Targeting Intestinal Macrophages as a Potential Therapeutic Option in Obesity

Abstract

Background: Chronic inflammation such as systemic or tissue inflammation has been well established in metabolic disease. Although macrophages thereby play a key role, not much is known about the initiation of inflammation. As the gut makes up the largest macrophage reservoir of the body and gastrointestinal changes occur in metabolic disease (altered gut microbiota, increased endotoxin and cytokines), the aim of our study was to assess the role of intestinal macrophages (iMϕs) in obesity. Research Design and Method: IMϕs were isolated from the colon of C57BL/6, germ-free or CCR2-/- mice fed a high fat diet (HFD) or control diet up to three months and characterized by flow cytometry as CCR2+ (“inflammatory”) or CCR2- (resident, anti-inflammatory) subpopulations. For dose-dependent iMϕ depletion, HFD-fed mice were orally treated with 50, 100 or 200 µg/g CSF-1R inhibitor (BLZ945) or its vehicle for up to ten weeks. Results: We found that within one week and up to three months of HFD, inflammatory iMϕs increase, preceding adipose tissue inflammation. Two mouse models protected from metabolic disease - germ-free and CCR2-/- mice - exhibited ≥10-fold lower inflammatory iMϕ numbers when compared to WT mice, suggesting that a threshold of iMϕs is required to elicit metabolic disease. Based on this finding, we depleted macrophages by increasing doses of CSF-1R inhibitor and observed a gradual iMϕ-reduction, which correlated with a dose-dependent improvement in fasting glucose, glucose tolerance and insulin levels. Conclusion: HFD-induced obesity is associated with an increase in inflammatory iMϕs, while mouse models protected from metabolic disease have lower numbers. Accordingly, dose-dependent depletion of iMϕs is accompanied by gradual improvements in glucose metabolism. This suggests that the number of iMϕs is involved in initiation of metabolic disease and thus could serve as a potential therapeutic target in obesity. Disclosure T.V. Rohm: None. S. AlAsfoor: None. A.J. Bosch: None. C. Cavelti-Weder: None.

Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation

“…Previously, we found that mice had more pronounced gut inflammation when their HFD was lard-based rather than coconut-based ( 20 ). To assess whether human intestinal macrophages also respond to dietary cues, we evaluated dietary habits of the study participants by a nutrition and lifestyle questionnaire.…”

“…Also other body weight parameters such as body weight, waist circumference, and waist-to-height ratio correlated with the frequency of P2 intestinal macrophages (Supplementary Figures 4A-C). They also positively correlated with the frequency of intermediate blood monocytes (Figure 3E and Supplementary Figures 4A-C Previously, we found that mice had more pronounced gut inflammation when their HFD was lard-based rather than coconut-based (20). To assess whether human intestinal macrophages also respond to dietary cues, we evaluated dietary habits of the study participants by a nutrition and lifestyle questionnaire.…”

“…Previously, we found that pro-inflammatory intestinal macrophage subpopulations P1 and P2 are increased in the colon of mice fed a HFD (20). It is currently unknown whether this innate immune response only occurs in the colon, or also in other parts of the gastrointestinal tract.…”

“…Previous studies indicate that innate gut immunity is involved in metabolic disease as mice fed a high-fat diet (HFD) have elevated levels of TLR4, TNF-alpha, and NF-kappaB in the gut wall ( 18 , 19 ), and an increased inflammatory tone of intestinal macrophages ( 17 ). Moreover, when assessing intestinal macrophage subpopulations in mice fed a HFD, we found increased pro-inflammatory macrophages in the gut ( 20 ). This is similar to what has been described in IBD and suggests disrupted differentiation of intestinal macrophages towards an anti-inflammatory/resident state.…”

“…This is similar to what has been described in IBD and suggests disrupted differentiation of intestinal macrophages towards an anti-inflammatory/resident state. As colon-specific macrophage depletion in mice fed a HFD improved glucose tolerance and insulin sensitivity in mice, colonic macrophages seem to be causally linked to glycemic control ( 20 ). However, a comprehensive analysis of intestinal macrophage subpopulations in human obesity has been missing so far.…”