The study examines the complex gut-brain-liver connection and its impact on health

In a recent study published in the journal Signal transduction and targeted therapyresearchers review existing data on the gut-brain-liver axis in health and disease.

survey: Gut-liver brain axis in disease: implications for therapeutic interventions. Image credit: Svetlana Pavlyuk / Shutterstock.com

What is the gut-brain-liver axis?

The axis connecting the gut, brain, and liver, otherwise known as the gut-brain-liver axis, is a tripartite interaction that has recently attracted increasing scientific interest. Over the past two decades, researchers have made significant progress in the study of gut-brain-liver communication by better understanding its developmental process and expanding therapeutic options. Interventions based on the gut-brain-liver connection could facilitate personalized treatment.

Mechanisms connecting the intestine and the liver

Communication between the liver and the gastrointestinal tract involves a complex network of interconnected pathways that play a critical role in various diseases, including chronic hepatitis B virus (HBV), HCV, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) ) and hepatocellular carcinoma (HCC).

Intestinal dysbiosis contributes to the development of liver disease by increasing the number of pathogens and their metabolites, such as lipopolysaccharide (LPS), destroying tight junctions (TJs) and altering intestinal permeability. This condition also affects the formation of short-chain fatty acids (SCFAs), fasting-inducible adipose factor (FIAF), intestinal ethanol and choline, as well as the metabolism of BAs. In association with dietary lipid molecules, these variables and metabolites contribute to fatty liver disease, inflammation, and HCC.

The gut microbiome controls the liver-gut axis, with metabolites such as LPS and pathogen-associated molecular patterns (PAMPs) binding to toll-like receptors (TLRs) on intestinal epithelial cell membranes. This stimulates the nuclear translocation of nuclear factor kappa B (NF-B) and cytokine production.

Intestinal dysbiosis reduces FIAF secretion, thereby increasing endogenous alcohol synthesis and allowing ethanol and endotoxins to enter the liver directly. This health condition also suppresses SCFA production, thereby prompting neuroendocrine cells to produce peptide YY (PYY) and glucagon-like peptide 1 (GLP-1).

Endotoxins produced by intestinal bacteria increase the production of inflammatory substances by immune cells. In the gut-liver axis, cytokines regulate intestinal permeability, while the Farnesoid X receptor (FXR) regulates BA production and transport.

BAs are formed in hepatocytes by oxidation of cholesterol by cytochrome P450 enzymes (CYPs) to create cholic acid (CA) and chenodeoxycholic acid (CDCA). These acids conjugate taurine or glycine to form conjugated BAs and are released from the liver into the gallbladder and then into the intestine.

Brain-Liver Communication

Communication between organs is mediated by neurological and blood signals, with the brain-liver axis mainly involving blood-brain barrier (BBB) ​​permeability, vagus nerve, epigenetic control, toxic metabolites, β-amyloid (A) metabolism and immunological response. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) proinflammatory cytokines in the liver induce indiscriminate uptake of toxins such as ammonia and xenobiotics, resulting in a proinflammatory response.

Changes in BBB permeability can stimulate the hypothalamic-pituitary-adrenal (HPA) axis, ultimately leading to cortisol production. Stress disrupts HPA regulation, which affects brain-gut communication, especially in irritable bowel syndrome (IBS).

The vagus nerve, a two-way highway connecting the brain and stomach, is intrinsically linked to the enteric nervous system (ENS) and can influence brain functions such as anxiety, stress response, depression, and social behavior. This nerve sends signals from the gut to the central nervous system (CNS) and can detect transmission of microbes from the CNS.

Additionally, neurotransmitters such as gamma-aminobutyric acid (GABA), glutamate, acetylcholine, dopamine, norepinephrine, and trace amines can be synthesized and modulated by the gut microbiota.

Therapies targeting the gut-brain-liver axis

Antibiotics, especially non-absorbable antibiotics, are critical to the management of gut microbiota and influence the evolution of diseases of the gut-brain-liver axis. For example, rifaximin, a broad-spectrum antibiotic, is effective in biopsy-proven NAFLD.

Containing probiotics Lactobacilli, Streptococciand bifidobacteria it may also help prevent the development of liver and brain diseases such as NAFLD, nonalcoholic steatohepatitis (NASH), autism spectrum disorder (ASD), depression, Parkinson’s disease (PD), schizophrenia, epilepsy, and migraines. Leptin, a probiotic molecule, affects gut bacteria and the vagus nerve, thus demonstrating its vital role in liver and brain function.

Prebiotics increase bacterial metabolites, enhance the development of bifidobacteria and Lactobacilli, reduces lumen pH and limits the growth of pathogens in liver disease, anxiety and depression. In addition, synbiotics, a mixture of prebiotics and probiotics, have been shown to be beneficial in a variety of diseases related to the gut-brain-liver axis.

Fecal microbiota transplantation (FMT) is a revolutionary treatment that involves transplanting intestinal bacteria from a healthy donor to a patient. FMT treats dysbiosis in the gastrointestinal tract and reduces inflammation caused by the LPS-TLR4 signaling pathway in the gut and brain.

Polyphenols, which are components of plant origin, are absorbed in the colon by intestinal bacteria and improve metabolic disorders such as type 2 diabetes, NASH, NAFLD and aging. Cranberry extract improves metabolic syndrome by reversing changes in gut flora caused by diets high in fat and sugar. Isoflavone, lignans and their metabolites generated by intestinal bacteria can penetrate the intestinal barrier and BBB and inhibit neuroinflammatory stimulation.

Conclusions

The present review highlights the mechanisms underlying the gut-brain-liver connection. Antibiotics, especially those that are not absorbed, regulate the gut microbiota and affect diseases of the gut-brain-liver axis. Rifaximin and solithromycin treat NAFLD and NASH, while probiotics such as Lactobacilli, streptococci, and bifidobacteria improving liver and brain related dysfunction.

Further research into gut-brain-liver axis interactions could facilitate the development and clinical translation of gut microbiota-based treatments to improve the standard of care for those with brain or liver disease.