Gut Microbiome Communication: The Gut-Organ Axis

Jan. 18, 2023

Human gut microbiota colonized along the inside of the large intestine. These bacteria play a major role in human health and disease.
Trillions of microbes colonize the intestine and are known as the human gut microbiota. Microbiome composition affects organ function and influences human health and disease.
Source: Marcon Klapczynski/iStock
There is accumulating evidence supporting the relationship between the human gut microbiome and organ function outside the gut. Researchers have coined the term “axis” to describe the bi- or multi-directional pathways through which one part of the body biochemically communicates with another part of the body. Specific axes between the gut and non-gastrointestinal organ systems have been identified. Axes can run along nerve pathways, through the portal vein or directly through the intestinal epithelial barrier into the bloodstream.

The trillions of microbes inhabiting the intestine are known as the human gut microbiota. The gut microbiome performs numerous functions, including protecting the barrier integrity of the intestine, producing vitamins such as B12 and K and regulating the immune system. The gut microbiome metabolizes available substrates and releases various metabolites, such as short-chain fatty acids (SCFA) and neuro-active compounds, that become the biochemical signals that travel through the various axes and modulate functions in remote tissue. This innate communication system demonstrates the impact the gut microbiome has on human physiology.

Gut-Brain Axis

Illustrative representation of the gut-brain axis.
Illustrative representation of the gut-brain axis.
Source: iStock
Communication between the gut and brain takes place along afferent spinal and efferent vagal nerve pathways and via neuroimmune and neuroendocrine signalsNeurotransmitter-receptor sites on intestinal microbes allow for efficient communication between the brain and gut.

Neurologically active compounds produced by the gut microbiome affect brain function by regulating production, metabolism and transmission of neurotransmitters. Microbes in the gut metabolize the amino acid tryptophan into serotonin and other metabolites, regulating serotonin levels in the brain. Cortisol release during fear- and stress-responses slows the migrating motor complexes, which control gastrointestinal peristalsis and chyme production in the stomach and small intestine. Disrupted microbial composition in the gut is an observed outcome. Furthermore, studies demonstrate patients with anxiety have elevated levels of pro-inflammatory cytokines and diminished anti-inflammatory, SCFA-producing microbiome.
Conversion of dietary tryptophan to tryptamine (of which serotonin is a derivative) can take place in the gut and is facilitated by the microbiome.
Conversion of dietary tryptophan to tryptamine (of which serotonin is a derivative) can take place in the gut and is facilitated by the microbiome.
Source: Kwingfield/Wikimedia

Gut-Skin Axis

Skin and the gastrointestinal tract share the following common traits, which form the basis of their axis:
  • Colonized by microbiota.
  • Rich in immune cells, nerve- and blood-supply.
  • Large organs with total surface area measuring >20 meters squared, on average.
  • Lined with epithelial cells that form a protective barrier from their outside environments.
Communication between the gut and skin is reported to involve multiple channels including the immune and endocrine systems. For example, wheat allergy manifests as gastrointestinal reactions (stomach cramps, diarrhea), immune reactions (runny nose, sneezing, itching) and skin reactions (rash, hives). Studies have found exposure to peanut protein from indoor dust through non-intact skin can elicit peanut allergy in atopic dermatitis patients. Evidence suggests close to 10% of patients with irritable bowel syndrome have psoriasis. Furthermore, study participants with skin exposure to narrow-band UVB light demonstrated increased serum vitamin-D levels and greater gut microbiome diversity, compared to those taking vitamin-D supplements alone. These examples illustrate bi-directional communication between the gut and skin via the immune and endocrine systems.

Gut-Pancreas-Liver Axis

In addition to serotonin, gut microbes metabolize tryptophan into the organic compound indole. Indole has been shown to regulate short- and long-term glucagon-like peptide 1 (GLP-1) secretion, a hormone released in the intestine to regulate blood glucose and insulin levels in response to a meal. GLP-1 stimulates pancreatic insulin production and reduces glucose production and insulin clearance by the liver. Microbial fermentation of dietary fiber yields SCFA, which are also known to stimulate GLP-1 secretion.

