© 2023 by Norah Horowitz, Ph.D. Proudly created with Wix.com

  • Steven Sandberg-Lewis, ND

Gut-Brain Communication: Major Mechanisms in Mental-Emotional Health and Disease (2017)

Updated: Oct 15, 2019

“I strongly feel that it is the engagement of the gut and its microbiome that plays a major role in determining the intensity duration and uniqueness of our emotional feelings”

Emeran A Mayer, MD, PhD

Director, Oppenheimer Center for Neurobiology of Stress

Professor, Medicine, Physiology & Psychiatry, UCLA School of Medicine

This article will review the gut-brain axis via the vagus nerve and microbial metabolic products including endotoxin and short chain fatty acids, hormones, neuropeptides and adipokines. Two- way communication between the gut brain (enteric nervous system or ENS) and the central nervous system (CNS) is a continuous process which optimizes functioning in both systems. In addition the gut microbiota can be thought of as a distinct “organ” which initiates and modifies much of this cross-talk. The gut microbiota includes oral, esophageal, gastric, small intestinal and colonic flora. The microbiome (genome of the gut flora) consists of about 4 million genes.

The term holobiome is defined as the sum of the approximately 26,000 human and the resident microbial genes. Clearly, humans are getting a free ride by relying on the gut flora to modify our genetic functions. In fact, there are over 100 microbial genes for every 1 human gene. The metabolome - the sum of metabolic products produced by the microbiome – comprises close to half of the total metabolities in human blood. Leo Galland, MD puts it succinctly in his 2014 review article: “The gut microbiome can be viewed as an anaerobic bioreactor programmed to synthesize molecules which direct the mammalian immune system, modify the mammalian epigenome and regulate host metabolism” (Galland, 2014). The gut microbiome is essential for the maturation and development of the enteric nervous system. These effects include both density and proper activity of the enteric neurons.

Cross talk between the gut and brain occurs through the vagus nerve, the metabolome and cytokines. The autonomic nervous system is the major anatomical connection between the enteric nervous system (ENS) and the central nervous system (CNS). The vast majority (90%) of the impulses are sensory from ENS to CNS. The shape and consistency of the bolus as well as the pressure of the bolus against the gut mucosa is transmitted through the vagus nerve. Additional information about food composition, levels of inflammation and quality of the microbiota is transmitted. This feedback helps to fine tune eating behavior, mood, blood glucose, digestive secretion, absorption and gut motility via the production of serotonin and other neuropeptides by enteroendocrine cells (EECs). Taste receptors throughout the length of the gut respond to food and stimulate production of various neuropeptides which have local and distant effects. These receptors are located on EECs and dendritic cells scattered throughout the mucosa. For example, the stimulation of bitter receptors triggers release of ghrelin which upregulates appetite when it reaches the CNS. Mechanoreceptors are stimulated by shearing forces as the bolus moves through the gut and stimulate the EECs to release serotonin which modifies both vagal and ENS function. As Emeran Mayer, MD states – “the gut is the NSA… the vagus nerve is the information highway for gut-brain traffic”. The ENS optimizes motility, secretion, mucosal blood flow as well as detecting toxins and irritants.

Microbial lipopolysaccharides, cytokines and inflammation

Remarkably, 40% of the circulating metabolites in human blood are microbiota derived. Lipopolysaccharide is a component of the outer membrane of gram negative bacterial cell walls. Gut microbial metabolites such as lipopolysaccharide (LPS or endotoxin) also have major effects on vagal input to the CNS with wide-ranging effects on mood, cognition, intestinal permeability and inflammation (Grigoleit, 2011). There are 1 million copies of LPS in each gram negative microbe (Quig, 2016) and these are released from both growing and dead bacteria ( (M Guerville, 2016)). Release may also be triggered by antibiotic therapy. Adults have approximately one gram of total gut LPS (Erridge, 2007) and (Bested, 2013). Locally LPS is a significant stimulus of the zonulin pathway which induces hyperpermeability. When absorbed into the portal vein LPS has major effects on the liver and when excessive, LPS serum levels rise and have far reaching effects. Clearly, intestinal bacteria do not need to cross the blood brain barrier in order to influence the CNS. LPS and inflammatory cytokines in serum can upregulate TNF alpha, IL-1B, and IL-6 in the brain (Quig, 2016).

