Food Bioactives and Their Effects on Obesity-Accelerated

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Food bioactives and their effects on obesityaccelerated inflammatory bowel disease Yi-Shiou Chiou, Pei-Sheng Lee, and Min-Hsiung Pan J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b05854 • Publication Date (Web): 02 Jan 2018 Downloaded from http://pubs.acs.org on January 4, 2018

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Journal of Agricultural and Food Chemistry

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Food bioactives and their effects on obesity-accelerated inflammatory bowel

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disease

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Yi-Siou Chiou†, Pei-Sheng Lee†, and Min-Hsiung Panζ,† § ≠,

, , *

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Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization; Hubei Collaborative Innovation Center for the

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Characteristic Resources Exploitation of Dabie Mountains; Huanggang Normal University, Huanggang, Hubei, China †

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Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan

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§

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan

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≠

Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

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*Please send all correspondence to: Dr. Min-Hsiung Pan Institute of Food Science and Technology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan. Tel. no. +886 2 33664133 Fax. no. +886-2-33661771 E-mail: [email protected]

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ACS Paragon Plus Environment


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ABSTRACT

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Current views support the concept that obesity is linked to a worsening of the course

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of inflammatory bowel diseases (IBD). Gut microbiota and adipose tissue

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macrophage (ATM) are considered key mediators or contributors in

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obesity-associated intestinal inflammation. Dietary components can have direct or

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indirect effects on ‘normal’ or ‘healthy’ microbial composition and participate in

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adiposity and metabolic status with gut inflammation. In this review, we highlight

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food-derived bioactives that have a potential application in the prevention of

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obesity-exacerbated IBD, targeting energy metabolism, M1 (classical activated)-M2

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(alternatively activated) macrophage polarization, and gut microbiota.

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KEYWORDS: IBD, ATM, obesity, Gut microbiota, bioactives

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INTRODUCTION

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The incidence of obesity has dramatically increased over the past decades in both

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developed and developing countries. Due to its prevalence, obesity and related

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metabolic complications such as dyslipidemia, insulin resistance, and steatohepatitis

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have become global health issues. Obesity is a result of energy intake exceeding

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energy expenditure over a prolonged period, causing abnormal fat accumulation. The

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overnutrition-induced adipocyte hypertrophy and hyperplasia lead to activation and

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recruitment of inflammatory cells into white adipose tissues (WATs) through

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secreting cytokines and chemokines, promoting a state of low-grade systemic chronic

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inflammation (1). Epidemiologic and experimental evidence has illustrated the

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relationship between obesity and IBD.

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One of the mechanisms responsible for IBD is chronic inflammation, which

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drives immune responses that exert their effect through changes in microenvironments

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such as gut microbiota and visceral adipose tissue (VAT). Most obese individuals

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with a variety of metabolic disorders such as insulin resistance have stimulated

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intestinal inflammation, which suggests that an alternatively activated macrophages

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(M2) to classically activated macrophages (M1) transition of adipose tissue

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macrophage (ATM) has a causative role in an obesity-associated proinflammatory

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environment (2). It is currently believed that the gastrointestinal (GI) tract is the first 3



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organ to be exposed to dietary components, which is considered a major linkage

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exacerbating IBD symptoms in obese individuals (3). Therefore, specific dietary

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factors clearly have a major impact on promotion or protection in obesity with

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intestinal inflammation.

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Despite all of the indications favoring a causative relationship between obesity

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and IBD outcomes, our understanding of how dietary components are responsible for

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the specific association between fat distribution and macrophage function at the

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dysbiosis of gut microbiota in obesity-linked IBD is limited. This review consists of

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three parts in which we discuss the current knowledge of the potential role of food

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bioactives and their possible mechanistic links concerning: 1) food bioactives as a

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master regulator of energy metabolism (Table 1), 2) M1-M2 macrophage polarization

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balance (Table 2), and 3) alterations of gut microbial composition (Table 3).

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ROLE OF FOOOD BIOACTIVES IN OBESITY-INDUCED INTESTINAL

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INFLAMMATION

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Imbalance between energy intake and expenditure ultimately results in fat deposition

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and weight gain. Generally, obese individuals with an increasing waist circumference

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and related metabolic complications are at an increased risk for developing IBD (1, 4).

