Current and Future Nutritional Strategies to Modulate Inflammatory Dynamics in Metabolic Disorders

Abstract

Obesity, type 2 diabetes, and other metabolic disorders have a large impact on global health, especially in Western countries. An important hallmark of metabolic disorders is chronic low-grade inflammation. A key player in chronic low-grade inflammation is dysmetabolism, which is defined as the inability to keep homeostasis resulting in loss of lipid control, oxidative stress, inflammation, and insulin resistance. Although often not yet detectable in the circulation, chronic low-grade inflammation can be present in one or multiple organs. The response to a metabolic challenge containing lipids may magnify dysfunctionalities at the tissue level, causing an overflow of inflammatory markers into the circulation and hence allow detection of early low-grade inflammation. Here, we summarize the evidence of successful application of metabolic challenge tests in type 2 diabetes, metabolic syndrome, obesity, and unhealthy aging. We also review how metabolic challenge tests have been successfully applied to evaluate nutritional intervention effects, including an "anti-inflammatory" mixture, dark chocolate, whole grain wheat and overfeeding. Additionally, we elaborate on future strategies to (re)gain inflammatory flexibility. Through epigenetic and metabolic regulation, the inflammatory response may be trained by regular mild and metabolic triggers, which can be understood from the perspective of trained immunity, hormesis and pro-resolution. New strategies to optimize dynamics of inflammation may become available.

Keywords: chronic low-grade inflammation; lifestyle; metabolism; nutrition; phenotypic flexibility; resilience.

Figure 1

(A) Generalized model of sequential steps involved in the inflammatory response in metabolic tissues resulting in chronic low-grade inflammation or return to a healthy homeostatic condition [inspired by Villeneuve et al. (17)] and (B) Manifestation of chronic low-grade inflammation in the different metabolic tissues [Reprinted with permission from Ralston et al. (18)].

Figure 2

Potential systemic biomarkers categorized following the sequential steps involved in the inflammatory cascade with chronic low-grade inflammation. Orange boxes represent the sequential steps involved in the inflammatory response within chronic low-grade inflammation. Gray boxes represent inflammatory biomarker classes and are categorized under the sequential inflammatory steps. White boxes present the biomarkers as positioned under the inflammatory biomarker classes.

Figure 3

Obesity-induced development of tissue inflammation in various organs. As an example, the long-term inflammatory dynamics and characteristics of lean toward obese WAT are illustrated. In lean WAT, immune cells are generally in an overall Type2 state (left black text), while in obese WAT the immune cells operate in a Type1 state (right black text). Red text indicates increase/abundancy of the mentioned adipokine and immune cells. Green text represents a decrease in the mentioned immune cell. M2, macrophage type 2; AAM, alternatively activated macrophages; T-reg, regulatory T-cells; Th2, T-helper type 2 cells; B-reg, regulatory B-cells; B1α, B-cells type 1 alpha; ILC-2, innate lymphoid cells type 2; NKT, natural killer T-cells; M1, macrophage type 1; CAM, classically activated macrophages; Th1, T-helper type 1 cells; B2, B-cells type 2; ILC-1, innate lymphoid cells type 1; NK, natural killer cells. Based on (1) (21); (2) (22); (3) (23); (4) (24); and (5) (25).

Figure 4

A framework for understanding the progression of healthy homeostasis to disease. For chronic diseases, the pathological development toward a disease state typically takes years. While the medical world has made tremendous progress toward the measurement of disease, the ability to measure the progress toward the disease is lacking. Resilience as measure of health status provides a promising solution to this problem. In contrast to the classical symptom/biomarker approach, challenge tests are used to measure resilience as an early biomarker of disease or (nutritional) effect. Reprinted with permission from van der Greef et al. (64).

Figure 5

Conceptual representation of challenge tests may evaluate the progression toward metabolic disorder. During progression from a healthy state toward a state of metabolic syndrome, only the early derailed processes respond differently to a challenge test in order to keep the core processes in balance. Eventually, the balance of the core processes is also disrupted. Modified with permission from Kardinaal et al. (51).

Figure 6

The effect of an “anti-inflammation dietary mixture” (AIDM) vs. placebo quantified at fasting and after Il-1B stimulation on humanCRP (A) and fibrinogen (B) in transgenic mice. Mice were fed the AIDM and the inflammation markers were quantified after 6 weeks of treatment. The effects of AIDM vs. placebo were only visible after IL1B stimulation and not at fasting, showing the added value of applying a perturbation test to show treatment effects on inflammation. Adapted with permission from Verschuren et al. (88).

Figure 7

An overview of potential ingredients and strategies for systemic low-grade inflammation therapy to optimize dynamics of inflammation and to maintain a flexible metabolic-inflammatory system. With impairment of flexibility, the system will develop toward metabolic disease development. This can be returned via static nutritional strategies by optimizing nutrients and calories, as well as training strategies through inflammatory triggers, trained immunity, hormesis, pro-resolution, or an alternating combination thereof.