Dysbiosis is Linked to Diseases of the Body and Mind 

Disruption to the gut microbiome composition is known as dysbiosis. A consequence of dysbiosis is altered amounts of metabolites produced by the microbiome, which may be tied to the development of various diseases, like inflammatory bowel diseasekidney disease and hepatic encephalopathy. Although more research is needed to fully understand the mechanisms explaining dysbiosis and disease, low-grade inflammation is a common theme in conditions associated with gut dysbiosis.

Lipopolysaccharides Trigger Immune Responses and Inflammation

Depiction of how LPS is recognized by a pattern recognition receptor (PRR) on the surface of a macrophage. Binding results in the eventual release of cytokines.
Depiction of how LPS is recognized by a pattern recognition receptor (PRR) on the surface of a macrophage. Binding results in the eventual release of cytokines.
Source: Wikimedia

Members of the gut microbiota synthesize lipopolysaccharides (LPS), which are also a part of the gram-negative bacterial cell wall Dysbiosis is often characterized by an increased Firmicutes to Bacteroidetes phyla ratio associated with decreased SCFA, increased LPS and inflammation. In the dysbiotic state, increases in LPS disrupt intestinal barrier integrity and trigger different immune response cascades, depending on their source. This inflammatory response further damages gut barrier integrity, allowing translocation of gut microbes and LPS directly into the bloodstream or through the portal circulation.

Increased concentration of LPS in the gut and in circulation is associated with cytokine-induced inflammation and even insulin resistance. LPS bind to Toll-like receptors (TLR), a receptor site expressed on most cells. LPS binding to TLR activates cytokine-induced inflammation observed in anxiety and depressionobesitytype 2 diabetes and Parkinson’s disease.

Mechanistic (Mammalian) Target of Rapamycin Implicated In Diabetes and Acne

Mechanistic (mammalian) target of rapamycin (mTOR) is a protein kinase enzyme involved in different metabolic processes. MTOR binds with other proteins to form complexes involved in specific metabolic processes. Overactivation of the mTOR pathway from increased microbial production of imidazole propionate, a histidine metabolite, is implicated in prediabetes and type 2 diabetes. MTOR activation also increases sebaceous gland cell proliferation, sebum production and keratinocyte production associated with acne.

Reduced SCFA Production Linked to Autism, Epilepsy and Schizophrenia

Dysbiosis with reduced production of SCFA, particularly butyrate, and high levels of cytokines are found in children and teens with autism spectrum disorders. Metabolism of amino acids tryptophan and glutamate is altered. This alteration reduces production of serotonin and gamma-aminobutyric acid, 2 important inhibitory neurotransmitters also associated with epilepsy and schizophrenia.

The Interplay between the Gut Microbiome, the Gut-Organ Axis and Dysbiosis

Possible roles of gut microbiota in gut barrier functions, health benefits and non-communicable diseases.
Possible roles of gut microbiota in gut barrier functions, health benefits and non-communicable diseases.
Source: Cintoni E. Rinninella, et al./Wikimedia

The state of your health might just lie within your intestines. One’s overall health can be explained, in part, by the diversity and composition of intestinal microbes and their genes, collectively known as the human gut microbiome. The gut-organ axis is a bi- or multi-directional, multi-channel communication system that allows the gut and extraintestinal organs to communicate with one another and is fundamental to understanding how the gut microbiome affects human health.

A growing number of studies are linking dysbiosis to acute and chronic diseases. In dysbiosis, pro-inflammatory microbiota produce metabolites that reach extraintestinal organs via distinct gut-organ axes, setting the stage for disease. 

A key takeaway from the scientific evidence surrounding the gut microbiome, the gut-organ axis and dysbiosis is that health can be impaired, improved and even restored, depending on the microbiome composition and the anti- or pro-inflammatory nature of their metabolites. It is these metabolites that are the biochemical signals impacting physiology and, thus, health and disease via the gut-organ axis.
Microbial communities exist on, in and around people, plants, animals and the environment, making the microbiome relevant to nearly all facets of life. Learn more about the function and compositions of these microbial communities. 


Author: Edina Fredell, MPH, MT(ASCP), CIC

Edina Fredell, MPH, MT(ASCP), CIC
Edina Fredell, MPH, MT(ASCP), CIC, is an infection preventionist with Kaiser Permanente, Kaiser Foundation Hospitals.