Establishment of a chronic biliary disease mouse model with cholecystoduodenal anastomosis for intestinal microbiome preservation

BACKGROUND Chronic biliary disease,including cholangitis and cholecystitis,is attributed to ascending infection by intestinal bacteria.Development of a mouse model for bile duct inflammation is imperative for the advancement of novel therapeutic approaches.Current models fail to replicate the harmful bacterial influx to the biliary tract observed in humans and spread of inflammation to the liver.Therefore,we aimed to establish an animal model of biliary disease that faithfully replicates the mechanisms of human diseases.AIM To establish a cholecystoduodenal anastomosis model capable of mimicking the mechanisms of ascending infection and inflammation observed in human biliary diseases.METHODS We established a mouse biliary disease model by directly connecting the gallbladder and duodenum,enabling ascending infection into the biliary tract without traversing the sphincter of Oddi.RESULTS In the cholecystoduodenal anastomosis mouse model,we observed impaired epithelial structure,wall thickening,and macrophage recruitment in the gallbladder.Despite the absence of postoperative antibiotics,we detected no changes in serum proinflammatory cytokine levels,indicating no systemic inflammation.Moreover,patency between the gallbladder and duodenum was confirmed via common bile duct ligation.Injection of patient-derived pathogenic bacteria into bile duct-ligated mice led to ascending infection,which significantly increased proinflammatory cytokine mRNA expression in the liver,duodenum,and ileum.These results indicate that our mouse model exhibited a direct connection between the gallbladder and duodenum,leading to ascending infection and closely mimicking the clinical features of biliary diseases observed in humans.CONCLUSION The cholecystoduodenal anastomosis mouse model is an effective chronic biliary disease model with significant relevance in the development of microbiome-based therapies for the prevention and treatment of biliary disease.

Roles of macrophages in tumor development: a spatiotemporalperspective

Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we knowthat TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just beingunraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized rolesassociated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enablethe growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth.Finally, we speculate on the challenges that remain to be overcome in TAM research.

Brain macrophage development,diversity and dysregulation in health and disease

Brain macrophages include microglia in the parenchyma,border-associated macrophages in the meningeal-choroid plexus-perivascular space,and monocyte-derived macrophages that infiltrate the brain under various disease conditions.The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies.As such,we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development,homeostasis and disease pathogenesis.In this review,we first outline the critical roles played by brain macrophages during development and healthy aging.We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders,autoimmune diseases,and glioma.Finally,we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.