Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis

Abstract

Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.

Keywords: cognition; cortisol; glucocorticoids; hypothalamic-pituitary-adrenal axis; microbiota-gut-brain axis; stress.

Figure 1

Overview of microbiota-gut-brain axis. Bidirectional communication mechanisms of the MGB axis include endocrine, neural, metabolic and immune system pathways. The hypothalamic-pituitary-adrenal axis is a major neuro-endocrine system responding to stress with the release of corticotrophin-releasing hormone (CRH) from the hypothalamus, and the subsequent release of ACTH from the pituitary, then cortisol from the adrenal cortex. Cortisol reaches target tissues through the circulation, modulates the immune system, and impacts on GM composition and gut permeability. The GM in turn is able to influence the stress response (for e.g., the HPA axis can be activated in response to increased circulating cytokines subsequent to bacterial translocation). Various GM and enteroendocrine cell interactions result in the release of hormones that work locally or on target tissues such as the brain, via the circulation. The vagus nerve, enteric nervous system, and spinal pathways provide rapid neural communication routes, while neurotransmitters or their precursors can be produced or metabolized by microbes. Metabolites such as SCFA, BA and eCB may be produced or modified by microbes and bind specific cell receptors in the gut or they may be absorbed into circulation and affect target tissues. Microbes and their products may interact with the immune cells with downstream pro-inflammatory or anti-inflammatory effects. ACTH, Adrenocorticotropic hormone; BA, bile acid; BCAA, branched chain amino acids; CCK, cholecystokinin; CRH, corticotropin-releasing hormone; eCB, endocannabinoid; GABA, γ-aminobutyric acid; GLP-1, glucagon-like peptide 1; GM, gut microbiota; HPA, hypothalamic-adrenal-pituitary; IL, interleukin; ILC, innate lymphoid cells; LPS, lipopolysaccharide; PYY, Peptide YY; NPY, neuropeptide Y; PAMP, Pathogen-associated molecular pattern; PG, peptidoglycan; SCFA, short chain fatty acid; Th, T helper cell; TJPC, tight junction protein complex; T reg, regulatory T cell; TNF-α, tumor necrosis factor-α. Figure created with BioRender.com.

Figure 2

Signalling mechanisms – microbial products, metabolites, and neurotransmitters. Cells of the gut express a variety of receptors which are able to sense and transmit signals from the intestinal lumen and mucosa. To communicate, the GM uses factors which include several microbial products, eCBs, BAs, SCFAs, and neurotransmitters. PAMPs, such as LPS and PG, are small molecular microbial motifs that are recognized by TLRs, while this signal is transferred to intracellular signaling pathways (for e.g., immune cell activation) by MYD88. The eCB system is not limited to the activity of CB1 and CB2, and eCBs can also interact with other GPCRs, TRPV1, and the nuclear receptors PPAR-α and PPAR-γ. To modulate gut function, BAs interact with two main receptors, the GPCR named TGR5, and the nuclear receptor FXR. In the gut, SCFAs can activate FFA2, FFA3, GPR109a and Olfr78, but may also enter the cell via transporters or via passive diffusion where they modulate the activity of several enzymes and transcription factors or provide a source of energy for the cell. Small amounts of SCFAs are taken up into circulation where they may be transported to target tissues such as the liver, pancreas and brain. The binding of these GM-derived molecules with their respective receptors leads to the activation of cellular signaling pathways which then leads to alterations in cellular activity and gene expression, with downstream effects on host physiological processes. AhR, aryl hydrocarbon receptor; AMPK, AMP-activated protein kinase; BA, bile acid; CB1 and CB2,, cannabinoid receptor type 1 and 2; eCB, endocannabinoid; ENS, enteric nervous system; FFA2 and FFA3, free fatty acid receptor 2 and 3; FXR, farsenoid X receptor; GABA, γ-aminobutyric acid; GLP-1, glucagon-like peptide 1; GNG, gluconeogenesis; GPR119 and GPR109a, G-protein coupled receptor 119 and 109a; HDAC, histone deacetylase; LPS, lipopolysaccharide; MCT, monocarboxylate transporter; MYD88, Myeloid differentiation primary response 88; Olfr78, Olfactory receptor 78; PAMP, Pathogen-associated molecular pattern; PG, peptidoglycan; PPARα/γ, peroxisome proliferator-activated receptors α/γ; PRRs, pattern recognition receptors; PYY, Peptide YY; SCFA, short chain fatty acid; SMCT, sodium-dependent monocarboxylate transporter; TGR5, Takeda G protein-coupled receptor 5; TJPC, tight junction protein complex; TLR, toll-like receptor; TPRV1, transient receptor potential cation channel subfamily V member 1. Figure created with BioRender.com.

