Sex hormones in the modulation of irritable bowel syndrome

Table 2 Sex hormone modulation of the brain-gut-microbiota axis

Level of the brain-gut-microbiota axis	Estrogen	Progesterone	Testosterone
Central nervous system	Analgesic or hyperalgesic effect[67] Excitatory action on neurons[72] Estrogen-induced increase in the number of μ-opioid receptors[68]Enhancement of serotonergic postsynaptic responsiveness in the brain[8] Central interaction with CRF signaling pathways-modulation of stress responsiveness[87,89]: Stimulation of CRF gene expression in PVN[83] Increase in glucocorticoid receptor expression in the amygdala[83] Influence on neuronal plasticity-related processes[73]	Activation of the γ-aminobutyric acid (GABA) receptors, major inhibitory receptors in the brain[77] Neuroprotective action in the hippocampus[80]	Analgesic effect[72] Inhibition of stress-induced ACTH release[103]
Autonomic nervous system	Attenuation of sympathetic responsiveness[108]	Reduced cholinergic responsiveness[5]	Regulation of parasympathetic tone[110]
Enteric nervous system/ Gut immune system	Expression of estrogen receptors in enteric neurons, regulation of neurogenic reflexes[73] Activation of colonic NK1 receptors in stress-induced visceral hypersensitivity[64] Augmentation of mast cells secretion[118] Effects on both pro- and anti-inflammatory pathways[113] Peripheral interaction with CRF signaling pathways, modulation of colonic motor and sensory responses to stress[87] Regulation of 5-HT3 receptor expression in rat colon[120] Regulation of secretory and absorptive function of gastrointestinal epithelial cells[128] Enhanced expression of trans-membrane tight junction protein in non-inflamed colon[124] Decreased production of proinflammatory cytokines in experimental colitis in female rats[125,126]	Inhibition of gastrointestinal motility[130] Inhibition of visceral signaling following colonic inflammation[100] Inhibition of mast cells degranulation[131] Immunosuppressive action related to inhibition of NFκB activation in macrophages[133]	Stimulation of smooth muscle contractions[135] Decreased production of proinflammatory mediators inducing visceral hyperalgesia[69,136] No effect on mast cells degranulation[137] Decreased TLR4 expression of macrophages and monocytes[138]
Gut microbiota	ER-β expression affects the gut microbiota composition[143] Microbial β-glucuronidase activity determines estrogens deconjugation enabling their reabsorbtion via enterohepatic circulation[146] Direct effect on bacterial metabolism, growth and expression of virulence factors[132]	Direct effect on bacterial metabolism, growth, and expression of virulence factors[132]	Reversible 17β reduction of androgens may regulate testosterone level[148] Commensal microbiota-dependent testosterone production protects against autoimmune disease in mice[149]
	Bacterial hydroxysteroid dehydrogenase regulates the balance between active and inactive steroids[132]

ACTH: Adrenocorticotropic hormone; CRF: Corticotropin-releasing factor; NFκB: Nuclear factor κB; PVN: Paraventricular nucleus; TLR4: Toll-like receptor 4.