Gut–brain axis

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The gut–brain axis is the two-way biochemical signaling that takes place between the gastrointestinal tract (GI tract) and the central nervous system (CNS).^[2] The term "microbiota–gut–brain axis" highlights the role of gut microbiota in these biochemical signaling .^[3][2] Broadly defined, the gut–brain axis includes the central nervous system, neuroendocrine system, neuroimmune systems, the hypothalamic–pituitary–adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system, the enteric nervous system, vagus nerve, and the gut microbiota.^[2]

Chemicals released by the gut microbiome can influence brain development, starting from birth. A review from 2015 states that the gut microbiome influences the CNS by "regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety and memory function".^[4] The gut, sometimes referred to as the "second brain", may use the same type of neural network as the CNS, suggesting why it could have a role in brain function and mental health.^[5]

The bidirectional communication is done by immune, endocrine, humoral and neural connections between the gastrointestinal tract and the central nervous system.^[4] More research suggests that the gut microbiome influence the function of the brain by releasing the following chemicals: cytokines, neurotransmitters, neuropeptides, chemokines, endocrine messengers and microbial metabolites such as "short-chain fatty acids, branched chain amino acids, and peptidoglycans".^[6] These chemical signals are then transported to the brain via the blood, neuropod cells, nerves, endocrine cells,^[7][8] where they impact different metabolic processes. Studies have confirmed that gut microbiome contribute to range of brain functions controlled by the hippocampus, prefrontal cortex and amygdala (responsible for emotions and motivation) and act as a key node in the gut-brain behavioral axis.^[9]

While Irritable bowel syndrome (IBS) is the only disease confirmed to be directly influenced by the gut microbiome, many disorders (such as anxiety, autism, depression and schizophrenia) have been reportedly linked to the gut-brain axis as well.^[6][10][7] According to a study from 2017, "probiotics have the ability to restore normal microbial balance, and therefore have a potential role in the treatment and prevention of anxiety and depression".^[11]

The first of the brain–gut interactions shown, was the cephalic 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 by Pavlov through Nobel prize winning research in 1904.^[12][13]

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 various neuroactive compounds that gut microbiota can produce. Studies with humans – measuring variations in gut microbiota between people with various psychiatric and neurological conditions or when stressed, or measuring effects of various probiotics (dubbed "psychobiotics" in this context) – had generally been small and were just beginning to be generalized.^[14] Whether changes to the 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, remain unclear.^[15]

The enteric nervous system is one of the main divisions of the nervous system and consists of a mesh-like system of neurons that governs the function of the gastrointestinal system; it has been described as a "second brain" for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the central nervous system (CNS) through the parasympathetic (e.g., via the vagus nerve) and sympathetic (e.g., via the prevertebral ganglia) nervous systems. However, vertebrate studies show that when the vagus nerve is severed, the enteric nervous system continues to function.^[16]

In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, 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 control peristalsis and churning of intestinal contents. Other neurons control the secretion of enzymes. The enteric nervous system also makes use of more than 30 neurotransmitters, most of which are identical to the ones found in CNS, such as acetylcholine, dopamine, and serotonin. 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.^[17][18][19]

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 the cephalic phase, or cephalic response of digestion.^[12][13]

Tryptophan metabolism by human gut microbiota ( v t e ) Tryptophan Clostridium sporogenes Lacto- bacilli Tryptophanase- expressing bacteria IPA I3A Indole Liver Brain IPA I3A Indole Indoxyl sulfate AST-120 AhR Intestinal immune cells Intestinal epithelium PXR Mucosal homeostasis: ↓TNF-α ↑Junction protein- coding mRNAs L cell GLP-1 T J Neuroprotectant: ↓Activation of glial cells and astrocytes ↓4-Hydroxy-2-nonenal levels ↓DNA damage –Antioxidant –Inhibits β-amyloid fibril formation Maintains mucosal reactivity: ↑IL-22 production Associated with vascular disease: ↑Oxidative stress ↑Smooth muscle cell proliferation ↑Aortic wall thickness and calcification Associated with chronic kidney disease: ↑Renal dysfunction –Uremic toxin Kidneys This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.[20] Indole is produced from tryptophan by bacteria that express tryptophanase.[20] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),[21] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[20][22][23] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[20] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.[20] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.[20] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.[20] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.[20] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[20]

The gut microbiota is the complex community of microorganisms that live in the digestive tracts of humans and other animals. The gut metagenome is the aggregate of all the genomes of gut microbiota.^[24] The gut is one niche that human microbiota inhabit.^[25]

In humans, the gut microbiota has the largest quantity of bacteria and the greatest number of species, compared to other areas of the body.^[26] In humans, the gut flora is established at one to two years after birth; by that time, the intestinal epithelium and the intestinal 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 to pathogenic organisms.^[27][28]

The relationship between gut microbiota and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.^[25] Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate.^[26][29] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.^[25][29] The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ;^[29] dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.^[26][30]

