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.

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.

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Background: Our previous studies in mice showed that high fat diet leads to a pro-inflammatory phenotype of intestinal macrophages. Colon-specific depletion of intestinal macrophages led to improved glycemic control, suggesting a causal link between intestinal macrophages and glycemia. The aim of the current study was to validate our findings in human disease by assessing human gut biopsies and circulating blood monocytes from lean and obese individuals. Research Design and Method: Peripheral blood monocytes were isolated using a Ficoll gradient and characterized by flow cytometry as classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes. Intestinal macrophages of the stomach, duodenum and colon were isolated from biopsies of lean (BMI <27 kg/m2) or obese (BMI >32 kg/m2) individuals undergoing colonoscopy or gastroscopy. Macrophages were characterized as CD14high or CD14low and further subdivided by HLA-DR, CD163 and CD209 into pro-inflammatory P1, P2, intermediate P3 and resident, anti-inflammatory subpopulations P4, P5. Results: Depending on the anatomical location, the composition of intestinal macrophages varied: In the stomach of lean subjects, the ratio of CD14high/CD14low macrophages was 80/20%, while the colon comprised more resident, anti-inflammatory macrophages (CD14high/CD14low: 60/40%). Consistent with our results in mice, we detected an increase in the CD14high pro-inflammatory macrophage subpopulation P2 in obese individuals (Corpus: 1.55±0.61-fold, Duodenum: 1.79±0.45-fold, Colon transversum: 1.71±0.72-fold). Interestingly, also human CD14high intermediate blood monocytes were increased in obese patients. Conclusion: Similar to our mouse data, pro-inflammatory intestinal macrophages are increased in gut biopsies of obese subjects. Higher CD14high blood monocytes suggest enhanced recruitment of monocytes to the gut as the prevailing mechanism. Disclosure T.V. Rohm: None. R. Fuchs: None. Z. Baumann: None. L. Keller: None. R. Schneider: None. D. Labes: None. C. Cavelti-Weder: None. Funding University of Basel