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Ulcerative colitis (UC) and Crohn's Disease (CD) are two diseases characterized by

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chronic relapsing inflammation of the gastrointestinal tract. Increasing obesity-related 4


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IBD incidence trends are associated with high-fat diets (HFD)/Western-style (HFW)

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diets (5). The quantities and composition of consumed nutrients, especially fats and

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carbohydrates, are important influencing factors on intestinal inflammation either

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directly or indirectly by modifying the metabolic/immunological activity of the host

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gut microbiota (5). It is already known that foods/diets are a source of not only

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nutrients but also bioactive constituents such as polyphenols, which are naturally

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present in a wide variety of fruits and vegetables. Growing evidence clearly

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demonstrates that food bioactives are good factors for improving obesity and

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inflammatory-related disorders (6, 7), and also have a positive influence on gut

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microbiota composition and implications in human health (8). In this context, we

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review possible mechanisms for potential roles of food-based bioactives and their

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associated mechanisms in obesity-induced intestinal inflammation.

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Activates energy metabolism

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Owing to the essential role of adipose tissue (AT) in controlling energy

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homeostasis including lipids and glucose metabolism, its alteration may trigger a

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systemic low-grade inflammatory state in various tissues such as muscle and liver.

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This contributes to the development of metabolic abnormalities like hepatic steatosis

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and insulin resistance. Previous reports also indicated that metabolic syndrome (MetS)

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is an important parameter in IBD patients (9), implying that the initial management of 5



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MetS is partly responsible for the superior effects in preventing intestinal

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inflammation. Evidence for recent studies demonstrated that the administration of

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(-)-epigallocatechin-3-gallate (EGCG) (10), resveratrol (11), luteolin (12), and chrysin

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(13) showed an improvement in hepatic and muscular steatosis, insulin resistance, and

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glucose intolerance via reducing blood glucose and lipid absorption, and increasing

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fecal lipids in HFD, high sucrose (HS), and HFW diet-induced obesity models. These

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results also suggest that the beneficial effects of resveratrol and luteolin may be

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mediated by simultaneously activating lipolysis, thereby reducing hepatic lipotoxicity

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and de novo lipogenesis. Interestingly, luteolin treatment further increased the

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elevated FA oxidation and tricarboxylic acid (TCA) cycle, which may contribute to

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reduced adiposity. Additionally, dietary supplementation of EGCG resulted in

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attenuation of hepatic and WAT lipogenesis due to its effect in reducing diet

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digestibility and promoting FA oxidation and energy expenditure (14).

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Traditionally, mammalian adipose tissues can be divided into two classes: white

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adipose tissue (WAT) and brown adipose tissue (BAT). Unlike the functional

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properties of WAT, BAT has been identified as an important site for energy

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expenditure through efficient thermogenesis. Activation of brown adipocytes or the

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browning of white adipocytes (termed beige or brite adipocytes), which are

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characterized as uncoupling protein 1 (UCP-1)-expressing and mitochondrial-rich 6


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adipocytes, contributes to whole body energy expenditure and therefore is also

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another attractive weapon against diet-induced obesity (7). Studies on EGCG’s effects

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on thermogenesis and induction of high mitochondrial density in BAT have shown an

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upregulation in the expression of uncoupling proteins (UCPs) and an increase in the

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markers of mitochondrial biogenesis such as peroxisome proliferator activated

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receptor gamma coactivator 1-alpha (PGC-1α) (10). Recent studies also have revealed

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that dietary farnesol (15) and chrysin (16) possess a development of beige adipocytes

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in both inguinal adipose tissue (IAT) and epididymis adipose tissue (EAT). They also

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enhance WAT browning as well as induce the brown-like phenotype, which certainly

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limit adipogenesis and TG accumulation. We can believe the possibility that the

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regulation of energy metabolism through consumption of food bioactives in obese

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individuals might indicate the involvement of preventing the development of IBD.

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Changes in M1–M2 macrophage polarization

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Adipose endocrine function is multifaceted. It secretes a great number of hormones

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and signaling molecules collectively called adipokines, which exert their biological

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roles in the regulation of energy, glucose/lipid metabolism, inflammation, and insulin

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sensitivity, immune responses, and host defense mechanisms (2).