The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes.^[26][30] 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. Additional health factors that may skew the composition of the gut microbiota are antibiotics and probiotics. 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. 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.^[31]

The gut–brain axis, a bidirectional neurohumoral communication system, is important for maintaining homeostasis and is regulated through the central and enteric nervous systems and the neural, endocrine, immune, and metabolic pathways, and especially including the hypothalamic–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 as acetylcholine, catecholamines, γ-aminobutyric acid, histamine, melatonin, and serotonin, which are essential for regulating peristalsis and sensation in the gut.^[32] Changes in the composition of the gut microbiota due to diet, drugs, or disease correlate with changes in levels of circulating cytokines, some of which can affect brain function.^[32] The gut microbiota also release molecules that can directly activate the vagus nerve, which transmits information about the state of the intestines to the brain.^[32]

Likewise, chronic or acutely stressful situations activate the hypothalamic–pituitary–adrenal axis, causing changes in the gut microbiota and intestinal epithelium, and possibly having systemic effects.^[32] Additionally, the cholinergic anti-inflammatory pathway, signaling through the vagus nerve, affects the gut epithelium and microbiota.^[32] 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.^[32]

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.^[15]

The concept is of special interest in autoimmune diseases such as multiple sclerosis.^[33] This process is thought to be regulated via the gut microbiota, which ferment indigestible dietary fibre and resistant starch; the fermentation process produces short chain fatty acids (SCFAs) such as propionate, butyrate, and acetate.^[34] The history of ideas about a relationship between the gut and the mind dates from the nineteenth century. ^[35]

While Irritable bowel syndrome (IBS) is the only disease confirmed to be directly influenced by the gut microbiome, many disorders such as anxiety, autism, depression and schizophrenia have been linked to the gut-brain axis as well.^[6][36][7]

Skin conditions such as acne were proposed as early as 1930,^[37] to be related to emotional states which altered the gut microbiome leading to systemic inflammation. Such conditions that have been improved by the use of probiotics.^[38] Studies have shown overlapping mechanisms in psoriasis and depression; psoriasis causing disturbances in the gut microbiota that reflect in the brain causing depression that in turn can cause the stress that affects the microbiome.^[39] Probiotics may reduce symptoms of depression through the vagus nerve and sympathetic pathways.

Irritable bowel syndrome (IBS) can cause many abdominal issues such as symptoms of constipation, diarrhea, gas, bloating, and abdominal pain. IBS can be stress-induced and flare-ups are associated with bouts of stress. The gut-brain axis may explain this. The use of probiotics has been shown to help to restore a balance of helpful and harmful bacteria.^[40]

Brain function is dependent on multiple neuropeptides including dopamine, GABA and serotonin, that are controlled in the gut microbiota. Imbalances in the gut microbiota intensifies anxiety as both the immune and metabolic pathways are affected. Specific microbes can lead to increased anxiety due to the activation of c-Fos proteins. These proteins serve as indicators of neuronal activation. Probiotics have beneficial impacts on anxiety.^[41]

Studies have shown that children with autism are four times more likely to develop gastrointestinal disorders. The severity of their behavioral symptoms is proportional to the severity of their gastrointestinal issues. Many children with autism have high focal levels of HMGB1.^{[42] [43]}

Different neurotrophins play a role in schizophrenia. One of the main ones is called Brain-Derived Neurotrophic Factor (BDNF). BDNF has been associated with schizophrenia and is believed to be a part of the molecular mechanism that has to do with cognitive dysfunction during neurodevelopmental changes. Those who have been diagnosed with schizophrenia tend to exhibit lower levels of BDNF in blood and levels of BDNF are also lower in the cortex and hippocampus. Levels of butyric acid have also been shown to be different between schizophrenic patients and non-schizophrenic patients. It is important to note that studies regarding the link between the gut-brain axis and schizophrenia are limited and further studies are underway. ^[44]

Braak's theory proposed that gut dysbiosis in Parkinson's causes the aggregation of alpha-synuclein in the gastrointestinal tract before its spreading to the brain.^[45]

Microbial derived secondary bile acids produced in the gut may influence cognitive function.^[46] Altered bile acid profiles occur in cases of mild cognitive impairment and Alzheimer's disease with an increase in cytotoxic secondary bile acids and a decrease in primary bile acids.^[47] These findings suggest a role of the gut microbiome in the progression to Alzheimer's disease.^[47] In contrast to the cytotoxic effect of secondary bile acids, the bile acid tauroursodeoxycholic acid may be beneficial in the treatment of neurodegenerative diseases.^[48]

As more bile acids are absorbed via apical sodium-bile acid transporters, there is a significant increase in age-related cognitive impairment. Levels of serum conjugated primary bile acids were monitored and increased levels revealed ammonia accumulation in the brain. These increased levels of ammonia led to hippocampal synapse loss. Because the hippocampus is largely responsible for memory, the loss of these synapses can have profound impacts on the memories of those affected. ^[49]

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