Through clinical samples, mice with angiopoietin (ANG) gene deletion and various enteritis models, this study proved that ANG secreted by intestinal tract can differentially regulate the growth of α -proteobacteria and Laxella, and maintain the intestinal microecological balance. The deletion of Ang 1 leads to the disorder of intestinal flora and promotes the progress of enteritis in mice.
Everyone in life has had similar experiences, such as stomachache, diarrhea, loss of appetite and so on. People really feel the feeling of intestinal discomfort and hope to have a healthy intestine. Unfortunately, the incidence of inflammatory bowel disease (IBD) is increasing year by year in China. It is characterized by chronic inflammation of digestive tract, and its clinical manifestations are recurrent diarrhea, abdominal pain and bloody stool. And with the gradual progress of the disease, IBD patients will have structural and functional disorders of the digestive tract, which will seriously damage the quality of life of patients and their families. It is called "green cancer".
At present, it is believed that genetic susceptibility genes and various environmental factors lead to the occurrence of IBD, but the specific pathogenesis is still unclear. In order to deeply understand the pathogenesis of IBD and find ways to prevent, diagnose and effectively treat IBD, researchers all over the world are exploring from many angles. Many studies have proved that intestinal flora plays an important role in the occurrence and development of IBD.
Intestinal flora is all bacteria designated to be planted in human digestive tract. Although we often ignore the existence of intestinal flora, they actually play a very important role in the health of the body. Intestinal flora is a diverse and vibrant bacterial community. The research shows that there are more than 1000 kinds of intestinal flora in a healthy adult, and the total is about 4× 10E 13+03, which is equivalent to the number of human cells.
A huge and complex microecosystem is composed of a wide variety of intestinal flora, which has many functions, such as helping digestion, promoting intestinal cell differentiation, protecting the host from pathogen infection, stimulating and regulating the immune system and so on. It is considered as a "hidden organ". However, under the influence of internal and external factors, the intestinal flora may be disordered in structure and/or function, which will induce many diseases.
Protein (AMPs), a kind of small molecule with antibacterial activity, is secreted by intestinal Paneth cell and intestinal epithelial cells, which has a wide range of antibacterial, antifungal and antiviral activities. At present, the intestinal antimicrobial peptides found include defensins, cathepsin inhibitors, regenerated islet-derived proteins, ribonuclease, lysozyme and so on.
Clinical trials and laboratory studies show that the abnormal expression of antimicrobial peptides is closely related to the occurrence and development of IBD. However, at present, there is a lack of research on the antibacterial effect of antibacterial peptides in vivo, and the relationship between specific flora regulated by antibacterial peptides and IBD has not yet been established. Therefore, exploring the interaction of antimicrobial peptides-bacteria -IBD and clarifying its regulatory mechanism may provide a new way for the diagnosis and treatment of IBD.
Xu Zhengping/Sheng's research team used clinical samples, mice with angiopoietin (ANG) gene deletion and various enteritis models to prove that ANG secreted by intestinal tract can differentially regulate the growth of α -proteobacteria and Laxella, and maintain the intestinal microecological balance. The deletion of Ang 1 leads to the disorder of intestinal flora and promotes the progress of enteritis in mice.
The research team found that a healthy intestine can secrete an appropriate amount of ANG protein into the intestinal cavity, while the ANG content of patients with IBD is only about half that of normal people. In order to answer whether the lack of ANG secretion is related to the occurrence and development of IBD, they induced enteritis in Ang 1 gene-deficient mice and wild-type mice, and found that the symptoms of enteritis in Ang 1 gene-deficient mice were obviously aggravated.
Furthermore, they transferred the feces of Ang 1 gene-deficient mice to the intestines of wild-type mice, and found that the symptoms of enteritis in the latter were also significantly aggravated. The above evidence shows that ANG can affect the progress of IBD by regulating intestinal flora.
Then, using high-throughput sequencing technique, they found that the intestinal flora of Ang 1 deficient mice changed significantly, which was mainly manifested by the increase of Proteus α and the decrease of Chaetomium. More importantly, they screened out strains regulated by ANG through bacterial culture and identification techniques, namely B. diminuta and S. paucimobilis belonging to the genus α Proteus, and Anaerostipes sp. And the Brautian species. It belongs to Chaetomium family, and it has been proved that the former can promote enteritis in mouse model, while the latter is the opposite.
The above results suggest that these different strains can be used as indicators for clinical diagnosis of IBD, and two strains of Chaetomium have the potential to prevent or treat IBD, which may be developed into probiotic preparations for clinical application in the future.
Then, the team revealed the mechanism of ANG regulating intestinal flora. Through in vitro antibacterial experiments and scanning electron microscopy, they found that ANG can selectively bind and effectively kill α Proteus. Further in vitro bacterial culture experiments show that Proteus α and Chaetomium can inhibit each other, which explains why ANG can promote the growth of Chaetomium while inhibiting Proteus α.
Finally, the research team explored the feasibility of ANG regulating intestinal flora and reducing IBD. By supplementing recombinant Ang 1 protein to the digestive tract of ANG 1 deficient mice, the disorder of intestinal flora in mice was effectively restored and the symptoms of enteritis were obviously alleviated. This provides experimental evidence support for the clinical transformation application of ANG.
It is reported that professors and lecturers from Zhejiang University School of Medicine and Liangzhu Laboratory (Zhejiang Systematic Medicine and Precision Diagnosis and Treatment Laboratory) are the * * * correspondence authors of this article. Sun Desen, a Ph.D. student at Zhejiang University School of Medicine, Bai Rongpan, a postdoctoral fellow, and Zhou Wei, chief physician of general surgery at Shaw Hospital, are the same works of this paper. The research results are supported by the National Natural Science Foundation of China and the Natural Science Foundation of Zhejiang Province.
Paper link:
http://dx . doi . org/ 10. 1 136/gut jnl-20 19-320 135