Figure 3

Tryptophan metabolism. Tryptophan metabolism occurs via the serotonin or kynurenine pathways to produce bioactive products. In the serotonin pathway, tryptophan is converted to 5-HTP by TPH1 in enterochromaffin cells, or TPH2 in neurons of the ENS or CNS. AAAD converts 5-HTP to serotonin, which can be further metabolized to melatonin, via a series of steps. The vast majority of tryptophan is, in fact, utilized in the kynurenine pathway, where tryptophan is converted to kynurenine by TDO in the liver (majority), or ubiquitously via IDO (including gut, brain, liver). Kynurenine can be converted to kynurenic acid by the KAT enzymes, quinolic acid and further NAD⁺, or XA. In the indole pathway, microbes of the gut metabolize tryptophan into indole and indole derivatives. 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan; AAAD, aromatic amino acid decarboxylase; IA, anholocyclic acid; IAA, indole-3-acetic acid; IAAld, indole-3-acetaldehyde; IAld, indole-3-aldehyde; IAM, indole-3-acetamide; IDO, indoleamine 2,3-dioxygenase; ILA, indole-3-lactic acid; IPA, indole-3-propionic acid; IPYA, indole-3-pyurvic acid; KAT, kynurenine aminotransferase; MAO, monoamine oxidase; NAD⁺, nicotinamide adenine dinucleotide; TDO, tryptophan 2,3-dioxygenase; XA, xanthurenic acid. Figure created with BioRender.com.

Figure 4

Endocannabinoid system. In the nervous system, presynaptic electrical impulses lead to calcium entry into the cell which drives the release of neurotransmitters into the synapse. Neurotransmitter receptors on the postsynaptic neurons are then activated and drive the action potential forward. The eCB system is a ubiquitous neuromodulatory system that functions throughout the body, including the nervous system to modulate cell signaling. DAG and NAPE are produced from phospholipid precursors, and are converted to the endocannabinoids (eCB) 2-AE and AEA by DAGL and NAPE-PLD, respectively. In retrograde signaling, these eCBs are mobilized from postsynaptic neurons and target presynaptic CB1 receptors to suppress neurotransmitter release by inhibiting AC, decreasing cAMP and therefore decreasing calcium ion flow into the cell, or alternatively influence receptor sensitivity and internalization via β-arrestin. eCB signaling in the CNS can also affect the functioning of microglia and astrocytes, with modulation of the release of cytokines and neurotransmitters, respectively. In the gut, eCBs secreted by certain microbes (or host cells) interact in microbiota-epithelial crosstalk, and include the immune and nervous systems, and metabolic, endocrine and barrier functions. 2-AG, 2-Arachidonoylglycerol; AA, arachidonic acid; AEA, N-arachidonoylethanolamine (aka anandamide); AC, adenylate cyclase; CNS, central nervous system; cAMP, cyclic AMP; DAG, diacylglycerol; DAGL, diacylglycerol lipase; EA, ethanolamine; FAAH, Fatty acid amide hydrolase; GLP-1, glucagon-like peptide 1; GPCR MAGL - monoacylglycerol lipase; MGB, microbiota-gut-brain; NAPE, N-Acyl-phosphatidylethanolamine; NAPE-PLD, NAPE phospholipase D; PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PYY, Peptide YY; TPRV1, transient receptor potential cation channel subfamily V member 1. Figure created with BioRender.com.