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As discussed in the previous sections, the circulating pro-inflammatory adipokines are 7



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released by obese VAT mainly in the mesenteric fat, which is integral to the

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inflammatory cascade involved in IBD (1). AT is recognized as a key endocrine organ

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that consist of adipocytes, connective and nerve tissue, immune system cells (T and B

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lymphocytes, macrophages), chondrocytes, osteocytes, and myocytes.

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The obesity-associated state of chronic low-grade systemic inflammation termed

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“metabolic inflammation” is a unique process driven by adipose tissue macrophages

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(ATMs)-produced inflammatory response. ATMs from obese individuals are polarized

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toward an M1 phenotype (pro-inflammatory) with upregulation of proinflammatory

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cytokines such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor

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alpha (TNF-α), and interleukin-6 (IL-6). Recently, diet supplementation with

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quercetin (17), chrysin (13), apigenin (18), and naringenin (19) has been documented

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to decrease obesity-induced systematic inflammation via preventing immune cell

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infiltration (mast, myocytes, and macrophages) and favoring M2 (anti-inflammatory)

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macrophage polarization. In addition, chrysin was also found to inhibit the biological

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functions (antigen-presenting ability, phagocytic activity, and ROS production) of the

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M1 macrophages. One of the most important sequela of AT inflammation is insulin

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resistance (2). Studies from obesity-related inflammation in vitro have further showed

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that food bioactives including quercetin (17), tangeretin (20), malvidin, peonidin (21),

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and luteolin (22) enhanced the glucose uptake and blocked inflammation by 8


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expressing glucose transporter 4 (GLUT4) and insulin receptor substrate (IRS) and

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suppressing proinflammatory cytokines production, which is thought to improve

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insulin sensitivity. This data strongly supports the fact that food-derived bioactives

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have an ability to modulate macrophage M1-M2 status and could be a potential

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strategy for dampening obesity-accelerated intestinal inflammation.

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Alterations in gut microbiota

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Gut microbiota are increasingly recognized as having pivotal roles in host energy

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metabolism, lipid accumulation, and immunity by producing pharmacologically active

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signaling molecules. Scientific efforts have been focused on understanding the

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mechanistic basis of the crosstalk between dietary components and gut microbiota in

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the incidence of IBD and obesity-related metabolic disorders, thus revealing the

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importance of the gut-microbial–host-immune axis (23). For example,

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microbial-derived short chain fatty acids (SCFAs) produced by fermentation of

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dietary fibers have been shown to interact with G protein-coupled receptors (GPCRs),

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affecting insulin sensitivity and thus regulating energy metabolism. Additionally,

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SCFAs also have been shown to reduce inflammatory cytokine production by

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inhibiting transcription factor nuclear factor kappa B (NFκB). However, HFD feeding

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in mice induced a low-grade inflammatory status that is associated with a decrease in 9



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the number of Bifidobacteria, which has been shown to decrease lipopolysaccharide

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(LPS) levels and to improve mucosal barrier function. Such findings are important

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because specific groups of bacteria may also provide beneficial effects on the

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intestinal mucosa and protection against IBD by using supplements and foods with

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probiotics and food ingredients-derived prebiotics (3, 24).

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Bacteroidetes and Firmicutes are the dominant phyla in both mice and human

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microbial populations (>90%). Several studies have found that a higher Firmicutes to

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Bacteroidetes ratio positively correlated with the obese phenotype (24). Unlike obese

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phenotypes, patients with IBD have an increased abundance of the ratio of

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Bacteroidetes to Firmicutes (23). In vivo studies have provided evidence that EGCG

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(25), resveratrol (26), and piceatannol (27) dietary supplements decreased lipid

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accumulation in adipocytes and the liver that are likely mediated by mechanisms of

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improving intestinal microbial balance and changing the composition of the colonic

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microbiota. In addition, complex interactions between genetics and nutrition are also

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involved in pathogenic mechanisms for IBD by the gut microbiome influencing

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epigenetic changes and therefore effects on the immune system and the mucosal

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barrier (28). In particular, EGCG supplementation may be partially derived from

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antioxidative activities as well as epigenetic modifications observed on CpG

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methylation (25) which alleviates conditions associated with obesity and metabolic 10


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syndromes. These results support the emerging view that the gut microbiota

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contributes to obesity and obesity-related IBD and suggest that consuming food

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bioactives may cause alterations in the intestinal microbiome and epigenome interface

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between the environment and genes, triggering a normal mucosal immune system and

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maintaining genomic stabilities.

