Gut Hormones in Microbiota-Gut-Brain Cross-Talk
The homeostasis of the gut-brain axis has been increasingly recognized as a critical factor influencing both physiological and psychological health. The gut hormones, released by enteroendocrine cells (EECs) scattered throughout the gastrointestinal tract, serve as essential signaling molecules within this axis. The interplay between gut microbiota and gut hormones has gained significant attention in understanding gut-brain cross-talk. Gut microbiota plays a pivotal role in modulating a range of diseases related to the gut-brain axis, from gastrointestinal disorders to psychiatric conditions. Similarly, gut hormones have multifaceted roles in maintaining health and are key signals in the gut-brain axis. Importantly, gut microbiota can influence the release and functions of these hormones. This review explores the role of gut microbiota in the gut-brain axis, focusing on how microbiota-related gut hormones modulate various physiological functions. Future research may target the microbiota-hormones-gut-brain axis to develop novel therapeutics for psychiatric and gastrointestinal disorders such as obesity, anxiety, and depression.
Introduction
Recent preclinical and clinical studies have highlighted the bidirectional interactions within the gut-brain axis. The brain exerts a profound influence on the gastrointestinal tract, and vice versa. Disruptions in this reciprocal interaction can lead to various conditions, including inflammatory disorders, abnormal stress responses, altered behaviors, and metabolic disturbances. However, the mechanisms underlying these conditions remain incompletely understood.
Advances in sequencing technology and bioinformatics have propelled the fields of microbiology and neuroscience, revealing the gut microbiota’s essential role in the development of numerous diseases, from gastrointestinal disorders to psychiatric conditions. Although the mechanisms of gut-brain interactions are not fully resolved, the concept of the gut-brain axis has become increasingly relevant as gut microbiota significantly influences the central nervous system (CNS). Similarly, gut hormones, produced and secreted by EECs, have a wide range of targets and play crucial roles in maintaining health. These hormones coordinate with nutrient-related signals in the gut, releasing various hormones that signal to the CNS. While traditionally associated with appetite and food intake regulation, recent studies suggest that gut hormones are also involved in inflammation and brain disorders such as anxiety and depression. Interestingly, the functions of EECs are modulated by gut microbiota, which influences the release of hormones like cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide. The interactions between microbiota and EECs may explain the complex communication between the gut and the brain, offering new therapeutic strategies for gut-brain axis-related disorders.
Microbiota-Gut-Brain Axis
The gut and brain communicate to regulate health and disease through the gut-brain axis. The CNS modulates intestinal function via the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS). Stressful experiences dysregulate the HPA axis, stimulating the release of signaling molecules like norepinephrine, catecholamines, serotonin (5-HT), and cytokines. These molecules, released by neurons, enterochromaffin cells, and immune cells, affect the composition and function of gut microbiota. For instance, norepinephrine, which increases after stress, can stimulate the proliferation of enteric pathogens. The ANS also influences gut microbiota through parasympathetic and vagal outputs, which modulate gut motility, permeability, acid secretion, and immune response. These changes affect the enteric environment, influencing microbial colonization in the small intestine and colon.
The CNS receives constant neural and chemical signals from the gut, integrating this information to generate appropriate responses that maintain homeostasis. The gut modulates CNS functions primarily through the immune system, neurotransmitters, and ANS, involving the vagus nerve, enteric nervous system, enteroendocrine signaling, and metabolites from gut microbiota. For example, the vagus nerve, which connects the gut and brain, detects specific stimuli from the gut and transmits these signals to the brain.
Growing evidence suggests that microbiota significantly impacts the CNS. Germ-free (GF) mice or those treated with broad-spectrum antibiotics exhibit altered neurophysiology and behaviors compared to conventional mice, underscoring the critical role of gut microbiota in the gut-brain axis. Neurological diseases, including neurodegenerative disorders, epilepsy, autism, and Parkinson’s disease, are associated with gut microbiota dysbiosis. Fecal microbiota transplantation (FMT) from patients with major depressive disorder or schizophrenia into GF mice induces depression-like or schizophrenia-relevant behaviors, respectively, supporting the link between microbiota and brain function.
Gut microbiota affects the brain through various molecules, including neurotransmitter homologs and metabolites. These molecules can interact with receptors on host cells, affecting nerve endings, immune cells, or EECs, or they can cross the intestinal and blood-brain barriers to directly influence the brain.
