Intestinal microecology: A crucial strategy for targeted therapy of liver diseases

Zeng-Rui Chen ,,Shui-Fng Jin ,,Wei-Bin M ,Rong-Lin Jing ,

a Intensive Care Unit, People’s Hospital of Yuhuan, Taizhou 31760 0, China

b Intensive Care Unit, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310 0 06, China

c Department of Pharmacy, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310 0 06, China

Intestinal microecology is an important part of human internal environment and is an extremely complex ecosystem consisting of gut microbiota, intestinal mucosa and intestinal immune sys-tem [1] . Gut is highly specialized for the digestion and absorption of different nutrients. The gut microbiota is the largest and most complex, which not only affects the local function of the intestine, but also plays an important role in the maturation and mainte-nance of the whole immune system.

Numerous studies [ 2,3 ] have deciphered that intestinal microe-cology plays a crucial role in the occurrence and development of multiple liver diseases, so called “gut-liver axis”. In nonalcoholic fatty liver disease (NAFLD) patients, intestinal microorganisms par-ticipate in NAFLD through a variety of mechanisms, e.g., increas-ing the production of short-chain fatty acids and energy absorp-tion in the intestine; the change of metabolism of dietary choline; the change of bile acid composition; the increase of endogenous ethanol caused by microorganisms. These factors may affect the metabolism of liver and damage the integrity of intestinal mucosa barrier, which enables endotoxin in the intestine to easily enter the liver through portal system, poisoning the liver.

Abnormal species, quantity, structure and distribution of intesti-nal flora were found in patients with alcoholic liver disease. Al-cohol intake favors the aerobic bacteria that produce alcohol de-hydrogenase in the small intestine, thus significantly increase ac-etaldehyde level in colon [4] . The high concentration of acetalde-hyde destroys the function of intestinal mucosa barrier, and en-ters the liver through portal vein system to aggravate liver injury. Alcohol intake also causes imbalance of composition of intestinal flora. Moreover, alcohol and its metabolite acetaldehyde directly damage intestinal mucosal epithelial cells, resulting in the destruc-tion of intestinal mucosal barrier function [5] . These factors lead to intestinal bacterial translocation and enterogenic endotoxemia. In alcoholic hepatitis, the tolerance of liver macrophages to endo-toxin disappears and liver macrophages are activated, which lead to of the secretion of cytokines and further damage of the liver. Similarly, the intestinal microecological system is disordered and the functional diversity of microbial groups is significantly reduced in patients with viral hepatitis and cirrhosis [6] . Pathogenic mi-croorganisms and metabolites (endotoxin, bacterial DNA) enter the blood sinuses through the gut-liver axis, causing chronic inflam-matory reaction and fibrosis of the liver.

Intestinal microorganisms are closely related to the immune system and systemic immune function of intestinal wall. Therefore, the changes of intestinal microecology affect liver function by af-fecting the immune system. The heterotopic activation of intesti-nal bacteria aggravates the liver disease in patients with autoim-mune liver disease: the diversity of intestinal flora is decreased, specific anaerobic bacteria are reduced, and potential pathogenic bacteria are enriched. Klebsiella pneumonia in patients with scle-rosing cholangitis destroys the intestinal epithelium, and promotes other bacteria to cross the intestinal barrier, which causes the liver inflammation reaction mediated by Th17 cells [7] . In the context of intestinal microecology imbalance, immune response is initi-ated against bacterial antigens, attacking the body’s own antigens with similar structure, thus inducing autoimmune response, lead-ing to autoimmune damage to liver and other tissues. The mi-gration of intestinal mucosal immune cells to the liver also ag-gravates the liver disease process: the endothelial cells in the si-nuses overexpress the endothelial adhesion molecule MAdCAM-1 and chemokine CCL25, which raise the lymphocytes from the in-testine to enter the liver and cause liver injury [8] .

Bile acid regulates the species and quantity of intestinal flora, and has cleaning function and direct antibacterial effect. It also af-fects intestinal flora indirectly through the action of farnesoid X receptor [9] . In intrahepatic cholestasis, the lack of bile acid in the gut results in imbalanced flora. The mechanical, chemical, immune and biological barriers of intestinal mucosa are destroyed. Then the metabolites and endotoxins of bacteria enter the blood, causing or-gan and tissue damage. Cholestasis and destruction of intestinal microecology affect each other. In patients with cholestasis, the barrier function of intestinal mucosa is damaged, and a large num-ber of bacteria and lipopolysaccharide shift, which leads to intesti-nal flora disorder, and the imbalance of intestinal flora further ag-gravates cholestasis.

The microbial group drives the occurrence of liver cancer through the inflammatory pathway among intestinal bacteria, im-mune system and liver. This process mainly involves the interac-tion of macrophages, Kupffer cells and pathogen-related molecu-lar models in the liver. Intestinal microecological disorders pro-mote the development of NAFLD associated liver cancer by alter-ing bile acid metabolism. The changes of intestinal microbiota may lead to the increase of deoxycholic acid, and then regulate the ag-ing related secretory phenotype of hepatic stellate cells. These will promote the secretion of various inflammatory factors and tumor promoting factors, and accelerate the progress of liver cancer [10] . The inflammatory environment of intestinal microbiota may also promote the development of cancer through the reduction of cyto-toxic effect of natural killer cells in the inflammatory environment.

With the development of molecular biology technology, metagenome sequencing and high-throughput sequencing technol-ogy, as well as the latest solid-state nanopore sequencing technol-ogy, it is possible for us to comprehensively and deeply analyze complex intestinal microorganisms. Considering its close relation-ship with intestinal microecology, it has become a hot spot to treat liver diseases and prevent their progression and deterioration by changing intestinal microecology.

The common methods of intestinal microecological intervention include dietary intervention, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation. So far, the research on dietary in-tervention has been focused on NAFLD, while the research on di-abetes and metabolic diseases in recent years provides more ev-idence that dietary intervention improves intestinal microecology and has therapeutic effects on chronic liver disease. Probiotics and prebiotics are widely used in clinical practice as microecological regulators. Probiotics have been used in the treatment of alcoholic liver disease, cirrhosis and complications [11] . Rifaximin, an antibi-otic that is not absorbed in the intestine, has been shown to im-prove liver damage caused by NAFLD and reduce the incidence of complications in patients with decompensated cirrhosis. Further-more, antibiotics and probiotics have shown some anticancer ef-fects in animal experiments. Fecal microbiota transplantation, as a hot method of microecological regulation, has been reported effec-tive in animal experiments and clinical applications in hepatitis B, alcoholic liver disease, NAFLD, and cirrhosis [12–14] . In the future, large sample clinical trials are still needed to further clarify the long-term efficacy and safety of fecal bacteria transplantation in chronic liver disease, and to explore the most suitable indications and applications.

Acknowledgments

None.

CRediT authorship contribution statement

Zeng-Rui Chen:Data curation, Investigation, Writing –original draft.Shui-Fang Jin:Data curation, Investigation, Writing –origi-nal draft.Wei-Bin Ma:Investigation, Writing –review & editing.Rong-Lin Jiang:Conceptualization, Funding acquisition, Writing –review & editing.

Funding

This study was supported by a grant from the National Natural Science Foundation of China ( 81774070 ).

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the sub-ject of this article.