Editor's note: On June 24-26, 2022, the "Fifth National Academic Conference on Liver Disease-Related Infections" sponsored by the Chinese Medical Association and the Liver Disease Branch of the Chinese Medical Association was successfully held in a combination of offline and online forms. The meeting invited well-known experts at home and abroad to give special academic reports on hot topics in clinical diagnosis, treatment and research of liver disease-related infectious diseases at home and abroad. During the period, Professor Zhou Yongjian, National Key Clinical Specialty and Director of the Gastroenterology Department of Guangzhou First People's Hospital made a wonderful special report on the progress of clinical research on intestinal microecology and liver disease. This journal specially invites Professor Zhou to write an article on this topic for the benefit of readers.
The intestinal microecosystem is composed of intestinal flora and the intestinal environment in which it lives. The intestinal flora is its core part. The normal structure of the intestinal mucosa and the stable function of intestinal barrier are the intestinal microecology. The most important factor for the normal operation of system . Intestinal flora is known as the "invisible organ" of human beings and plays an important role in the occurrence and development of many diseases. Since Marshallpo proposed the concept of "gut-liver axis" in 1998 [1], with the development of high-throughput sequencing technology and the progress of metagenomics and metabolomics , more and more studies have suggested that the intestinal Tract flora dysbiosis plays an important role in the process of liver diseases such as hepatic steatosis, liver cell damage and fibrous connective tissue remodeling [2]. Diagnosis and treatment methods targeting intestinal flora are also gradually recognized.
Non-alcoholic fatty liver disease (nonalcoholic fatty liver disease, NAFLD) has become one of the most important liver diseases and important public health issues in the world [3]. The cause and pathogenesis of NAFLD are still controversial. The latest research believes that intestinal flora disorder and the resulting intestinal metabolites are the key to the development of NAFLD, leading to persistent inflammatory damage to the liver. The liver and intestines are closely connected in structure and function. Intestinal microorganisms and their metabolites play an important role in the development of liver damage, chronic fibrosis and inflammation through the liver-gut axis [4].
The research results of the author's team suggest that the occurrence of NAFLD is related to intestinal flora imbalance: On the one hand, the intestines of NAFLD mice include Prevotella, Lactobacillus (Lactobacillus), Roseburia The distribution of bacterial groups such as Roseburia and Coprococcus showed obvious differences; on the other hand, NAFLD mice with intestinal flora dysbiosis had significantly aggravated hepatic steatosis and fibrosis , and were given probiotics. The condition of mice with intestinal flora imbalance treated with bacteria has been alleviated [5], but the mechanism through which intestinal flora imbalance affects body metabolism and thereby promotes the occurrence and progression of NAFLD remains to be further clarified.
Follow-up research by the author's team showed that macrophages deficient in FoxO1 tend to be in a state of M2 polarization. M1 polarization of macrophages plays a key role in the occurrence and development of NAFLD. Based on this, it is speculated that macrophage intervention FoxOs in cells can play a role in treating NAFLD. In addition, macrophages in the liver are highly heterogeneous, and FoxOs may have different regulatory mechanisms for different subpopulations of macrophages. By designing nanoparticles that target different subpopulations of macrophages, precise regulation of FoxOs treatment can be achieved, thereby achieving the purpose of treating NAFLD (data to be published).
Previous studies have shown that compared with healthy people, the intestinal flora of patients with HBV-related cirrhosis has a 10-fold increase in the number of Proteobacteria and a 13-fold decrease in the Bacteroidetes amount [6]. Intestinal flora and related products, as external stimuli, can be recognized by the body's immune system and cause a series of immune responses. Currently, the lipopolysaccharide-Toll-like receptor 4 (TLR4) pathway is well studied. lipopolysaccharide is the main component of the Gram-negative bacterial cell wall. It can activate TLR4, cause related pro-inflammatory reactions, and can promote the differentiation of liver cells, inhibit cell apoptosis , and promote the progression of liver cancer [7].Compared with healthy controls, the diversity of intestinal flora in patients with AIH decreases and the composition of the overall flora changes, characterized by a decrease in obligate anaerobic bacteria and an enrichment of potentially pathogenic bacteria such as Veillonella [8] .
There are many clinical strategies to regulate the intestinal microecology, including antibiotics, probiotics, prebiotics , synbiotics and fecal microbiota transplantation (fecal microbiota transplantation, FMT). FMT is a new method developed in recent years to treat various diseases by adjusting the intestinal microecology. It transplants the microflora/microbiome of healthy donors, or even human cells, into the patient's intestines to rebuild the intestines. Tao microecology, treating diseases inside and outside the intestines. The therapeutic effect of FMT on NAFLD has been positively evaluated in multiple animal and clinical studies. The author's previous open-label controlled clinical study showed that 11 NAFLD patients who underwent multiple times of fresh fecal bacteria FMT via colonic TET, including transaminase, HOMA-IR (homeostasis model insulin resistance index), serum LDL- C and triglycerides , liver transient elastography fat attenuation index and other indicators were significantly improved (data to be published).
In addition, Stadlbauer et al. reported a study using Lactobacillus casei to treat patients with alcoholic cirrhosis. The results showed that Lactobacillus casei can regulate the expression of TLR4 and the secretion of IL-10, thereby restoring neutropenia in patients with alcoholic cirrhosis. Phagocytic ability of granulocytes [9]. Clinical trials on viral hepatitis have shown that fecal transplantation can induce clearance of HBeAg in a significant proportion of patients with persistent HBeAg positivity [10]. Administration in the form of fecal bacteria capsules can significantly improve the cognitive ability of patients with hepatic encephalopathy and increase the abundance of Bifidobacteriaceae and Ruminococcaceae and decrease the abundance of Streptococcaceae and Veillonellaceae [11].
