Obesity is marked by chronic, low-grade inflammation. Here, we examined whether intrinsic differences between white and brown adipocytes influence the inflammatory status of macrophages. White and brown adipocytes were characterized by transcriptional regulation of UCP-1, PGC1α, PGC1β, and CIDEA and their level of IL-6 secretion. The inflammatory profile of PMA-differentiated U937 and THP-1 macrophages, in resting state and after stimulation with LPS/IFN-gamma and IL-4, was assessed by measuring IL-6 secretion and transcriptional regulation of a panel of inflammatory genes after mono- or indirect coculture with white and brown adipocytes. White adipocyte monocultures show increased IL-6 secretion compared to brown adipocytes. White adipocytes cocultured with U937 and THP-1 macrophages induced a greater increase in IL-6 secretion compared to brown adipocytes cocultured with both macrophages. White adipocytes cocultured with macrophages increased inflammatory gene expression in both types. In contrast, macrophages cocultured with brown adipocytes induced downregulation or no alterations in inflammatory gene expression. The effects of adipocytes on macrophages appear to be independent of stimulation state. Brown adipocytes exhibit an intrinsic ability to dampen inflammatory profile of macrophages, while white adipocytes enhance it. These data suggest that brown adipocytes may be less prone to adipose tissue inflammation that is associated with obesity.

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The gastrointestinal tract represents one of the largest body surfaces that is exposed to the outside world. It is the only mucosal surface that is required to simultaneously recognize and defend against pathogens, while allowing nutrients containing foreign antigens to be tolerated and absorbed. It differentiates between these foreign substances through a complex system of pattern recognition receptors expressed on the surface of the intestinal epithelial cells as well as the underlying immune cells. These immune cells actively sample and evaluate microbes and other particles that pass through the lumen of the gut. This local sensing system is part of a broader distributed signaling system that is connected to the rest of the body through the enteric nervous system, the immune system, and the metabolic system. While local tissue homeostasis is maintained by commensal bacteria that colonize the gut, colonization itself may not be required for the activation of distributed signaling networks that can result in modulation of peripheral inflammation. Herein, we describe the ability of a gut-restricted strain of commensal bacteria to drive systemic anti-inflammatory effects in a manner that does not rely upon its ability to colonize the gastrointestinal tract or alter the mucosal microbiome. Orally administered EDP1867, a gamma-irradiated strain of Veillonella parvula, rapidly transits through the murine gut without colonization or alteration of the background microbiome flora. In murine models of inflammatory disease including delayed-type hypersensitivity (DTH), atopic dermatitis, psoriasis, and experimental autoimmune encephalomyelitis (EAE), treatment with EDP1867 resulted in significant reduction in inflammation and immunopathology. Ex vivo cytokine analyses revealed that EDP1867 treatment diminished production of pro-inflammatory cytokines involved in inflammatory cascades. Furthermore, blockade of lymphocyte migration to the gut-associated lymphoid tissues impaired the ability of EDP1867 to resolve peripheral inflammation, supporting the hypothesis that circulating immune cells are responsible for promulgating the signals from the gut to peripheral tissues. Finally, we show that adoptively transferred T cells from EDP1867-treated mice inhibit inflammation induced in recipient mice. These results demonstrate that an orally-delivered, non-viable strain of commensal bacteria can mediate potent anti-inflammatory effects in peripheral tissues through transient occupancy of the gastrointestinal tract, and support the development of non-living bacterial strains for therapeutic applications.

mutation and the degree of differentiation or node invasion (p¼0.46 and p¼0.24 respectively). Conclusion:The prognostic impact of RAS mutation was demonstrated in our patients. Treatment for metastatic cancers remains challenging in Tunisia despite recent advances. Thanks to the identification of RAS status, unjustified expenses of anti-EGFR targeted therapy could be avoided.Legal entity responsible for the study: The authors.

e14241 Background: Systemic immunity is regulated by interactions of commensal bacteria with immune cells in the gut. Enrichment of specific intestinal microbes has been shown to enhance the anti-tumor response to PD-1 blockade in both murine models and cancer patients. Here we report that oral administration of a monoclonal microbial, EDP1503, induces systemic anti-tumor immunity. Methods: The mechanism of action and efficacy of EDP1503 was investigated in isograft tumor models and a variety of ex vivo and in vitro studies in murine and human cells. Results: EDP1503 increases expression of costimulatory molecules on CD11c+ dendritic cells (DCs) within the mesenteric LNs with an accompanying increase in proinflammatory CD103+ DCs within tumor draining lymph nodes. In addition, EDP1503 amplifies both myeloid and lymphocyte responses via production of DC-derived growth factors, M1 polarization of macrophages, and production of the lymphocyte-recruiting chemokines, CXCL9 and CXCL10. Mechanistically, EDP1503 triggers specific pattern recognition receptors and induces proinflammatory responses in antigen presenting cells. Moreover, in vivo, treatment of mice with EDP1503 results in decreased tumor volume and delayed tumor growth. The prominent anti-tumor effects of EDP1503 are further augmented by combination with anti-PD-1 neutralizing Abs. Dissection of the tumor microenvironment reveals increased activated Ki67+ NK cells and CD8+ T cells producing IFNg. Conclusions: Together, these data clearly demonstrate the ability of an orally delivered non-colonizing monoclonal microbe to enhance innate and adaptive anti-tumor immunity and substantiates the rationale for ongoing clinical trials. EDP1503 is currently in Phase 1b/2 studies (NCT03775850; NCT03595683) with enrollment open at multiple sites.