The brain/gut axis
What we know so far...
The vagus nerve supplies signals from the brain to various organs (list below) (sympathetic nerve signals). The vagus nerve also sends signals from the same organs to the brain (parasympathetic nerve signals).
Studies prove that there is bidirectional communication between brain and gut. This communication system uses three main pathways; neural—enteric nerves and vagus nerve, inflammatory—cytokines and immune cells, and humoral— Hypothalamic Pituitary Adrenal (HPA) axis
What the vagus nerve effects....
Brain, heart, lungs, digestive system, liver, pancreas, gallbladder, kidneys and spleen.
The vagus also controls a few skeletal muscles, including:
Levator veli palatini muscle
Superior, middle and inferior pharyngeal constrictors
Muscles of the larynx (speech).
The vagus nerve is an autonomic nerve. The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions, such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal. This system is the primary mechanism in control of the fight-or-flight response.
The autonomic nervous system is regulated by integrated reflexes through the brainstem to the spinal cord and organs. Autonomic functions include control of respiration, cardiac regulation (the cardiac control center), vasomotor activity (the vasomotor center), and certain reflex actions such as coughing, sneezing, swallowing and vomiting.
Gut microbiota are the microorganisms including bacteria, archaea (single-celled organisms) and microscopic eukaryotes (organisms whose cells have a nucleus enclosed within a nuclear envelope) that live in the digestive tracts of humans. The composition of the gut microbiota varies across the digestive tract. The colon contains the highest microbial density recorded in any habitat on Earth, representing between 300 and 1000 different species. However, 99% of gut bacteria come from about 30 or 40 species. Bacteria also make up to 60% of the dry mass of feces. Over 99% of the bacteria in the gut are anaerobes (not oxygen breathers), but in the cecum, aerobic (oxygen breathing) bacteria reach high densities.
Stress, anxiety and depression significantly alter the microbiome concentrations in the digestive tract.
Intermittent fasting and aerobic training have demonstrated beneficial effects on intestinal microbiota composition, but little is known about benefits to the brain through the gut-brain axis
Lactobacillus species play a critical role in the bidirectional communication between the gut and the brain. Consequently, they have the potential to aid in the treatment of psychological disorders.
Clinical studies show that the gut-brain axis is a major contributor to development of irritable bowel syndrome (IBS), mental disorders such as autism, schizophrenia, Parkinson's disease, Alzheimer's disease, anxiety disorders, and MDD.
A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures.
Disturbances of the gut-brain axis have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target.
The etiology of alcohol dependence is not completely understood. Increasing evidence reveals that gut microbiota dysbiosis (Dysbiosis is an imbalance in your gut flora caused by too few beneficial bacteria and an overgrowth of bad bacteria, yeast, and/or parasites) is associated with certain psychiatric disorders, including alcoholism, through the "microbiota-gut-brain" axis. The results showed that alcohol intake altered the composition and structure of the colonic microbiota, especially the relative abundance of the commensal microbes Lachnospiraceae and Prevotellaceae, which was significantly decreased.
Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus.
Only a couple of dozen probiotics have been studied in any detailed while there is still a lot unknown about even those species.
Probiotics and prebiotics can reduce anxiety and stress symptoms. Male mice underwent vagotomy (is a procedure to surgically remove a part or the whole of the portion of the vagus nerve that controls the digestive system) or sham surgery, followed by administration of L.rhamnosus for 14 days. L.rhamnosus administration following sham surgery resulted in reduced anxiety-like behaviour, and an attenuation (a reduction in the activity) of the hypothalamic-pituitary-adrenal axis (HPA axis), as indicated by reduced plasma corticosterone after acute restraint stress. The anxiolytic effects, HPA modulation and increase in T regulatory cells were prevented by vagotomy.
Chronic stress causes persistent immunological changes to the periphery and brain which causes the patient to have a disproportional respond to recurrent stresses.
Introducing probiotics resulted in a decrease in gray matter in the amygdala and an increase in density of the hippocampus.
Gut microbes produce molecules that can act as local neurotransmitters, such as GABA, serotonin, melatonin, histamine, and acetylcholine.
Gut bacteria have a critical role in the development of the lymph structures and in the function of immune system cells.
Gut microbes control the maturation and function of immune cells in the CNS, such as microglia, and also in peripheral immune cells.
Emerging evidence implicates the kynurenine pathway (KP), an immune-inflammatory pathway, in the pathophysiology of mood disorders (MD), including depression and bipolar disorder characterized by a low-grade chronic pro-inflammatory state. The metabolites of the KP, an important part of the microbiota-gut-brain axis, serve as immune system modulators linking the gut microbiota (GM) with the host central nervous system.
Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated.
The gut bacteria release biologically active peptides (broken down proteins) from enteroendocrine cells (Enteroendocrine cells are specialized cells found within the gastrointestinal tract, stomach and pancreas. They produce and release hormones in response to a number of stimuli. The hormones may be released into the bloodstream to generate systemic effects or may be distributed as local messengers. They may also stimulate a nervous response.). The digestive tract is a source of regulatory peptides that act locally on the epithelial cells and the digestive nervous system and also have distant targets in the brain.