Not all bacterial LPS is the same. For example, Enterobacter derived LPS may be 1000 times more

potent than LPS derived from other gram negative bacteria (Mayer, 2016). The

microbial balance affects body habitus and obesity multiplies the volume of LPS. These levels may

be 2-3 times higher in the obese population compared to lean individuals. LPS binding protein can

be measured in serum and is considered a useful inflammatory marker.

How LPS is metabolized

In the neonate, LPS is bound and inactivated by a bacterial pattern recognition receptor CD14 found in human breast milk. CD14 is not detectable in commercial cow’s milk or infant formula, but is found in bovine colostrum. Lactoferrin in breast milk also binds to LPS (M Guerville, 2016). After weaning LPS binds to Toll-like receptor 4 (TLR-4) on intestinal epithelial cells. In addition, endosomal SIgA inactivates LPS, thereby reducing the NF-KB pathway and its cascade of proinflammatory cytokines interferon, IL-6, TNF alpha (Boullier, 2009) (Fernandez, 2003). Mucins (from goblet cells) and antimicrobial peptides such as defensins (from Paneth cells) act on gram negative bacteria and therefore reduce exposure of intestinal epithelia to LPS. Defensins also alter the structure of developing bacterial cell walls to weaken the gram negative microbes (Sass, 2010).

Intestinal alkaline phosphatase is a brush border enzyme secreted into blood and the intestinal lumen. It regulates lipid absorption, duodenal pH and removal of LPS. Also produced in the liver, it helps reduce LPS arriving via the portal vein. When LPS from gut bacteria - is absorbed into the bloodstream at slightly higher levels it the alkaline phosphatase mechanism may not be adequate and serum levels of LPS rise. The ensuing inflammatory cascade has emotional and cognitive effects. These effects may include anxiety, depression and cognitive effects as well as visceral hypersensitivity (Grigoleit, 2011).

In addition to this LPS effect, adipose tissue in obese humans contains a tenfold increase in macrophages – 50 vs 5%. Increased systemic inflammation can trigger CNS inflammation by activating microglia (Hannestad, 2012). When CNS inflammation is initiated it is difficult to turn off (Fenn, 2014).

The Enteric Nervous System (ENS), Microbiome and Neurotransmitter Synthesis

The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Bacteria may synthesize neurotransmitters directly (e.g., gamma-amino butyric acid) or may modulate the synthesis of neurotransmitters (e.g., dopamine, norepinephrine, and brain-derived neurotropic factor).

The composition of the microbiota determines the levels and nature of tryptophan catabolites which in turn have profound effects on epithelial barrier integrity. This determines whether there will be an inflammatory or tolerogenic environment in the gut and other organs. (Leclercq, 2016) and (Galland, 2014).

Gut bacteria strongly affect both the peripheral and central nervous systems by production of functionally active neurotransmitters:



Gamma-aminobutyric acid


Epinephrine (Bailey, 2011)

