Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI<27kg/m2) and obese individuals (BMI>32kg/m2). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially via recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.

The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.

Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancerrelated deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed-forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue-specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.

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Background We previously found that air pollution particles reaching the gastrointestinal tract elicit gut inflammation as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. This inflammatory response was associated with beta-cell dysfunction and glucose intolerance. So far, it remains unclear whether gut inflammatory changes upon oral air pollution exposure are causally linked to the development of diabetes. Hence, our aim was to assess the role of immune cells in mediating glucose intolerance instigated by orally administered air pollutants. Methods To assess immune-mediated mechanisms underlying air pollution-induced glucose intolerance, we administered diesel exhaust particles (DEP; NIST 1650b, 12 µg five days/week) or phosphate-buffered saline (PBS) via gavage for up to 10 months to wild-type mice and mice with genetic or pharmacological depletion of innate or adaptive immune cells. We performed unbiased RNA-sequencing of intestinal macrophages to elucidate signaling pathways that could be pharmacologically targeted and applied an in vitro approach to confirm these pathways. Results Oral exposure to air pollution particles induced an interferon and inflammatory signature in colon macrophages together with a decrease of CCR2− anti-inflammatory/resident macrophages. Depletion of macrophages, NLRP3 or IL-1β protected mice from air pollution-induced glucose intolerance. On the contrary, Rag2-/- mice lacking adaptive immune cells developed pronounced gut inflammation and glucose intolerance upon oral DEP exposure. Conclusion In mice, oral exposure to air pollution particles triggers an immune-mediated response in intestinal macrophages that contributes to the development of a diabetes-like phenotype. These findings point towards new pharmacologic targets in diabetes instigated by air pollution particles.

Background: Besides classical risk factors such as sedentary lifestyle and unhealthy diet, air pollution has emerged as an unexpected risk factor for type 2 diabetes. However, the causal mechanism remains poorly understood. Air pollution particles are known to reach the gastrointestinal tract by mucociliary clearance. Underlining the clinical relevance of oral exposure, air pollution has been associated with a variety of gastrointestinal diseases. Therefore, we aim to study the effects of oral air pollution exposure on glucose metabolism and a potential immune-mediated mechanism. Research Design and Method: Male C57B6/N, Rag2-/- and CCR2-/- mice or mice on a diet supplemented with a Csfr1-inhibitor were exposed to diesel exhaust particles (DEP; 12µg 5 days/week) or PBS by gavage for up to 6 months. Glycemia, tissue inflammation and immune cells were assessed. Results: Mice orally treated with DEP developed impaired glucose tolerance with reduced insulin secretion, while insulin resistance, systemic, adipose tissue and liver inflammation were not induced. This effect was independent of the adaptive immunity as Rag2-/- mice, which are devoid of B and T cells, also became glucose intolerant. In contrast, glucose intolerance did not develop in CCR2-/- mice and mice treated with a Csfr1-inhibitor. Supporting a causative role of intestinal macrophages in air pollution-induced diabetes, wild type mice exposed to oral DEP had reduced anti-inflammatory, resident macrophages in the lamina propria of the gut. Conclusion: Oral exposure to air pollutants results in impaired glucose tolerance, which is mediated by innate immunity as we found a loss of anti-inflammatory, resident macrophages in the gut. Moreover, mice devoid of macrophages are protected from air pollution-induced diabetes. Our findings provide a new understanding how environmental pollutants affect metabolic health, which is crucial for preventing the worldwide disease burden of air pollution-induced diabetes. Disclosure A.J.T. Bosch: None. T.V. Rohm: None. S. AlAsfoor: None. Z. Baumann: None. C. Cavelti-Weder: None.

15Air pollution has emerged as an unexpected risk factor for diabetes 1-6 . The mechanisms 16 linking air pollution and diabetes remain, however, unknown. It has been postulated 17 that lung exposure mediates diabetes via systemic inflammation and insulin resistance 7-9 . 18 By contrast, gut exposure to pollutants has received little attention, even though a large 19 proportion of air pollution particles are swallowed after mucociliary clearance from the 20 upper airways 10 . Here, we identified intestinal macrophages as key mediators linking air 21 pollutants with impaired beta-cell function. Upon oral exposure to air pollution, 22 intestinal macrophages up-regulated inflammatory-and interferon-response pathways, 23 which disrupted their normal differentiation towards an anti-inflammatory/resident 24 phenotype. The resulting pro-inflammatory milieu in the gut impaired beta-cell identity 25

Background Air pollution has emerged as an unexpected risk factor for diabetes. However, the mechanism behind remains ill-defined. So far, the lung has been considered as the main target organ of air pollution. In contrast, the gut has received little scientific attention. Since air pollution particles can reach the gut after mucociliary clearance from the lungs and through contaminated food, our aim was to assess whether exposure deposition of air pollution particles in the lung or the gut drive metabolic dysfunction in mice. Methods To study the effects of gut versus lung exposure, we exposed mice on standard diet to diesel exhaust particles (DEP; NIST 1650b), particulate matter (PM; NIST 1649b) or phosphate-buffered saline by either intratracheal instillation (30 µg 2 days/week) or gavage (12 µg 5 days/week) over at least 3 months (total dose of 60 µg/week for both administration routes, equivalent to a daily inhalation exposure in humans of 160 µg/m3 PM2.5) and monitored metabolic parameters and tissue changes. Additionally, we tested the impact of the exposure route in a “prestressed” condition (high-fat diet (HFD) and streptozotocin (STZ)). Results Mice on standard diet exposed to particulate air pollutants by intratracheal instillation developed lung inflammation. While both lung and gut exposure resulted in increased liver lipids, glucose intolerance and impaired insulin secretion was only observed in mice exposed to particles by gavage. Gavage with DEP created an inflammatory milieu in the gut as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. In contrast, liver and adipose inflammation markers were not increased. Beta-cell secretory capacity was impaired on a functional level, most likely induced by the inflammatory milieu in the gut, and not due to beta-cell loss. The differential metabolic effects of lung and gut exposures were confirmed in a “prestressed” HFD/STZ model. Conclusions We conclude that separate lung and gut exposures to air pollution particles lead to distinct metabolic outcomes in mice. Both exposure routes elevate liver lipids, while gut exposure to particulate air pollutants specifically impairs beta-cell secretory capacity, potentially instigated by an inflammatory milieu in the gut.