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SUMMARY AND FUTURE DIRECTIONS

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In this paper, we review the recent advances in dietary factors and intestinal

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microbiota-host interaction in adiposity and dissect the plausible relationship

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mechanisms between obesity and IBD, focusing on the key pathways of energy

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metabolism, M1-M2 macrophage polarization, and gut microbiota alteration. We also

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highlight the potential role of food-based bioactive compounds underpinning the

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mechanisms linking obesity with intestinal inflammation that can be utilized to

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outline directions for obesity-associated IBD prevention and therapeutic targets. We

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assume from present results that food-derived bioactives may have the ability to

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prevent obesity-exacerbated intestinal inflammation, which is partially associated

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with the induction of energy metabolism, activation state of ATMs from an

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M2-polarized state, and alteration of gut microbiota composition in diet-induced

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obese individuals (Figure 1). However, further mechanistic studies of in vivo are

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required to solidify the role of food-derived bioactives and directly test this 11



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hypothesis.

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Acknowledgment

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This study was supported by the Ministry of Science and Technology

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[105-2320-B-002-031-MY3, 105-2628-B-002-003-MY3].

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Conflicts of interest

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The authors declare no conflict of interest.

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Table 1. Potential effects of food bioactives on energy metabolism Mechanism studied and outcome

Model

Mode of action and molecular/signaling target

Food bioactives Sources

Compounds

Upregulate brown adipose tissue thermogenesis and mitochondrial biogenesis

a. HFD-induced obesity in C57BL/6J mice

Green tea

EGCG

(10)

Induce the beige adipocytes development in both IAT and EAT Enhance WAT browning in HFD-induced obese mice

a. MDI-induced differentiation in 3T3-L1 preadipocytes b. hAMSCs c. HFD-induced obesity in C57BL/6J mice a. HFW-induced obesity and metabolic syndrome in C57BL/6J mice a. HFD-induced obesity in New Zealand black mice

↑Body temperature and mtDNA replication ↓Lipids and leptin (Plasma, Liver and Fecal) ↑AMPK activity, UCP1, UCP2, PRDM16, CPT-1β, PGC-1α, NRF1, ACC2 and Tfam (BAT) ↓Adipogenesis ↓PPARγ, CEBPα, FABP4, adiponectin, resistin and lipin1 (3T3-L1, hAMSCs, EAT and IAT) ↑p-AMPK, p-ACC, UCP1, PGC-1α, TMEM26, TBX1 and CD137 (3T3-L1, hAMSCs, EAT and IAT) ↓Blood glucose, liver damage and lipid absorption ↓TC, IL-6, G-CSF, MCP-1 and CRP (Plasma)

Peaches Tomatoes Corn, Lemon Chamomile Green tea

Farnesol

(15)

EGCG

(29)

Green tea

EGCG

(14)

Grape

Resveratol

(11)

Passion fruit Whole raw Honey Propolis, Cocoa

Chrysin

(16)

Spinach Kale Perilla Parsley Onions Thyme

Luteolin

(12)

Activates energy metabolism

Alleviate fatty liver incidence, insulin resistance

Promote fat oxidation and energy expenditure Reduce diet digestibility and lipogenesis Inhibit fatty acid uptake and de novo lipogenesis Induce brown fat phenotype Block lipid catabolism and lipogenesis

a. HSD/HFD-induced obesity in Sprague-Dawley rats a. MDI-induced differentiation in 3T3-L1 preadipocytes

Improve hepatic steatosis and insulin resistance Normalize hepatic metabolite expressions