For example, galanin (a peptide) stimulates the release of cortisol-releasing factor (CRF) and ACTH, thereby enhancing cortisol secretion. Galanin also seems to stimulate cortisol secretion directly from adrenocortical cells and norepinephrine release from the adrenal medulla.
A human study suggests that ghrelin, another psychoactive peptide, has a marked ACTH/CRF effect, and it is probably involved in the controlling of the HPA response to stress. Recent studies have proved that one of the major human gastric bacteria, Bacteroides thetaiotaomicron, promotes new nerve production in the digestive nervous system and regulates enteroendocrine networks through its major fermentation products, acetate, propionate, and succinate.
Microbiota dysbiosis can impair the epithelial barrier lining the digestive tract leading to the so-called “leaky gut,” allowing the intestinal content to be in contact with the host's blood, potentially inducing inflammatory response. There is evidence that the probiotic Bacteroides fragilis normalizes increased intestinal epithelial permeability in a mouse model of autism spectrum disorders. Studies suggest that probiotic bacteria enhance the intestinal barrier, causing changes in the tight junction protein expression and distribution. Commensal bacteria, together with intestinal inflammation and dietary components, are the main factors affecting epithelial permeability.
Some probiotics such as L. helveticus R0052 and B. longum R0175 seem to restore tight-junction integrity in the intestinal barrier and also affect hippocampal neurogenesis.
Microbiome in Depression/Anxiety
The absence of gut microbiota induces depression-like behavior in mice. Another study demonstrated that transplantation of gut microbiota from depressed patients to microbiota-depleted rats induces depressive-like and altered tryptophan metabolism. Gut microbiota play a role in the development of depression through the immunomodulatory pathway and provide a target in the treatment and prevention of this disorder.
Chronic probiotic administration can reduce anxiety and depressive symptoms and correlates with the normalization of biological indicators of depression, such as corticosterone, noradrenaline, BDNF levels, and cytokines.
A recent systematic meta-analysis including 29 trials of probiotics in humans shows that probiotics have a small, but significant, effect on depression and anxiety.
Gut–Brain Barrier in Depression (MDD)
Major depressive disorder is associated with an increased translocation of bacterial products from the gut. According to the “leaky gut hypothesis,” increased intestinal permeability in depressed patients may contribute to inflammatory response via bacterial translocation across the enterocytes. In depression, bacteria translocate from the epithelium to lamina propria and mesenteric lymph nodes (i.e., site of antigen presentation), and cause immunoglobulin production. These markers correlated with the IL-6 levels and I-FABP (a tissue protein released after injuries) concentration and correlated with the severity of depressive symptoms. The authors suggested that “leaky gut hypothesis” may elucidate the association between inflammation and suicidal behavior.
Bacteria that produce short-chain fatty acids (SCFAs) decreases the permeability of the BBB.
Gut Microbiota and Antidepressants
Drugs affect microbiota composition. Among them, there are psychotropic drugs including antidepressants, Sertraline is a strong antimicrobial agent which inhibits the growth of Staphylococcus aureus, E. coli, and Pseudomonas aeruginosa, and it also augments the effect of antibiotics. Fluoxetine shows a strong antimicrobial activity in vitro against L. rhamnosus and E. coli. Study on fluoxetine found that this antidepressant completely inhibited the growth of Succinivibrio and Prevotella taxa. Although the role of its effect on antidepressant properties may be contrary, its side effects are still not clear. Five different antidepressants (i.e., fluoxetine, escitalopram, venlafaxine, duloxetine, or desipramine) revealed that all the drugs except desipramine reduced richness (i.e., the variation of microbes in a single sample) of mice gut microbiota, while simultaneously increasing beta diversity (i.e., the variation of microbial communities between samples). This observation can cause concern because it is generally accepted that reduced microbiota richness is more common in conditions such as IBS and obesity. Based on a series of experiments, duloxetine and Ruminococcus flavefaciens found that the supplementation of R. flavefaciens reduced or even abolished antidepressive and antianhedonic properties of duloxetine. Most importantly, the authors found reduced levels of serotonin and noradrenaline as a result of R. flavefaciens supplementation.
Note - A possible treatment for Cymbalta withdrawal?
Long-term acetate deficiency due to depletion of acetate-producing bacteria resulted in the reduction of synaptophysin (SYP) in the hippocampus as well as learning and memory impairments. Exogenous acetate supplement or fecal microbiota transplant recovered hippocampal SYP level in vancomycin-treated T1D mice, and this effect was attenuated by vagal inhibition or vagotomy.
(Gilbert et al., 2018; Cryan et al., 2019; Zhang et al., 2019; Pennisi, 2020).
(Long-Smith et al., 2020).
(Mufson et al., 1981).
(Hoban et al., 2016). (Keogh et al., 2021)
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