Effects Of Visceral Adipose Derived Exosomes In Mice Colitis Regulation And Intervention Strategy

Inflammatory bowel diseases(IBD),mainly including Crohn's disease(CD)and ulcerative colitis(UC),are complicated intestinal inflammatory diseases affected by multiple factors.The symptoms of IBD include abdominal pain,diarrhea,blood in the stool and weight loss,which seriously reduces life quality of the patients.In addition,inflammatory bowel disease is inclined to recur,thus it is difficult to be cured completely.Repeated courses of the disease further aggravate the physical and psychological burden of patients,which causing tremendous investments in economic and medical resources as well.At present,the incidence and prevalence of IBD are increasing all over the world.Although there is no significant gender difference in IBD,it is closely related to the degree of social industrialization.The number of patients in developed countries is significantly larger than that in developing countries,and also cities has larger number of patients than rural areas.The incidence of IBD in China has increased dramatically in recent years.At present,it is the second highest in Asia,right after India.At the same time,the regional differences are significant.The incidence of IBD in urban areas is higher than that rural areas,and in the East is higher than that the west.It is believed that the regional differences of IBD incidence are due to the rapid development of economy,urbanization and population as well as the abundance of food and energy resulting from the industrialization of developed countries,which promotes the transformation of diet and living habits into "westernized" patterns such as high fat,high calories,sedentary and lack of exercise.More and more reports recognized the close correlation between the environmental factors and IBDincidence.Obesity is the most direct pathological change in the body caused by a high-fat and high-calorie diet.A large number of studies have confirmed that obesity,high-fat and highcalorie diet are significant risk factors of metabolic syndrome,cardiovascular diseases and multiple cancers such as colorectal cancer.This is because adipose tissue is not only an energy storage organ,but also an active secretory organ.Adipocytes can respond to other metabolic organs by secreting adipokines or inflammatory factors.A large number of studies have shown that exosomes are important for information exchange,especially in the communication between distant organs.At the same time,exosomes can also be engineered for drug loading and targeted delivery,which has broad application prospects of disease treatment.Recent studies have found that adipose tissue is one of the major organs of exosomes secretion.Macrophages,adipose stem cells and mature adipocytes in adipose tissue are all capable of exosome secretion.There are also a large number of exosomes in adipose tissue of obese patients which can activate macrophages and participate in the development of insulin resistance.In addition,it has been reported that adipose tissue-derived exosomes in obese individuals regulate Wnt and TGF-? signaling pathways and affect body condition through a group of micro RNAs.By analyzing various kinds of adipokines,we believe that exosomes,the extracellular vesicles that carry and transport biological macromolecules,may mediate the interaction between visceral fat and colonic tissue.This study aims to clarify the relationship between high-fat diet and colitis from the perspective of exosome and is expected to provide a new theoretical basis for the predisposing factors,prevention and treatment of colitis.The conclusions from the present study include:1.High-fat diet induces obesity in mice,and visceral fat-derived exosomes in obese mice can aggravate the phenotype of DSS-induced acute colitis.2.The visceral fat-derived exosomes of obese mice carry pro-inflammatory micro RNAs,which can effectively reach the lamina propria of colon and be taken up by macrophages in the lamina propria,promoting macrophages towards the pro-inflammatory M1 type.Induction of micro RNA-155 inhibitor into the above-mentioned exosomes via electroporation can significantly alleviate the phenotype of DSS-induced colitis in high-fat mice.3.Macrophages in adipose tissue are an important source of visceral adipose inflammatory exosomes.After removing macrophages from mice fed with high-fat diet,the abundance of inflammatory mi R-155 in visceral fat exosomes decreased significantly,and also alleviated the damage of colonic epithelium.In this study,we confirmed the important function of visceral fat exosome regulation pathway in the occurrence and development of colitis.At the same time,we have verified that modification of the exosome by loading micro RNA inhibitor can alleviate colitis.This study provides a new theoretical basis for the mechanism of colitis susceptibility,and offers new insights and strategies for the prevention and treatment of colitis as well.