↓Respiratory quotient during night ↓Leptin, SCD1, ME and GK (WAT and liver) ↓Lipogenic enzyme activities ↓HR-LPL, HSL, G6PDH, FASN and ACC (WAT) ↓Adipogenesis and TG accumulation ↓CEBP/α (3T3-L1) ↑Browning, lipolysis and fat oxidation ↑PGC-1α, PPARα/γ/δ, UCP1, PRDM16, CEBP/β, HSL, PLIN, CPT1, ACO, p-ACC and p-AMPK (3T3-L1) ↑CIDEA, CITED1, FGF21, PGC-1α, PRDM16, TBX1, TMEM26, and UCP1 (3T3-L1) ↓Lipogenesis, lipid droplets and lipid absorption ↓G6PD, FAS, ME, PAP, HMGCR, ACAT, ACC, SREBP2, PPARγ, glycogen, glucokinase, PEPCK, and G6Pase (Liver) ↓FA and TG synthesis-associated genes (Liver) ↑Glucose tolerance ↑SREBP1, PPARγ, ACC (EAT)

17


Ref.

Berries


↑Lipids (Fecal) ↑FA oxidation-associated genes (Liver) ↑Lipolysis/ FA oxidation-associated genes (EAT) ↑TCA cycle -associated genes (WAT)

Page 18 of 24

Peppermint

Abbreviations: ACC, acetyl-CoA carboxylase; ACO, acyl-CoA oxidase; ACAT, acyl-CoA:cholesterol acyltransferase; AMPK, Adenosine monophosphate-activated protein kinase; CPT1, carnitine palmitoyltransferase 1; CEBPα, CCAAT/enhancer-binding protein alpha; CIDEA, cell death-inducing DFFA-like effector a; CITED1, CREB-binding protein/p300-interacting transactivator with Asp/Glu-rich C-terminal domain; EAT, epididymis adipose tissue; FABP4, FABP4 fatty acid binding protein 4; FASN, Fatty acid synthase; FA, fatty acid; FGF21, fibroblast growth factor 21; Fizz1, found in inflammatory zone 1; G6Pase, glucose-6-phosphatase; G6PDH, Glucose-6-phosphate dehydrogenase; G6PD, Glucose-6-Phosphate Dehydrogenase deficiency; GK, Glycerolkinase; G-CSF, granulocyte colony-stimulating factor; HR-LPL, heparin-releasable lipoprotein lipase; HFD, high fat diet; HFW, Western-style diet; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; HSL, hormone sensitive lipase; hAMSCs, human adipose tissue-derived mesenchymal stem cells; IAT, inguinal adipose tissue; IL-6, interleukin-6; ME, malic enzyme; MCP-1, monocyte chemoattractant protein-1; NRF1, Nuclear respiratory factor 1; PAP, phosphatidate phosphohydrolase; PEPCK, Phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator- activated receptor gamma coactivator-1α; PLIN, PPARγ, peroxisome proliferator–activated receptor γ; PRDM 16, PR domain containing 16; SCD1, Stearoyl-CoA desaturase-1; SREBP2, sterol-regulatory element binding protein 2; TBX1, T-box transcription factor; TC, total plasma cholesterol; Tfam, Mitochondrial transcription factor A; TG, triglyceride; TMEM26, transmembrane protein 26; UCP, uncoupling proteins; WAT, white adipose tissue.

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Table 2. Potential effects of food bioactives on M1/M2 macrophage polarization Mechanism studied and outcome

Model


Sources

Compounds

a. HFD-induced obesity in C57BL/6J mice b. MDI-differentiated 3T3-L1+ RAW264.7 co-cultured in a contact system a. HFD-induced obesity in C57BL/6J mice b. LPS-induced inflammation in BMDMs c. MDI + indomethacin-induced differentiation in 3T3-L1 preadipocytes

↓Blood glucose and lipids ↓Mac-2, MCP-1 and JNK/p-IκBα (EAT) ↓MCP-1 (3T3-L1 and RAW264.7)

Citrus peel Grapes

Naringenin

(19)

