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.

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