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Thegut–brain axis is the two-way biochemical signaling that takes place between thegastrointestinal tract (GI tract) and thecentral nervous system (CNS).[2] The term "microbiota–gut–brain axis" highlights the putative role ofgut microbiota interacting with brain functions, according to preliminary research.[3][2] Broadly defined, the gut–brain axis includes thecentral nervous system,neuroendocrine system,neuroimmune systems, thehypothalamic–pituitary–adrenal axis (HPA axis),sympathetic andparasympathetic arms of theautonomic nervous system, theenteric nervous system,vagus nerve, and the gut microbiota.[2]
Chemicals released by thegut microbiome can influencebrain development, starting from birth. A review from 2015 states that the gut microbiome influences theCNS by "regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety and memory function".[4]
The bidirectional communication may involveimmune,endocrine,humoral and neural connections between the gastrointestinal tract and the central nervous system.[4] A 2019 review of laboratory research suggests that the gut microbiome may influence brain function by releasing chemical signals, possibly includingcytokines,neurotransmitters,neuropeptides,chemokines, endocrine messengers and microbialmetabolites, such as "short-chain fatty acids, branched chain amino acids, andpeptidoglycans".[5] These chemical signals are then transported to the brain via theblood,neuropod cells,nerves,endocrine cells,[6] where they may impact different metabolic processes.
The first of the brain–gut interactions shown, was thecephalic phase of digestion, in the release of gastric and pancreatic secretions in response to sensory signals, such as the smell and sight of food. This was first demonstrated byPavlov throughNobel prize winning research in 1904.[7][8]
As of October 2016, most of the work done on the role of gut microbiota in the gut–brain axis had been conducted in animals, or on characterizing the variousneuroactive compounds that gut microbiota can produce.[5]
Theenteric nervous system is one of the main divisions of thenervous system and consists of a mesh-like system ofneurons that governs the function of thegastrointestinal system; it has been described as a "second brain" for several reasons. The enteric nervous system can operate autonomously. It normally communicates with thecentral nervous system (CNS) through theparasympathetic (e.g., via thevagus nerve) andsympathetic (e.g., via theprevertebral ganglia) nervous systems. However,vertebrate studies show that when thevagus nerve is severed, the enteric nervous system continues to function.[9]
In vertebrates, the enteric nervous system includesefferent neurons,afferent neurons, andinterneurons, all of which make the enteric nervous system capable of carrying reflexes in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons controlperistalsis and churning of intestinal contents. Other neurons control the secretion ofenzymes. The enteric nervous system also makes use of more than 30neurotransmitters, most of which are identical to the ones found in CNS, such asacetylcholine,dopamine, andserotonin. More than 90% of the body's serotonin lies in the gut, as well as about 50% of the body's dopamine; the dual function of these neurotransmitters is an active part of gut–brain research.[10][11][12]
The first of the gut–brain interactions was shown to be between the sight and smell of food and the release of gastric secretions, known as thecephalic phase, or cephalic response of digestion.[7][8]
 Tryptophanase- expressing bacteria Intestinal immune cells Neuroprotectant: ↓Activation ofglial cells andastrocytes ↓4-Hydroxy-2-nonenal levels ↓DNA damage –Antioxidant –Inhibitsβ-amyloid fibril formation Maintains mucosal reactivity: ↑IL-22 production Associated withvascular disease: ↑Oxidative stress ↑Smooth muscle cellproliferation ↑Aortic wall thickness andcalcification Associated withchronic kidney disease: ↑Renal dysfunction –Uremic toxin  |
Thegut microbiota is the complex community ofmicroorganisms that live in thedigestive tracts of humans and other animals. The gutmetagenome is the aggregate of all thegenomes of gut microbiota.[17] The gut is one niche thathuman microbiota inhabit.[18]
In humans, the gut microbiota has the largest quantity of bacteria and the greatest number of species, compared to other areas of the body.[19] In humans, the gut flora is established at one to two years after birth; by that time, theintestinal epithelium and theintestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier topathogenic organisms.[20][21]