↓Mast and macrophage cell recruitments ↓M1/M2 subtype ratio and BMDMs polarization ↓Insulin, leptin, adiponectin, TNF-α, IL-6 and MCP-1 (Serum and EAT) ↓mMcp-4, Cd11c and Nos2 (EAT) ↓Nos2, IL-6, IL-1β, MCP-1 (BMDMs) ↑Glucose uptake ↑GLUT4 translocation and p-Akt (EAT and 3T3-L1) ↑UCP1 (BAT) ↑Mgl2, Chil3l and IL-10 gene, AMPKα1 activity, SIRT1, p-LKB1 and AMP/ATP ratio (EAT and BMDMs) ↑Glucose uptake ↓IL-6, IL-1β, TNF-a, iNOS, COX-2 (3T3-L1 and RAW264.7) ↓M1 macrophages phenotype, lipid droplets (Liver, Skeletal Muscle and WAT) ↓Monocytes differentiation (THP-1 cells) ↓Macrophages antigen-presenting and phagocytic abilities and ROS production (ANA-1 and RAW264.7 cells) ↓MHCII+, CD80, CCR7, IL-1β, TNF-α and NO (ANA-1 cells) ↓ALT, AST, IL-1β and TNF-α (Serum) ↑IL-10 and adiponectin (Serum)

Apple Onions Broccoli Tea Strawberries

Quercetin

(17)

Citrus peels

Tangeretin

(20)

Passion fruit Whole raw honey Propolis Cocoa

Chrysin

(13)

Changes in M1–M2 macrophage polarization Suppress macrophage infiltration

Reduce obesity-associated ATM infiltration and systematic inflammation Improve obesity-induced insulin resistance

Attenuate obesity-induced insulin resistance and inflammation Reduce obesity-induced inflammation, hepatic and muscular steatosis, Prevent adipose tissue monocytes and macrophages infiltration

a. MDI-differentiated 3T3-L1+ RAW264.7 co-cultured in a contact system a. HFD-induced obesity in C57BL/6J mice b. Mouse primary macrophages derived from ND or HFD mice c. TPA/LPS-induced M1 macrophage in THP-1 cells d. TPA/IL-4-induced M2 macrophage in ANA-1 and RAW264.7 cells

19


Food bioactives

Ref.


Impair inflammation and insulin resistance

a. LPS-induced inflammation in primary human SV cells

Inhibit obesity-induced inflammation and hepatic steatosis Restore the M1/M2 macrophages status

a. HFD-induced obesity in C57BL/6J mice b. C57BL/6J ob/ob mice c. Peritoneal macrophages derived from C57BL/6J mice d. ATM derived from EAT e. LPS-induced M1 and IL-4-induced M2 macrophages in ANA-1 and RAW264.7 cells f. pIRES-hPPARγ/PPRE-Luc expressed HEK293 cells a. TLI-induced inflammation in 3T3-L1 adipocytes

Oppose inflammation Improve insulin sensitivity

↑M2 macrophages phenotype ↑MGL1/2, Arg1 activity, PPARγ transcriptional activity, IL-10, CD206, Ym1, Arg1, Fizz1 and CD36 (ANA-1 cells and Mouse primary macrophages) ↓Inflammation ↓MCP-1, IL-1β, IL-6, IL-8, TNFα, COX-2, TLR-2, IP-10 and PTP-1B (SV cells) ↑Lipolysis and glucose uptake ↑HSL (SV cells) ↓Inflammatory cells infiltration and M1/M2 subtype ratio ↓lipid accumulation and cell structures derangement (Liver and Skeletal muscle) ↓IL-12, TNF-α, IL-6, IL-1β and MCP-1 (Serum) ↓NOS2, TNF-α, IL-1β and CXCL-10 (RAW264.7 cells) ↓p65 and p-IκBα (Mouse primary macrophages) ↓p65 and PPARγ interaction (ANA-1 cells) ↑IL-10 (Serum) ↑Ym1, CD163, CD206, Arg1 and IL-10 (RAW264.7 cells) ↑PPARγ transcriptional activity (293T cells) ↑CD36 (ANA-1 cells) ↓Inflammation and NO production ↓iNOS, COX-2, IL-6, resistin and MCP-1 (3T3-L1) ↓p-IκBα, NF-κBp65 translocation and MAPKs (3T3-L1) ↑IRS1/2, GLUT4 and p-PI3K (3T3-L1)

Page 20 of 24

California table grapes

Malvidin Peonidin

(21)

Spices Parsley Onions Celery

Apigenin

(18)

Spinach Kale Thyme Peppermint

Luteolin

(22)

