Highlights d SARS-CoV-2-infected RMs mimic signatures of inflammation seen in COVID-19 patients d Baricitinib suppresses production of pro-inflammatory cytokines in lung macrophages d Baricitinib limits recruitment of neutrophils to the lung and NETosis d Baricitinib preserves innate antiviral and SARS-CoV-2specific T cell responses

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, California). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

Despite the well-known cutaneous beneficial effect of thermal water on the skin, no data exist regarding the potential biological effect of orally consumed water on healthy skin. Thus, in this single-center, double-blind, randomized controlled clinical trial conducted on age and menstrual cycle timing-matched healthy female volunteers (24 + 24) consuming water A (oligo-mineral) or water B (medium-mineral) for 1 month (T1), the cutaneous lipidomics were compared. Interestingly, only water A consumers had a statistically significant (p < 0.001) change in cutaneous lipidomics, with 66 lipids different (8 decreased and 58 increased). The cutaneous lipidomics of consumers of water A vs. water B were statistically different (p < 0.05). Twenty cutaneous lipids were necessary to predict the water type previously consumed (AUC ~70). Our study suggests that drinking oligo-mineral water may change skin biology and may influence the cutaneous barrier, so future dermatological clinical trials should also account for the water type consumed to avoid potential confounders.

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