The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4 + CD45RB hi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

IL‐17 and IL‐22 are typical cytokines produced by the Th17 T cell subset, but it is unclear if Th17 cytokines can be produced by other cell types. We demonstrate that IL‐10‐deficient and IL‐10R‐deficient macrophages stimulated with lipopolysaccharide produce high levels of IL‐17 and IL‐22. Addition of exogenous IL‐10 to IL‐10‐deficient macrophages abolished IL‐17 production. When IL‐10‐deficient and IL‐10R‐deficient splenocytes were cultured under Th17 polarizing conditions, the population of IL‐17‐producing cells was increased and the cultures produced significantly higher levels of IL‐17 and IL‐22. The addition of recombinant IL‐10 to IL‐10‐deficient splenocytes significantly decreased the percentage of IL‐17‐producing CD4+ T cells. Finally, the mRNA for the Th17 transcription factor retinoic acid‐related orphan receptor (ROR)γt was significantly elevated in IL‐10‐deficient spleen cells and macrophages. These data demonstrate that Th17 cytokines and RORγt are also expressed in macrophages and that IL‐10 negatively regulates the expression of Th17 cytokines and RORγt by both macrophages and T cells.

The negative feedback mechanism is essential to maintain effective immunity and tissue homeostasis. 1,25-dihydroxyvitamin D (1,25(OH)2D3) modulates innate immune response, but the mechanism remains poorly understood. Here we report that vitamin D receptor (VDR) signaling attenuates Toll-like receptor-mediated inflammation by enhancing the negative feedback inhibition. VDR inactivation leads to hyper inflammatory response in mice and macrophage cultures when challenged with lipopolysaccharide (LPS), due to miR-155 overproduction that excessively suppresses SOCS1, a key regulator that enhances the negative feedback loop. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation, confirming that 1,25(OH)2D3 stimulates SOCS1 by down-regulating miR-155. 1,25(OH)2D3 down-regulates bic transcription by inhibiting NF-κB activation, which is mediated by a κB cis-DNA element located within the first intron of the bic gene. Together these data identify a novel regulatory mechanism for vitamin D to control innate immunity.

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ABSTRACT Background Currently, there is no direct evidence to prove the active SARS-CoV-2 replication in the intestinal tract and relevant pathological changes in the colon and rectum. We investigated the presence of virions and pathological changes in surgical rectal tissues of a clinically confirmed COVID-19 patient with rectal adenocarcinoma. Methods Here, the clinical data were collected during hospitalization and follow-up of this patient. Quantitative RT-PCR was performed on the rectal tissue specimens obtained from surgical resection, succus entericus and intestinal mucosa of ileostomy, and rectal mucosa during follow-up after recovery. Ultrathin sections of surgical samples were observed for SARS-CoV-2 virions using electron microscopy. Histopathological examination was performed using hematoxylin-eosin stain. Immunohistochemical analysis and immunofluorescence were carried out on rectal tissues to evaluate the distribution of SARS-CoV-2 antigen, and immune cell infiltrations. Results The patient had fever and cough on day 3 postoperatively, was diagnosed with COVID-19 on day 7, and was discharged from the hospital on day 41. RNA of SARS-CoV-2 was detected in surgically resected rectal specimens, but not in samples collected on 37 day after discharge. Notably, coincidence with rectal tissues of surgical specimens tested nucleic acid positive for SARS-CoV-2, typical coronavirus virions in rectal tissue were observed under electron microscopy. Moreover, abundant lymphocytes and macrophages (some are SARS-CoV-2 positive) infiltrating the lamina propria were found with no significant mucosal damage. Conclusions We firstly reported that direct evidence of the active SARS-CoV-2 replication in the patient's rectum during the incubation period, which might explain SARS-CoV-2 fecal-oral transmission.