated with changes in anorexigenic and orexigenic peptide levels in the brainstem and hypothalamus, as well as with changes in motor control, memory, and anxiety behavior, while the development and activity of the ENS has been shown to be affected by an altered or absent gut microbiota. In addition, the gut microbiota has been associated with changes in EEC differentiation, expression of nutrient receptors, the expression and release of gut peptides, and activation of EECs via SCFAs. CNS central nervous system, ENS enteric nervous system, EEC enteroendocrine cell, SCFA short-chain fatty acid

Fig. 3

Effects of an altered gut microbiome on the gut–brain axis potentially contributing to obesity. High fat feeding can alter host gut microbiota to impair gut–brain axis signaling pathways described within the current review, which can lead to increased food intake and weight gain. Detailed are the currently known mechanisms through which the gut microbiota can negatively impact the gut–brain axis control of energy homeostasis, such as changes in both nutrient sensing and gut peptide response, production of bacterial metabolites, namely SCFAs, and via increased intestinal permeability and metabolic endotoxemia. Numerous other mechanisms likely exist but remain to be further explored. Furthermore, perturbations in early life development or use of antibiotics may lead to an aberrant gut microbiota that can promote similar harmful physiological changes. EEC enteroendocrine cell, LPS lipopolysaccharide, SCFA short-chain fatty acid