As people’s understanding of the gut-liver axis deepens, the role of intestinal microecology in liver diseases has received more and more attention, and treatment methods centered on intestinal flora are constantly being re-recognized. However, the research on intestinal microecology in liver diseases still has the following limitations: (1) Intestinal flora disorder is one of the important causes of liver system diseases. Current research is mostly focused on exploring the correlation. The pathogenesis still needs in-depth study; (2) There are increasing reports of characteristic flora as biomarkers of liver diseases, but the characteristics of intestinal flora have obvious regional differences, and more large-scale samples, large-scale, and multiple Research support from the center; (3) Treatment methods centered on flora, especially the application of fecal microbiota transplantation. Early studies are mostly based on animal models. There are species differences in the intestinal flora of animals and humans, and similar liver diseases Whether animal models can be a good substitute for human diseases needs to be considered, especially the fecal eating behavior in rodent models, which will interfere with the study of flora; (4) The treatment methods with flora as the core involve microbial preparations, which are different from The preparation process and source of microorganisms have an impact on the disease intervention effect, and may even cause adverse reactions. The establishment of standardized and scientific industry standards is an important guarantee for the treatment of liver diseases with flora as the core.
In summary, intestinal microecology is closely related to liver diseases. There is still an urgent need for large-scale, high-quality, multi-center research in this field, and the effectiveness and effectiveness of intestinal flora as a diagnostic and treatment method for liver diseases need to be carefully evaluated. Safety, providing scientific and reliable basis for the prevention and treatment of liver diseases.
Reference:
[1] MARSHALL J C. The gut as a potential trigger of exercise-induced inflammatory responses[J]. Canadian journal of physiology and pharmacology, 1998,76(5): 479-484.
[2] PHILIPS C A, AUGUSTINE P, YEROL P K, et al. Modulating the Intestinal Microbiota: Therapeutic Opportunities in Liver Disease[J]. Journal of clinical and translational hepatology, 2020,8(1): 13-87.
[3] Younossi ZM . Non-alcoholic fatty liver disease - A global public health perspective. Journal of hepatology 2019, 70(3): 531-544.
[4] Hui-Ting Chen, Hong-Li Huang, Yong-Qiang Li, Hao-Ming Xu , Yong-Jian Zhou. Therapeutic advances in non-alcoholic fatty liver disease: Amicrobiota-centered view. World J Gastroenterol. 2020 Apr 28;26(16):1901-1911.
[5] Zhou Y, Zheng T, Chen H , Li Y, Huang H, Chen W, Du Y, He J, Li Y, Cao J, Nie Y, Zhou Y. Microbial Intervention as a Novel Target in Treatment of Non-Alcoholic Fatty Liver Disease Progression. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2018, 51(5): 2123-2135.
[6] WEI X, YAN X, ZOU D, et al. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach[J]. BMC gastroenterology, 2013,13(1): 175.
[7] Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell, 2012, 21(4): 504-516.
[8] Wei Y, Li Y, Yan L, et al. Alterations of gut microbiome in autoimmune hepatitis. Gut. 2020;69(3):569-577 .
[9] STADLBAUER V, MOOKERJEE R P, HODGES S, et al. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis[J]. Journal of Hepatology, 2008,48(6): 945 -951.
[10] REN Y, YE Z, YANG L, et al. Fecal microbiota transplantation induces hepatitis B virus e-antigen (HBeAg) clearance in patients with positive HBeAg after long-term antiviral therapy[J]. Hepatology ( Baltimore, Md.), 2017,65(5): 1765-1768.
[11] BAJAJ J S, SALZMAN N H, ACHARYA C, et al. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo ‐Controlled Trial[J]. Hepatology (Baltimore, Md.), 2019,70(5): 1690-1703.
Expert introduction
Professor Zhou Yongjian
Professor, MD, Chief Physician, Doctoral supervisor, National Key Clinical Specialty, Guangzhou Director of the Gastroenterology Department of the First People's Hospital of Guangzhou, a high-level health talent in Guangzhou. He currently serves as a member of the Liver Disease Branch of the Chinese Medical Association, the chief expert of a member unit of the National Center for Early Gastrointestinal Cancer Prevention and Treatment, a member of the Interventional Gastrointestinal Endoscopy Branch of the Chinese Medical Doctor Association, the Chairman of the Liver Disease Branch of the Guangdong Medical Association, and the Immune Hepatology Group of the Guangdong Medical Association. Team leader, director of the Inflammatory Bowel Disease Diagnosis and Treatment Regional Center (IBDQCC), deputy chairman of the Liver Disease Branch and Endoscopy Branch of Guangdong Medical Doctors Association, chairman of the Endoscopy Branch of Guangzhou Medical Doctors Association, etc. In the past five years,
has received 2 National Natural Science Foundation general projects, 2 Guangdong Provincial Natural Science Foundation projects, 1 Guangzhou Science and Technology Plan Project, and 1 Guangzhou High-tech Project, with a total of RMB 6 million in scientific research funding. In the past five years, he has published 30 SCI articles as the first author or corresponding author, with an impact factor of 104.
Expert profile
Chen Huiting
National key clinical specialty, chief physician of the Department of Gastroenterology, Guangzhou First People's Hospital, master's tutor. He first concurrently served as a member and secretary of the Liver Disease Branch of the Guangdong Medical Association, a standing committee member of the Liver Disease Specialist Branch of the Guangdong Medical Doctors Association, and a deputy director of the Digestive Endoscopy Physician Branch of the Guangzhou Medical Doctors Association. In the past three years, he has won 1 Guangdong Provincial Medical Research Fund, 1 Guangzhou Science and Technology Plan Project, and 1 Guangzhou High-tech Project. In the past 5 years, he has published 5 SCI articles as the first author or corresponding author.