Short Chain Fatty Acids – a major class of ENS to CNS cross-talk molecules

Short chain fatty acids (SCFAs) are produced by anaerobic bacterial fermentation of either dietary soluble fiber or intestinal mucin. Clostridia (Firmicutes phylum) are the most studied in this respect (Barcenilla, 2000) yet Lactobacillus and Bifidobacter species also produce butyrate by a “complex interspecies cross-feeding mechanisms” (Rios-Covian, 2015). Significant quantities of butyrate are also present in human breast milk as well as butter, full fat cow’s milk and most cheeses. Parmesan, as well as goat and sheep derived cheeses may be especially rich in butyrate (Jaeggi, 2003). Measurement of fecal SCFAs may not fully represent concentrations in the colon because much of it is quickly taken up by colonocytes. In addition, new research is finding that certain Clostrdia adhere tenaciously to the colonic mucin are not often present in stool samples. The major SCFAs butyrate, propionate and acetate are small organic acids with less than 6 carbon atoms. Butyrate is an energy source for colonocytes via beta oxidation. By this mechanism, butyrate decreases appetite and reduces the risk of immune modulated disease by balancing inflammation. Inflamm-ageing is a term for the chronic inflammatory state affecting many tissues including the brain (Franceschi, 2000). Butyrate is essential in neuroprotection and modulates microglial NF-KB signaling and optimizes apoptosis (Sun, 2016) (Ferrante, 2003).

A unique liver-specific transporter carries SCFAs into hepatocytes (Shin, 2007). Other SCFA transporters are present on the luminal aspect of enterocytes. Two types, monocarboxylate transporters and sodium coupled monocarboxylate transporters are also located on brain neurons, astrocytes (N Vijay, 2014), microglia (Moreira, 2009), oligodendrocytes (Lee, 2012) and the endothelia of the blood brain barrier (Bergesen, 2002).

The effects of SCFAs in the gut and the brain are due to G protein coupling receptor signaling and inhibition of histone deacetylases, promoting gene expression in human cells (Stilling, 2016). SCFAs are absorbed into the systemic circulation and cross the blood brain barrier. In the CNS these fatty acids modulate the inflammatory cascade (Saint-Georges-Chaumet, 2015). A recent study suggests that butyrate is a major factor controlling the permeability of the blood brain barrier via its effect on levels of the tight junction proteins claudin and occludin (Braniste, 2014).

Butyric acid is also partially responsible for the modest acidity of the colon (pH 5.7-6.7). Beta-hydroxybutyric acid and lactic acid are related molecules. A ketogenic diet induced by very low carbohydrate intake may raise the blood and cerebrospinal fluid content of beta-hydroxybutyric acid and mimic some of the effects of butyric acid (Iriki, 2009). SCFAs are mediators of the cross talk among microbes, mitochondria and the host. Along with microbially deconjugated secondary bile metabolites the SCFAs react with receptors on EECs. This influences serotonin levels and therefore modulates colonic motility (Yano, 2015) (Reigstad, 2015), mood (anxiety), sleep and pain sensitivity. Some of the signaling is also mediated by more direct vagal stimulation via 5 HT3 receptors (Fukumoto, 2003).

SCFAs, Microbes, Diabesity and CNS Inflammation

Microbial metabolites including butyrate have crucial regulatory effects on the health of nearly every organ system (O'Mahony, 2015). In experimental animals on a high-fat diet there is a reduction in obesity and insulin resistance after dietary supplementation with butyrate (Gao, 2009). This decrease in diabesity is likely due to down-regulation of the peroxisome proliferator-activated receptor gamma (den Besten, 2015). This down regulation promotes a shift from lipid synthesis to lipids oxidation. The SCFAs butyrate and propionate have been shown to have the most significant effects on this mechanism (Lin, 2012). When visceral adiposity enlarges it increases production of free fatty acids, adipokines such as tumor necrosis factor-α (TNF-α), resistin, and interleukin-6 (IL-6) and decreases levels of insulin sensitizing adiponectin. The adipokines stimulate the tenfold increase in the percentage of macrophages in the obese visceral fat. In turn, these macrophages produce pro-inflammatory cytokines, inducing more chronic inflammation, exacerbating insulin resistance, systemic and CNS inflammation. The insulin resistance and elevated glucose can contribute to neurodegenerative changes (Cherbuin, 2012). Following high carbohydrate meals, rapid fluctuations in blood glucose deplete serotonin, dopamine, B vitamins and magnesium. These changes contribute to glycation, insulin resistance, depression and neurodegeneration (Geroldi, 2005) (Perlmutter, 2013).


Bailey, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. , 25(3):397-407.

