The HPA cascade — step by step
Psychological or physiological stressors activate the paraventricular nucleus of the hypothalamus. CRH (corticotropin-releasing hormone) is released into the hypophyseal portal blood supply, travelling to the anterior pituitary.
Stage 1CRH binds CRH receptor 1 (CRHR1) on anterior pituitary corticotrophs, triggering ACTH (adrenocorticotropic hormone) release into systemic circulation.
Stage 2Circulating ACTH binds receptors on adrenal cortex cells, stimulating cortisol synthesis and release from the zona fasciculata. Cortisol circulates systemically and crosses cell membranes to bind intracellular glucocorticoid receptors.
Stage 3Cortisol binds GRs in gastric epithelial cells, simultaneously: (1) Suppresses COX-1/2 → prostaglandins drop → mucus and bicarbonate decrease + ROS accumulate → NF-kB via oxidative stress pathway; (2) Stimulates parietal cells via vagal/direct mechanisms → acid output increases; (3) Activates NF-kB via non-canonical GR-NF-kB signalling pathway → IL-6, IL-8, TNF-α production → mucosal inflammation.
Stage 4Parallel channels — mast cells and ENS
Peripheral CRH → mast cell activation: CRH receptors are present on mucosal mast cells directly in the gastric submucosa. Local CRH release from peripheral neurons activates these mast cells, producing histamine, tryptase, and cytokines that contribute to mucosal inflammation — a direct gut-level stress response that does not require the full HPA cascade.
Vagal disruption → ENS motility effects: Cortisol and sympathetic activation disrupt vagal input to the ENS. Reduced vagal parasympathetic tone alters gastric motility, produces the dysmotility (delayed emptying, uncoordinated contractions) that causes nausea and bloating, and reduces the mucosal blood flow that supports barrier integrity.
NF-kB convergence — the H. pylori connection
H. pylori activates NF-kB through CagA injection and LPS-TLR4 binding. The HPA cascade activates NF-kB through cortisol glucocorticoid receptor signalling and ROS from COX suppression. Both pathways produce the same NF-kB-driven cytokine cascade (IL-6, IL-8, TNF-α) and the same EGFR/ERK repair suppression. In H. pylori-positive patients under significant stress — 62% of symptomatic Indians who are already managing multiple stressors — both NF-kB activation sources are active simultaneously. The inflammatory state is additive.
The bidirectional axis — gut inflammation and the stress response
The gut-brain relationship is genuinely bidirectional. The gastric mucosal inflammation produced by either cortisol or H. pylori generates pro-inflammatory cytokines (IL-6, TNF-α) that cross the blood-brain barrier and activate neuroinflammatory pathways — contributing to the low-grade depression and anxiety that many patients with chronic gastritis describe as coincidental. The gut\'s inflammation is not just a consequence of stress; it becomes a driver of it through the cytokine feedback loop. Addressing mucosal inflammation is not just about the stomach — it is about interrupting the feedback cycle that sustains the stress response itself.
References
- Crowe SE. Helicobacter pylori infection. New England Journal of Medicine. 2019;380:1158–1165. PMID 30699316. H. pylori NF-kB mechanism — the convergent endpoint shared with the cortisol HPA cascade described in this article.
- Merlin Annie Raj, RD. TumGard India Gut Health Report 2026. Hugg Beverages Pvt. Ltd. 2026. tumgard.com/india-gut-health-report-2026. India-specific context: 62% H. pylori positivity in symptomatic patients — the prevalence that makes the HPA-H. pylori NF-kB convergence clinically significant for the Indian patient population.