Huimin Chen

Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.

Objective Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) is highly expressed in inflamed mucosa of inflammatory bowel disease (IBD) and negatively regulates immune response, while the underlying mechanisms regulating mucosal macrophage functions remain unknown. Here, we investigated the roles of MCPIP1 in modulating the differentiation and functions of intestinal macrophages in the pathogenesis of IBD. Design ScRNA-seq was used to cluster the monocyte/macrophage lineage from macrophage-specific Mcpip1 -deficient ( Mcpip1 ∆Mye ) mice and Mcpip1 fl/fl littermates. The differentially expressed genes were confirmed by RNA-seq, luciferase assay, CUT&Tag assay and Western blotting. Effects of MCPIP1 and the activating transcription factor 3 (ATF3)-AP1S2 axis were assessed in patients with IBD. Results Mcpip1 ∆Mye mice developed more severe dextran sulfate sodium (DSS)-induced colitis characterised by an increase in macrophage migratory capacity and M1 macrophage polarisation but a decrease in the monocyte-to-macrophage maturation in gut mucosa compared with their littermates. ScRNA-seq unravelled a proinflammatory population (Ccr2 + Il-1β + Tlr2 + Cx3cr1 − Cd163 − Mrc1 − Ly6c + ) of the monocyte/macrophage lineage from lamina propria CD11b + cells and an arrest of Mcpip1 ∆Mye monocyte-to-macrophage maturation in an Atf3-Ap1s2 axis-dependent manner. Silencing of Ap1s2 or Atf3 markedly suppressed Mcpip1 ∆Mye macrophage migration, M1-like polarisation, and production of proinflammatory cytokines and chemokines. Notably, in vivo blockage of Ap1s2 ameliorated DSS-induced colitis in Mcpip1 ΔMye mice through enhancing intestinal macrophage maturation. Furthermore, MCPIP1, ATF3 and AP1S2 were highly expressed in inflamed mucosa of active patients with IBD and blockage of ATF3 or AP1S2 significantly suppressed IBD CD14 + -derived M1-like macrophage polarisation and proinflammatory cytokine production. Conclusions Macrophage-specific Mcpip1 deficiency polarises macrophages towards M1-like phenotype, arrests macrophage maturation and exacerbates intestinal inflammation in an Atf3-Ap1s2-dependent manner, thus providing novel mechanistic insight into intestinal macrophage functions during IBD.