Microbiome-Immune-Metabolic Axis: Inflammation and Obesity

Obesity is an impactful disease favored by multiple factors with no signs of abating. Despite massive health campaigns and multiple dietary, surgical and pharmacological options to treat obesity, this health problem is winning the battle. However, research has shown that many factors are left behind in previous obesity treatments, and studies in the gut microbiome show that the treatment focus should change. Despite an excessive calorie intake and lack of physical activity, the microbiome– immune-metabolic axis plays a crucial role in developing obesity since childhood. Resulting in dysbiosis, increasing the levels of inflammatory cytokines, consequently shifting the function of white and brown adipose tissue.

Obesity as a multifactorial disease:

Orthomolecular treatment focuses on preventing or reversing disease from the root. Finally, obesity is an excess of body fat caused by an elevated caloric intake and low physical activity. However, if we look closer, these two “simple” factors can heavily impact the microbiome-immune-metabolic axis contributing to inflammation.

Metabolic factors

Body fat excess: There are two types of fat, brown adipose tissue (BAT) and white adipose tissue (WAT). Consequently, these two types of fat have different functions in our body and interact with the microbiome-immune-metabolic axis.

• BAT: This type of adipose tissue is abundant in childhood, and it especially expresses uncoupling protein 1 (UCP-1). In turn, UCP-1 has the specific function of uncoupling the electron transport chain to produce heat instead of ATP. This function results in heat production use to protect the essential organs in the children’s body. Also, BAT’s amount is associated with obesity prevention and weight reduction. BAT can be stimulated by many factors such as:

1. Exposure to cold weather.
2. Exercise.

• WAT: White adipose tissue is fat’s principal storage, as adipocytes are mainly made of triglycerides. In addition, it has important influences on metabolism since it releases adipokines like adiponectin, resistin, and leptin. However, a WAT excess impacts metabolic function and increases the risk of developing chronic diseases such as Diabetes Mellitus by producing pro-inflammatory cytokines.

In the presence of sedentarism and fat accumulation, WAT begins to replace BAT. Nevertheless, the influence of the microbiome-immune-metabolic axis remains unknown and needs further study.

Brown Adipose Tissue

Immune factors

Energy surplus and the immune reaction to infection: Infections and caloric intake are essential obesity influencers, acting bidirectionally and increasing obesity risk.

On the one hand, the immune cells use glucose caloric energy to release cytokines and cell proliferation and fight infections. On the other hand, however, when there is an energetic surplus and excessive fat tissue, adipocytes produce and release pro-inflammatory cytokines. The combination of these pro-inflammatory factors contributes to low-grade inflammation and insulin resistance in adipocytes, resulting in an adipocyte functional alteration. 

Another significant interaction is the one between macrophages and its stimulation on BAT’s UCP-1 expression. Furthermore, the conversion of WAT to BAT is increased by type 1 (M1) and type 2 cytokines (M2). The first one activates macrophages, and the latter polarizes macrophages to an alternative M2 state.

Microbiome

In the past decade, many studies have reported the role of the gut’s microbiome and how it influences adiposity. Recent reports state that BAT and insulin sensitivity growth are higher in gut microbiome-depleted mouse models or germ-free mice. In addition, there existed high numbers of UCP-1 small lipid droplets in these animal models than in the control group.

Metabolites such as bile acids also play an essential role in balancing the gut’s microbiota. This balance characterizes by an increased number of Bacteroidetes and a lower number of Firmicutes. In turn, this B/F ratio reflects an environment where thermogenesis and proper glucose and lipid metabolism.

Prebiotics and other host-microbiome metabolites can impact the function and number of UCP-1 in BAT. Indeed, short-chain fatty acids supplementation can act like a browning agent on adipose tissue, resulting in BAT growth. In turn, and stimulates peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator (PGC)1α, which enhances fatty acid metabolism and upregulates UCP-1-mediated thermogenesis.

As human beings, we depend on a carefully organized environment. The Microbiome-Immune-Metabolic axis is an orchestrated interaction that needs a constant rearrangement. For instance, an acute disease can cause dysbiosis, and treatment with probiotics and prebiotics is the best way to bring homeostasis back. Also, the elimination diet can provide benefits by reducing the immune response, replenishing beneficial bacteria, and providing a better environment. The combination of these approaches can improve metabolic function by decreasing the inflammatory response. – Ana Paola Rodríguez Arciniega, MS

References:

Kincaid, Halle J et al. “Microbiome-immune-metabolic axis in the epidemic of childhood obesity: Evidence and opportunities.” Obesity reviews: an official journal of the International Association for the Study of Obesity vol. 21,2 (2020): e12963. doi:10.1111/obr.12963

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