Barcenilla, A. (2000). Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol. , 66(4):1654-61.

Bergesen, L. (2002). Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system. Neurochem Res., 27(1-2):89-96.

Bested, A. (2013). Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II - contemporary contextual research. Gut Pathog. , 5(1):3. doi: 10.1186/1757-4749-5-3.

Boullier, S. (2009). Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits. J Immunol. , 183(9):5879-85.

Braniste, V. (2014). The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. , 6(263):263ra158.

Cherbuin, N. (2012). Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology. , 79(10):1019-26.

den Besten, G. (2015). Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1. PLoS One., 10(8):e0136364.

Erridge, C. (2007). A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. , 86(5):1286-92.

Fenn, A. (2014). Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol Psychiatry. , 76(7):575-84.

Fernandez, M. (2003). Anti-inflammatory role for intracellular dimeric immunoglobulin a by neutralization of lipopolysaccharide in epithelial cells. Immunity. , 18(6):739-49.

Ferrante, R. (2003). Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci, , pp. 9418–9427.

Franceschi, C. (2000). Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. , 908:244-54.

Fukumoto, S. (2003). Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol., 284(5):R1269-76.

Galland, L. (2014). The gut microbiome and the brain. J Med Food. 2014 Dec;J Med Food. , 17(12):1261-72.

Gao, Z. (2009). Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. , 58(7):1509-17.

Geroldi, C. (2005). Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol. , 62(7):1067-72.

Grigoleit, J. (2011). Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PLoS One., 6(12):e28330.

Hannestad, J. (2012). Endotoxin-induced systemic inflammation activates microglia: [¹¹C]PBR28 positron emission tomography in nonhuman primates. Neuroimage. , 63(1):232-9.

Iriki, T. (2009). Concentrations of ketone body and antidiuretic hormone in cerebrospinal fluid in response to the intra-ruminal administration of butyrate in suckling calves. Anim Sci J. , 80(6):655-61.

Jaeggi, J. (2003). Hard ewe's milk cheese manufactured from milk of three different groups of somatic cell counts. J Dairy Sci. , 86(10):3082-9.

Leclercq, S. (2016). Posttraumatic Stress Disorder: Does the Gut Microbiome Hold the Key? Can J Psychiatry. , 61(4):204-13.

Lee, Y. (2012). Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. , 487(7408):443-8.

Lin, H. (2012). Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. , 7(4):e35240.

M Guerville, G. B. (2016). Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation. Am J Physiol Gastrointest Liver Physiol. , 311(1):G1-G15.

Mayer, E. (2016). The Mind-Gut Connection. New York: Harper Collins.

Moreira, T. (2009). Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells. J Cereb Blood Flow Metab. , 29(7):1273-83.

N Vijay, M. M. (2014). Role of monocarboxylate transporters in drug delivery to the brain. Curr Pharm Des. , 20(10):1487-98.

O'Mahony, S. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. , 277:32-48.

Perlmutter, D. (2013). Grain Brain. Boston: Little Brown and Co.

Quig, D. (2016). The underappreciated Role of the Gastrointestinal Microbiome in Innate Detoxification. The Gastrointesitinal Metabolome (p. 183). Seattle: AKH Inc and Clinical Education.

Reigstad, C. (2015). Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. , 29(4):1395-403.

Rios-Covian, D. (2015). Enhanced butyrate formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis. FEMS Microbiol Lett. , 362(21).

Saint-Georges-Chaumet, Y. (2015). Targeting microbiota-mitochondria inter-talk: Microbiota control mitochondria metabolism. Cell Mol Biol (Noisy-le-grand)., 61(4):121-4.

Sass, V. (2010). Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci. Infect Immun. , 78(6):2793-800.

Shin, H. (2007). Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate. Hepatology. , 45(4):1046-55.

Stilling, R. (2016). The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int. , 99:110-32.

Sun, J. (2016). Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. Neurosci Lett. , 613:30-5.

Yano, J. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. , 161(2):264-76. .