Which brain regions (hypothalamus, brainstem nuclei such as nucleus tractus solitarius and dorsal vagal complex, amygdala, hippocampus, prefrontal cortex) are influenced by gut‑brain axis signaling, and which chemicals (vagal afferent activity, short‑chain fatty acids (SCFAs), serotonin (5‑hydroxytryptamine, 5‑HT), dopamine, γ‑aminobutyric acid (GABA), glutamate, peptide YY (PYY), glucagon‑like peptide‑1 (GLP‑1), cholecystokinin (CCK), ghrelin, cortisol, interleukin‑6 (IL‑6), tumor necrosis factor‑α (TNF‑α)) mediate this effect?

Gut-Brain Axis: Affected Brain Regions and Mediating Chemicals

The gut-brain axis primarily affects the hypothalamus, hippocampus, brainstem nuclei (nucleus tractus solitarius and dorsal vagal complex), and amygdala, with communication mediated by serotonin (5-HT), neuropeptide Y (NPY), corticotropin-releasing hormone (CRH), glutamate, short-chain fatty acids (SCFAs), gut peptides (PYY, GLP-1, CCK, ghrelin), and pro-inflammatory cytokines (IL-6, TNF-α, IL-1β). 1, 2

Primary Brain Regions Affected

Hypothalamus

• The hypothalamus serves as the central integration hub for gut-derived signals, responding to visual cues of food and food intake through the gut-brain axis 3
• CRH expression in the hypothalamus is modulated by gut signals, with electroacupuncture studies demonstrating down-regulation of hypothalamic CRH in IBS models, directly linking gut inflammation to stress response regulation 4
• NPY affects stress and mood regulation by influencing the hypothalamus, with increased NPY levels altering cholinergic transmission 4
• The hypothalamic response to glucose intake is considerably altered in patients with type 2 diabetes mellitus, indicating the hypothalamus's involvement in metabolic disease pathophysiology 3

Hippocampus

• The hippocampus is affected by NPY signaling from the gut, which regulates stress and mood through this brain region 4
• Reduced hippocampal volume is associated with HPA axis dysregulation, a key mechanism linking gut dysfunction to depression 5
• Electroacupuncture increases hippocampal serotonin (5-HT) and 5-HT1A receptor expression, demonstrating direct gut-to-hippocampus signaling pathways 5

Brainstem Nuclei

• The nucleus tractus solitarius (NTS) receives vagal afferent signals from the gut, serving as the primary relay station for peripheral gut signals 2
• The dorsal vagal complex interprets and relays peripheral signals from the gut, playing a crucial role in gut-brain communication 6
• Serotonergic neurons in the dorsal raphe nucleus (DRN) and norepinephrinergic neurons in the locus coeruleus (LC) are modulated by gut-derived serotonin transmitted via vagal afferent fibers 2

Amygdala

• High activity in the amygdala contributes to HPA axis dysregulation, making the gut more susceptible to stress and less able to recover from stressful events 4
• The amygdala is part of the bidirectional neurohumoral communication system connecting gut and brain through autonomic nervous system interactions 4

Key Chemical Mediators

Neurotransmitters

Serotonin (5-HT)

• 5-HT is a major neurotransmitter in the gut-brain axis, synthesized predominantly by enterochromaffin cells in the gut 4, 2
• Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the NTS and modulating emotional regulation, stress responses, and immune function 2
• Electroacupuncture decreases 5-HT levels in the gut-brain axis, restoring balance in IBS-D 4

Glutamate

• Glutamate acts as a neurotransmitter/neuromodulator in bidirectional communication along the microbiota-gut-brain axis 7
• Glutamatergic receptor activity influences gut functions (taste, visceral sensitivity, motility) and brain functions (stress response, mood, behavior) 7
• NMDAR (N-methyl-d-aspartate receptor), an ionotropic glutamate receptor, plays a key role in spinal cord central sensitization and visceral hypersensitivity 4

Neuropeptide Y (NPY)

• NPY is a major neurotransmitter in the enteric plexus that affects cholinergic transmission and regulates stress and mood by affecting the hippocampus and hypothalamus 4

GABA and Dopamine

• These neurotransmitters participate in interkingdom communication between eukaryota and prokaryota along the microbiota-gut-brain axis 7

Gut Peptides

Appetite-Suppressing Peptides

• Peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and cholecystokinin (CCK) suppress appetite through afferent vagal fibers to the caudal brainstem or directly to the hypothalamus 6
• GLP-1 receptors on the myenteric plexus activate nitrergic pathways to inhibit vagal activity, reducing gastric contractions and delaying emptying 8
• PYY also modulates bone metabolism, demonstrating systemic effects beyond appetite regulation 3

Appetite-Stimulating Peptides

• Ghrelin increases appetite through afferent vagal fibers to the caudal brainstem or directly to the hypothalamus 6

Stress Hormones and HPA Axis Mediators

Corticotropin-Releasing Hormone (CRH) and Cortisol

• CRH plays an important role in stress response and can induce profound enhancement of GI motility and visceral hypersensitivity 4
• Elevated CRH and ACTH with increased cortisol production characterize HPA axis dysregulation in depression 5
• Chronic stress causes the autonomic nervous system to produce CRH, which impairs gut function and leads to gastrointestinal symptoms 4

Pro-Inflammatory Cytokines

IL-6, TNF-α, and IL-1β

• IL-18 is an important pro-inflammatory factor that can excite macrophages, differentiate Th1 cells, and induce production of IL-1β and TNF-α 4
• Neuroinflammatory changes with elevated pro-inflammatory cytokines directly contribute to depression and anxiety 5
• Post-inflammatory IBS is associated with significant increases in IL-18 levels and changes in microbiota diversity 4

Microbial Metabolites

Short-Chain Fatty Acids (SCFAs)

• SCFAs enhance serotonin synthesis and vagal activity, thereby shaping gut-brain communication 2
• The microbiome influences gut-brain communication through its effects on endocrine, neural, and immune pathways 4

Primary Communication Pathways

Vagal Nerve Pathway

• The vagus nerve serves as the primary conduit for neural pathways, transmitting signals between gut and brain 1, 2
• Vagal afferent activity relays information about gut health and regulates gut motility and immune responses 1
• The vagus nerve can sense the gut microenvironment and transfer this information to the brain 8

HPA Axis

• The HPA axis mediates stress responses and directly impacts gut function, with dysregulation meaning the gut becomes more susceptible to stress and less able to recover 4, 1
• HPA axis dysregulation is a key pathophysiological mechanism shared between IBS and depression 4, 5

Clinical Significance

Common Pitfalls

• Do not dismiss the bidirectional nature of gut-brain communication—brain dysfunction can cause gut symptoms and vice versa, as genetic studies show shared risk factors rather than one condition causing the other 4
• Avoid focusing solely on peripheral gut treatments without addressing central nervous system dysregulation, particularly in patients with psychiatric comorbidity 4
• Recognize that persistent gut symptoms despite mucosal healing may indicate barrier dysfunction requiring specific therapeutic targeting 1

Therapeutic Implications

• Target multiple pathways simultaneously: psychological interventions (CBT, brain-gut behavior therapy) address HPA axis dysregulation while dietary modifications and probiotics modulate microbiome-mediated signaling 4, 1, 5
• Consider electroacupuncture as adjunctive therapy for patients with documented HPA axis hyperactivity, as it decreases hypothalamic CRH, reduces ACTH and cortisol, and increases hippocampal serotonin 5
• Probiotic supplementation may improve both mood and gastrointestinal symptoms by restoring barrier integrity and modulating neurotransmitter production 4, 1