Neuroactive Substances and Microbiota-Derived Metabolites
Neuroactive substances like 5-HT, gamma-aminobutyric acid (GABA), and tryptophan metabolites play crucial roles in CNS modulation. Interestingly, gut microbes can synthesize and release these molecules. For example, Candida and Escherichia can produce 5-HT from tryptophan, while Bacillus can produce dopamine. Although these microbial neurochemicals cannot cross the blood-brain barrier, they may influence brain function by acting on the enteric nervous system.
Microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) and tryptophan metabolites, also exert central effects. SCFAs, produced by the fermentation of carbohydrates, include acetate, propionate, and butyrate. These metabolites play roles in glucose homeostasis, food intake reduction, and lymphocyte function modulation, acting through G-protein-coupled receptors (GPCRs) or as epigenetic modulators. For instance, GPCRs like GPR41 and GPR43 allow SCFAs to influence the nervous system and energy expenditure in tissues like adipose, muscle, and liver.
Tryptophan metabolism by gut microbiota produces indole derivatives, which activate the aryl hydrocarbon receptor (AHR) and play roles in immune regulation and mucosal barrier maintenance. Species like Lactobacillus reuteri and Lactobacillus johnsonii provide indole derivatives from dietary tryptophan, influencing T cell differentiation and inflammation, which are critical in CNS diseases like Parkinson’s and Alzheimer’s.
Microbiota-Derived Products
Microbiota-derived products like lipopolysaccharide (LPS), LPS binding protein (LBP), peptidoglycan, and flagellin also mediate gut-brain communication. LPS, a component of gram-negative bacteria, triggers immune responses by activating toll-like receptors (TLRs), leading to cytokine production associated with anxiety, depression, and memory impairment. Conversely, polysaccharide A from Bacteroides fragilis protects against CNS inflammation through TLR2-dependent pathways.
Gut Hormones in Gut-Brain Crosstalk
EECs, though representing only 1% of gastrointestinal epithelial cells, release a variety of gut hormones in response to dietary stimuli, playing key roles in gut motility, appetite, and hormone release. These cells are classified into ten types based on the primary hormone they produce, including ghrelin, CCK, GLP-1, and PYY. Gut hormones have diverse functions, ranging from nutrient detection and digestion modulation to insulin release and behavioral adaptation.
Gut Hormones and Metabolic Control
The CNS, particularly the hypothalamus, governs metabolic control by expressing nutrient sensors and hormone receptors. Gut hormones like ghrelin, PYY, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and CCK are key signals in gut-brain crosstalk and energy metabolism. Ghrelin, produced by stomach X/A-like cells, increases appetite and food intake by activating ghrelin receptors in the vagus nerve and hypothalamus. CCK, released by intestinal I cells, inhibits food intake by interacting with leptin and activating CCK receptors in the brain. GLP-1 and PYY, secreted by L cells, promote satiety and reduce energy intake, with GLP-1 also playing a role in glucose homeostasis.
Gut Hormones and Mood Disorders
Gut hormones are also implicated in mood disorders. Serotonin (5-HT), produced by enterochromaffin cells, regulates mood, sleep, and appetite, while also influencing immune responses and vagal afferent activity. The neuropeptide Y (NPY) family, including NPY, PYY, and pancreatic polypeptide (PP), affects stress-related disorders and neuroinflammation. GLP-1 and CCK are involved in stress responses and anxiety-like behaviors, while ghrelin regulates stress adaptation and fear memory.
Microbiota and Gut Hormones
Gut microbiota influences host hormones directly by producing or metabolizing them and indirectly by modulating adrenal cortex function and inflammatory responses. For example, microbiota-derived SCFAs and indole derivatives stimulate the release of GLP-1 and CCK from EECs. Conversely, gut hormones like 5-HT can influence microbiota composition, creating a bidirectional interaction between microbiota and hormones.
Conclusion
The gut microbiota and gut hormones play critical roles in the gut-brain axis, influencing a wide range of physiological and psychological processes. Understanding the interactions between microbiota, hormones, and the brain may lead to novel therapeutic strategies for disorders like obesity, anxiety, and depression. Future research should focus on the microbiota-hormones-gut-brain axis to uncover new insights and treatments for these conditions.
doi.org/10.1097/CM9.0000000000000706
Was this helpful?
0 / 0