Francesca Invernizzi

Context: Increasing evidences suggest a correlation between gut and type 1 diabetes (T1D). Objective: The objective of this study is to evaluate the gut inflammatory profile and microbiota in patients with T1D compared with healthy control (CTRL) subjects and patients with celiac disease (CD) as gut inflammatory disease controls. Design/Setting/Participants: The inflammatory status and microbiome composition were evaluated in biopsies of the duodenal mucosa of patients with T1D (n = 19), in patients with CD (n = 19), and CTRL subjects (n = 16) recruited at San Raffaele Scientific Institute, in Milan, Italy, between 2009 and 2015. Main Outcome Measures: Inflammation was evaluated by gene expression study and immunohistochemistry. Microbiome composition was analyzed by 16S ribosomal RNA gene sequencing. Results: An increased expression of CCL13, CCL19, CCL22, CCR2, COX2, IL4R, CD68, PTX3, TNFα, and VEGFA was observed in patients with T1D compared with CTRL subjects and patients with CD. Immunohistochemical analysis confirmed T1D-specific inflammatory status compared with healthy and CD control tissues, mainly characterized by the increase of the monocyte/macrophage lineage infiltration. The T1D duodenal mucosal microbiome results were different from the other groups, with an increase in Firmicutes and Firmicutes/Bacteroidetes ratio and a reduction in Proteobacteria and Bacteroidetes. The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in the duodenum. Conclusions: This study shows that duodenal mucosa in T1D presents disease-specific abnormalities in the inflammatory profile and microbiota. Understanding the mechanisms underlying these features is critical to disentangle the complex pathogenesis of T1D and to gain new perspectives for future therapies targeting the intestine.

Significance Oxysterols promote tumor growth directly or through the dampening of tumor-infiltrating immune cells. Whether oxysterols contribute to pancreatic neuroendocrine tumor (pNET) development and how they are generated within the pNET microenvironment are currently unknown. Here, we show that the 24S-hydroxycholesterol (24S-HC) oxysterol-generating enzyme Cyp46a1 is overexpressed during the angiogenic switch in rat insulin promoter 1–T-antigen 2 (RIP1-Tag2) pNET formation. Moreover, we report that Cyp46a1 overexpression requires hypoxia inducible factor-1a (HIF-1α). Importantly, we show that pharmacologic blockade and genetic inactivation of 24S-HC delays angiogenic switch and therefore tumor formation in RIP1-Tag2. Overexpression of Cyp46a1 transcripts in some human pNET samples suggests that targeting this axis in patients affected by pancreatic neuroendocrine tumors may be an effective therapeutic strategy.