Anti-inflammatory mechanisms of polyphenols in adipose tissue: role of gut microbiota, intestinal barrier integrity and zinc homeostasis

Obesity is a complex metabolic disease characterized by excessive expansion of white adipose tissue (WAT) [1]. By the year 2030, about 60% of the world's adult population could suffer from overweight or obesity [2]. In the US, the prevalence of obesity among adults increased from 39.8% to 42.4% between the years 2015–2016 and 2017–2018 [3,4]. The annual total cost of obesity treatment in the US is reported to be $113.9–147 billion [5,6] which is predicted to increase by $48–66 billion each year until 2030 [7]. Thus, exploring cost-effective therapeutics for obesity is a public health priority [8].

Recent research highlighted the important roles of the gut microbiota in modulating obesity, metabolic diseases, such as type two diabetes (T2D), and related inflammation [9,10]. Metabolic endotoxemia, or the low-grade release of lipopolysaccharide (LPS) through the intestinal barrier into the blood circulation, correlates with the pathogenesis of related systemic inflammation, metabolic diseases, and obesity [11], [12], [13]. The increased LPS is due to the abundance of gram-negative bacteria in the gut with obesity.

Dietary polyphenols may reduce inflammation in WAT through reduced metabolic endotoxemia, improving intestinal barrier integrity (IBI), and altering gut microbiota [14,15]. The intestinal tight junction is believed to be maintained by interactions between the transmembrane proteins (TMP) and zonula occludens-1 (ZO-1) which is a tight junction protein [16,17]. Intestinal tight junction proteins (TJPs) and intestinal alkaline phosphatase (IAPs) are key in reducing gut-originated LPS activity by repairing the leaky gut and subsequent deactivation of LPS [18,19]. Polyphenols play a unique role in ameliorating leaky gut by increasing the availability of TJP zonula occludens-1 (ZO-1) and repairing the injured intestinal epithelial cell [20]. Increasing activity of IAP, by the influence of polyphenol, helps to deactivate gut-originated LPS [18,19].

Zinc is the second most abundant trace element found in the human body, and cellular levels of free zinc play a critical role in immunity, inflammation, and cellular function [21]. It is important to note that serum zinc concentration is independent of dietary or supplemental zinc intake if the zinc homeostasis is maintained by the body [22]. Zinc is one of the factors that modulates LPS-induced and toll-like receptor 4 (Tlr-4) dependent inflammation [23,24]. It is a critical micronutrient responsible for the proper functions of most enzymes, for example, intestinal alkaline phosphatase – the enzyme involved in maintaining intestinal barrier integrity [25,26]. The daily recommended zinc intake is 8 mg for adult women and 11 mg for men respectively [27], and at least 5–6 mg of dietary zinc intake is required to maintain zinc homeostasis in the body [22]. Normal serum zinc concentration in US adults was found to be around 83 µg/dL [22]. Interestingly, individuals with obesity exhibit low serum zinc levels [28,29]. Therefore, zinc homeostasis appears critical for a healthy life.

The role of polyphenols, including curcumin, resveratrol, anthocyanins, and flavonoids, as anti-obesity bioactive compounds have been discussed extensively elsewhere [30,31]. In this review, we discuss the role of polyphenols in reducing inflammation during diet-induced obesity, linking gut microbiota, intestinal barrier integrity, inflammatory signaling, and zinc homeostasis.

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