Figure 5

Bile acids, BA receptors, and signaling pathways. In the liver, the classical pathway of bile acid (BA) synthesis begins with the conversion of cholesterol into 7α-hydroxycholesterol by the rate-limiting enzyme cholesterol 7α-hydroxylase (7α-OHase; CYP7A1). The 7α-hydroxycholesterol is then further metabolized into cholic acid (CA) and chenodeoxycholic acid (CDCA) through a series of enzymatic reactions. Once synthesized, BAs are conjugated with either glycine or taurine, which increases their solubility and reduces their toxicity. The conjugated BAs are then secreted into bile canaliculi, stored in the gallbladder, and released into the small intestine following a meal. After completing their role, approximately 95% of BAs are reabsorbed in the ileum and transported back to the liver via the enterohepatic circulation. As BAs pass through the gastrointestinal tract, they encounter a diverse population of gut bacteria and the synthesis of secondary BAs occurs in the large intestine as a result of microbial biotransformation. Secondary BAs are important for maintaining the overall BA pool in the body and contribute to the regulation of cholesterol homeostasis, energy metabolism, and the immune system. BAs can also act as signaling molecules, interacting with specific receptors such as the nuclear receptor FXR and the cell membrane receptor TGR5 (expressed in various tissues, including the liver, gut, enteric nervous system, CNS, and adrenal glands) which are involved in the modulation of numerous physiological processes, including glucose metabolism, lipid metabolism, and the regulation of the gut-brain axis. In the gastrointestinal tract, BAs bind FXR in enterocytes and this activates the expression of FGF19, which is then secreted into the bloodstream and plays a crucial role in MGB communication. FGF19 acts as an endocrine signal crossing the BBB to reach the CNS and then binding to its cognate receptor, FGFR4, and co-receptor β-Klotho. This interaction leads to the activation of intracellular signaling cascades, such as the MAPK pathway and the PI3K/Akt pathway. These signaling pathways regulate various processes, including cell growth, differentiation, and metabolism, and contribute to the modulation of the gut-brain axis. Additionally, activation of TGR5 by BAs can lead to the release of GLP-1, an incretin hormone that modulates insulin secretion and glucose homeostasis. In the CNS, TGR5 activation has been implicated in the regulation of energy balance, neuroinflammation, and neuroprotection. BAs can influence the HPA axis through both direct and indirect mechanisms involving signaling pathways in the CNS and the adrenal glands. In the CNS, BAs can modulate the HPA axis by interacting with FXR and TGR5, which are expressed in various brain regions, including the hypothalamus and the hippocampus. Activation of these receptors by BAs can influence the release of CRH from the hypothalamus and ACTH from the pituitary gland, leading to the modulation of cortisol secretion from the adrenal cortex. Furthermore, BAs can directly affect the adrenal glands, influencing the release of cortisol. BA can alter adrenal steroidogenesis by modulating the expression and activity of key enzymes involved in the biosynthesis of cortisol, including HSL, StAR, and cytochrome P450 enzymes (e.g., CYP11A1, CYP11B1, and CYP11B2). Additionally, BAs can influence adrenal cell function by activating FXR and TGR5, which may regulate intracellular signaling pathways and gene expression patterns related to steroid hormone production, inflammation, and oxidative stress. Primary bile acids: CA, cholic acid; CDCA, chenodeoxycholic acid; GCA, glycocholic acid; TCA, taurocholic acid; GCDCA, glycochonedeoxycholic acid; TCCDA, taurochenodeoxycholic acid. Secondary bile acids: DCA, deoxycholic acid; G/T-DCA, glyco/tauro-deoxycholic acid; G/T-LCA, glyco/tauro-lithocholic acid; G/T-UDCA, glyco/tauro-ursodeoxycholic acid; UDCA, ursodeoxycholic acid; LCA, lithocholic acid; UDCA, ursodeoxycholic acid. ACTH, adrenocorticotropic hormone; Akt, protein kinase B; BA, bile acid; BBB, blood brain barrier; CNS, central nervous system; CRH, corticotrophin-releasing hormone; FGF19, fibroblast growth factor 19; FGFR1-4, fibroblast growth factor receptors 1 to 4; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide 1; GLP-1R, glucagon-like peptide 1 receptor; HSL, hormone sensitive lipase; MAPK, mitogen-activated protein kinase; MGB, microbiota-gut-brain; PI3K, phosphatidylinositol 3-kinase; StAR, steroidogenic acute regulatory protein; TGR5, Takeda G protein-coupled receptor 5. Figure created with BioRender.com.

Figure 6

The gut microbiota, HPA axis and cognition. Schematic summary representation of the relationship between the gut microbiota, HPA axis, and cognition. The gut microbiota influences the HPA axis and cognition through the production of metabolites (e.g., SCFAs, and bile acids), neurotransmitters (e.g., serotonin, GABA, catecholamines), and immune system modulation. The HPA axis, comprising the hypothalamus, pituitary gland, and adrenal glands, regulates cortisol release, which in turn affects both gut microbiota and cognitive function. Cognitive processes involve various brain regions (e.g., hippocampus, amygdala, and prefrontal cortex), neurotransmitters, and plasticity, and are modulated by the interplay between the gut microbiota and HPA axis. ACTH, adrenocorticotropic hormone; CRH, corticotrophin-releasing hormone. Figure created with BioRender.com.