The relationship between gut microbiota and humans is not merelycommensal (a non-harmful coexistence), but rather amutualistic relationship.[18] Human gut microorganisms benefit the host by collecting the energy from thefermentation of undigestedcarbohydrates and the subsequent absorption ofshort-chain fatty acids (SCFAs),acetate,butyrate, andpropionate.[19][22] Intestinalbacteria also play a role in synthesizingvitamin B andvitamin K as well as metabolizingbile acids,sterols, andxenobiotics.[18][22] The systemic importance of the SCFAs and other compounds they produce are likehormones and the gut flora itself appears to function like anendocrine organ;[22] dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[19][23]
The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes.[19][23] In general, the average human has over 1000 species of bacteria in their gut microbiome, with Bacteroidetes and Firmicutes being the dominant phyla. Diets higher in processed foods and unnatural chemicals can negatively alter the ratios of these species, while diets high in whole foods can positively alter the ratios.[citation needed] Additional health factors that may skew the composition of the gut microbiota areantibiotics andprobiotics. Antibiotics have severe impacts on gut microbiota, ridding of both good and bad bacteria. Without proper rehabilitation, it can be easy for harmful bacteria to become dominant.[citation needed] Probiotics may help to mitigate this by supplying healthy bacteria into the gut and replenishing the richness and diversity of the gut microbiota. There are many strains of probiotics that can be administered depending on the needs of a specific individual.[24]
The gut–brain axis, a bidirectional neurohumoral communication system, is important for maintaininghomeostasis and is regulated through thecentral andenteric nervous systems and the neural, endocrine, immune, and metabolic pathways, and especially including thehypothalamic–pituitary–adrenal axis (HPA axis).[2] That term has been expanded to include the role of the gut microbiota as part of the "microbiome-gut-brain axis", a linkage of functions including the gut microbiota.[2]
Interest in the field was sparked by a 2004 study (Nobuyuki Sudo and Yoichi Chida) showing that germ-free mice (genetically homogeneous laboratory mice, birthed and raised in an antiseptic environment) showed an exaggerated HPA axis response to stress, compared to non-GF laboratory mice.[2]
The gut microbiota can produce a range of neuroactive molecules, such asacetylcholine,catecholamines,γ-aminobutyric acid,histamine,melatonin, andserotonin, which are essential for regulating peristalsis and sensation in the gut.[25] Changes in the composition of the gut microbiota due to diet, drugs, or disease correlate with changes in levels of circulatingcytokines, some of which can affect brain function.[25] The gut microbiota also release molecules that can directly activate thevagus nerve, which transmits information about the state of the intestines to the brain.[25]
Likewise, chronic or acutely stressful situations activate thehypothalamic–pituitary–adrenal axis, causing changes in the gut microbiota andintestinal epithelium, and possibly havingsystemic effects.[25] Additionally, thecholinergic anti-inflammatory pathway, signaling through the vagus nerve, affects the gut epithelium and microbiota.[25]Hunger and satiety are integrated in the brain, and the presence or absence of food in the gut and types of food present also affect the composition and activity of gut microbiota.[25]
Most of the work that has been done on the role of gut microbiota in the gut–brain axis has been conducted in animals, including the highly artificial germ-free mice. As of 2016, studies with humans measuring changes to gut microbiota in response to stress, or measuring effects of various probiotics, have generally been small and cannot be generalized; whether changes to gut microbiota are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut–brain axis, remains unclear.[5]
The concept is of special interest inautoimmune diseases such asmultiple sclerosis.[26] This process is thought to be regulated via the gut microbiota, which ferment indigestible dietary fibre and resistant starch; the fermentation process producesshort chain fatty acids (SCFAs) such as propionate, butyrate, and acetate.[27] The history of ideas about a relationship between the gut and the mind dates from the nineteenth century.[28]
Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125].Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacteriumClostridium sporogenes.
[Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
Media related toGut–brain axis at Wikimedia Commons