see also:

• the brain
• the GIT microbiome

• the gut-brain axis links emotional and cognitive centers of the brain with peripheral intestinal functions which is modulated by gut microbiome - microbiota and GBA appears to be bidirectional, through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links
• unlike other peripheral organs, the gut has its own intrinsic nervous system which controls GIT functions even when completely separated from the CNS
• of the 100 trillion bacteria in the human body, 80% are in the digestive tract and produce metabolites that are involved in the modulation of host physiological functions including immunity, energy homeostasis, selection of diets, activate EECs, directly act upon vagal nerve afferents, and the production of toxins which can affect mood ¹⁾
• a 2025 study in mice showed that vagal activity was significantly reduced in mice without bacteria in the gut and it was restored when bacteria were introduced
• an intermittent energy restriction (IER) diet where days of relative fasting alternate with days of eating normally, changes the human brain-gut-microbiome axis ²⁾

• see the GIT microbiome

• this is mainly via:
  • the autonomic nervous system governed by the hypothalamus, amygdala and other CNS nuclei
    • parasympathetic via vagal nerve
      • hastens food transit time by increasing gut motility
    • sympathetic
      • delays food transit time by slowing gut motility
  • the the hypothalamic–pituitary–adrenal (HPA) axis is the main endocrine pathway via corticotropin-releasing factor (CRF), secreted by the hypothalamus
• main activity is after a meal is eaten to regulate gut motility and secretions

• orixogenic (stimulate food intake):
  • neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons
• anorexigenic (inhibit food intake):
  • proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons

• enteroendocrine cells (EECs) in the gut mucosa secrete hormones which can have local and distant actions in response to luminal content
• over 20 different types of EECs have been identified
• EECs are able to detect a wide range of substances present in the lumen, mainly nutrients, but also chemicals, toxins and microorganisms via receptors:
  • sugars and carbohydrates via Taste Receptor 1 family members 2 and 3 (T1R2/T1R3) and via sodium-coupled glucose transporter (SGLT1)
  • amino acids and proteins via:
    • T1R1/T1R3 heterodimer
    • calcium-sensing receptor (CaSR)
    • GPRC6A
    • GPR92/93
    • metabotropic glutamate receptors (mGLUR)
    • PEPT1 or SLC15A1
    • neutral AA transporter 1 (BOAT1 or SLC6A19)
  • fatty acids and lipids via:
    • CD36
    • FATP4
    • FFAR1/2/3/4
    • GPR119
• the main peptide hormones released by EECs are:
  • ghrelin
    • from P/D1-cells mainly in the stomach in humans as closed type EECs
    • secretion in mammals increases in the pre-prandial and fasting states, when it promotes food intake, and falls rapidly after a meal
  • cholecystokinin (CCK)
    • mainly secreted by I-cells in the upper small intestine (duodenum and jejunum) and by CCK neurons in response to the ingestion of proteins and lipids
    • acts via activation of CCK1 receptors in vagal afferent terminals
      • stimulation of gallbladder contraction and relaxation of the sphincter of Oddi in order to allow bile to flow into the duodenum
      • delay of gastric emptying
      • stimulation of gut motility
      • potent anorexigenic role
  • peptide tyrosine tyrosine (PYY)
    • secreted by L-cells, which are most abundant in the distal small intestine (jejunum and ileum) and large intestine esp. in response to lipids
    • acts to reduce food intake via direct action on hypothalamus
  • glucagon-like peptide-1 (GLP-1)
    • also secreted by L-cells, but mainly in response to carbohydrates and lipids
    • role as an incretin hormone:
      • it contributes, together with the gastric inhibitory peptide (GIP), to postprandial glucose clearance through the stimulation of insulin secretion from the pancreatic β-cells
• vagal afferent pathways convey stimuli generated by EECs to the CNS, specifically to the nucleus of the solitary tract (NTS) in the brainstem, which receives and distributes the information to other central areas, the most important of which is the hypothalamus.

• the most important microbial metabolites are short-chain fatty acids (SCFAs) with 2-6 carbon atoms such as butyrate, acetate and propionate which are mainly from bacterial anaerobic fermentation of non-digestible carbohydrates with only minimal amounts ingested
  • SCFAs are known to play a critical role in food intake regulation
    • via binding to FFAR2 and FFAR3 in L-cells, these metabolites stimulate the release of satiety peptides, such as PYY and GLP-1
  • SCFAs have been implicated in improving sleep³⁾
    • sodium butyrate supplementation enhances sleep quality in patients with active ulcerative colitis, while animal studies demonstrate that butyrate alleviates inflammatory responses and memory impairment induced by sleep deprivation
• other important bacterial metabolites are:
  • secondary bile acids
    • can promote the release of GLP-1 by the activation of protein-coupled bile acid receptors in L-cells, thus affecting food intake
    • chronic insomnia associates with elevated levels of primary bile acids including murocholic acid and norcholic acid, alongside reduced secondary bile acids such as isolithocholic acid, lithocholic acid, and ursodeoxycholic acid ⁴⁾
  • tryptophan
    • plays a central role in gastric motility-mediated appetite regulation in mammals as well as being the precursor to serotonin
    • as a result of the tryptophan absorption, the gut produces 90% of the serotonin in the body
    • chronic inflammation of the gut via type 1 interferon appears to result in reduced absorption of tryptophan and reative depletion of serotonin levels and thus persistent Covid-19 viral presence in the gut is suggested to cause long Covid “brain fog” by depleting serotonin and this reduces vagal nerve impulses back to the brain and resultant reduced activity of the hippocampus - mouse models seem to be able to reverse this effect by stimulating the vagus nerve or by restoring serotonin levels ⁵⁾