Abbreviations: ALT, Alanine aminotransferase; Arg1, arginase 1; AST, Aspartate aminotransferase; BMDMs, Bone Marrow Derived Macrophages; CCR7, C-C chemokine receptor type 7; Chil3l, chitinase-like 3; COX-2, cyclooxygenase-2; CXCL-10, C-X-C motif chemokine 10; GLUT4, Glucose transporter type 4; iNOS, inducible nitric oxide synthase; IRS1/2, insulin receptor substrate 1/2; IP-10, Interferon gamma-induced protein 10; IL-1β, Interleukin 1 beta; IL-10, Interleukin 10; IL-12, Interleukin 12; IL-4, Interleukin 4; IL-8, Interleukin 8; JNK, c-Jun N-terminal kinase; LPS, Lipopolysaccharide; Mgl2, macrophage galactose N-acetyl-galactosamine specific lectin 2; MGL1/2, macrophage galactose-type lectin-1/2; MHCII+, major histocompatibility complex II+; MAPKs, mitogen-activated protein kinases; mMcp-4, mouse mast cell protease 4; Nos2, Nitric oxide synthase 2; 20


Page 21 of 24


p-IκBα, phospho-inhibitor of kappa Bα; p-LKB1, phospho-liver kinase B1; p-PI3K, phospho-Phosphoinositide 3-kinase; PTP-1B, protein-tyrosine phosphatase 1B; ROS, Reactive oxygen species; SIRT1, silent information regulator 1; TLI, tumor necrosis factor-α, lipopolysaccharide, and interferon-γ; TLR-2, Toll-like receptor 2; TNF-α, Tumor necrosis factor alpha; TPA, 12-O-Tetradecanoylphorbol-13-acetate.

21



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Table 3. Potential effects of food bioactives on gut microbiota Mechanism studied and outcome

Model


Alterations in gut microbiota

Sources

Lighten DNA damage in liver


Improve the gut microbiota dysbiosis Reduce de novo lipogenesis

a. HFD-induced obesity in Kunming mice

Decrease lipogenesis in adipose tissue and liver Alter gut microbiota composition

Food bioactives


↓Firmicutes/Bacteroidetes ratio (Fecal) ↓MLH1 gene (Liver) ↑MLH1 promoter CpG2 methylation and DNMT1 promoter CpG1 methylation (Liver) ↑DNMT1 promoter CpG2 methylation and IL-6 gene (Colon) ↓Blood glucose, insulin and lipids ↓Enterococcus faecalis growth (Fecal) ↓LPL, Cyp7a1, and SCD1 gene (Ileum and Liver) ↓PPARγ, ACC1 and FASN (EAT) ↑Bacteroidetes/Firmicutes ratio, Lactobacillus and Bifidobacterium growth (Fecal) ↑Fiaf (Ileum tissue) ↓Blood glucose and lipids ↓C/EBPα, PPARα and FASN (EAT and Liver) ↓Bacteroidetes (Fecal) ↑p-AMPK and p-ACC (EAT and Liver) ↑Firmicutes and Lactobacillus (Fecal)

Ref.

Compounds

Green tea

EGCG

(25)

Grape skin Grape seeds

Resveratrol

(26)

Piceatannol

(27)

Berries Peanuts

Red wine Blueberries Grapes Passion fruit

Abbreviations: Cyp7a1, cytochrome P450 family 7 subfamily A member 1; DNMT1, DNA (cytosine-5)-methyltransferase 1; LPL, Lipoprotein lipase; MLH1, mutL homolog 1.

22


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Figure 1. Mechanisms linking food bioactives with obesity-associated IBD. Mechanisms by which food-based bioactives could contribute to prevention of obesity-associated intestinal inflammation are proposed. Diet induced obesity and the gut microbiota dysbiosis can directly and indirectly participate in low grade inflammation and fat deposition via alteration of immune homeostasis in the intestine, disruption of intestinal mucosa and induction of intestinal permeability, which in turn enhances fat-derived inflammatory adipokines. Daily consumption of vegetables and fruits improves the obese adipose tissue-associated metabolic syndromes and intestinal inflammation by the HFD/HFW diet, including activating energy metabolism, switching from M1 (pink) to M2 (blue) macrophages, increasing gut microbiota diversity, and reversing epigenetic changes.

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Table of Contents (TOC) Graphic

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Food Bioactives and Their Effects on Obesity-Accelerated

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