Dietary fucoidan improves metabolic syndrome in association with increased Akkermansia population in the gut microbiota of high-fat diet-fed mice
Introduction
Recent years have witnessed a devastating worldwide epidemic of metabolic syndrome (MetS), a constellation of obesity, insulin resistance, dyslipidemia and hypertension (Beltrán-Sánchez et al., 2013, Kaur, 2014). Given the accumulating knowledge that gut microbiota plays a critical role in modulating metabolism, nutrition and immunity of its host (Nicholson et al., 2012, Tremaroli and Bäckhed, 2012), an evolving body of literature has linked gut dysbiosis, an imbalance of intestinal microbiota, to the development of obesity, insulin resistance and other characteristics of MetS (Cani et al., 2008, Ley et al., 2006, Ussar et al., 2015). Recently and more strikingly, some species of gut flora, including Enterobacter cloacae and Akkermansia muciniphila, were found to be causally associated with the development of MetS (Everard et al., 2013, Fei and Zhao, 2013, Shin et al., 2013). Mono-association of germ-free mice with E. cloacae causes fully-developed obesity and insulin resistance on a high-fat diet (HFD) while oral administration of A. muciniphila to HFD-fed mice remarkably enhanced glucose tolerance and attenuated systematic inflammation (Fei and Zhao, 2013, Shin et al., 2013). Combined with the fact that dietary interventions and pre- or probiotic treatment have been successfully used to prevent or alleviate MetS during the past few years (Delzenne, Neyrinck, Bäckhed, & Cani, 2011), these studies rationalize gut microbiota as a desired target for MetS management.
Fucoidans are a class of sulphated fucose-rich polysaccharides which are mainly found in edible brown seaweeds (Li, Lu, Wei, & Zhao, 2008). Naturally occurring fucoidan usually has two types of chain with type I chain composed of α (1 → 3) linked fucose and type II chain composed of altering α (1 → 3) and α (1 → 4) linked fucose (Cumashi et al., 2007). Since its first discovery by Kylin in 1913 (Li, Lu, Wei, & Zhao, 2008), research into fucoidans has continued to gain pace over years of study(Fitton, 2011, Fitton et al., 2015). Until now, substantial evidence has demonstrated an attractive array of bioactivities which makes fucoidan a promising candidate for drug and functional food development (Fitton et al., 2015). Recently, fucoidan stands out as a potential lever to attenuate MetS due to its desired properties including anti-inflammation (Lee et al., 2013), anti-diabetes (Shan et al., 2016) and anti-obesity (Kim, Jeon, & Lee, 2014). However, although this possibility has been proposed, no systematic study is currently available regarding to this issue. Besides, as for the mechanisms by which fucoidan improve glucose homeostasis and inhibit lipid accumulation, while down-regulation of peroxisome proliferator-activated receptor γ (Kim, Chang, & Lee, 2009) and up-regulation of total hormone sensitive lipase (Park, Jung, & Roh, 2011) have been documented, it is still difficult to explain the clinical efficacy of fucoidan owing to its extremely low bioavailability after oral administration (Irhimeh et al., 2005, Nagamine et al., 2014, Tokita et al., 2010). Lately, intake of unabsorbed polysaccharide from Ganoderma lucidum has been illustrated to protect against MetS by targeting gut microbiota (Chang et al., 2015). Considering that fucoidan is also largely unabsorbed in the gastrointestinal tract, this study indicates an underlying role for fucoidan in modulating gut microbiota during the treatment of obesity-related metabolic diseases. However, unfortunately, this hypothesis has been the subject of relatively few investigations.
In the present study, fucoidan from Laminaria japonica (FuL) with type I chain (Cumashi et al., 2007, Vishchuk et al., 2011) and fucoidan from Ascophyllum nodosum (FuA) with type II chain (Cumashi et al., 2007, Marais and Joseleau, 2001) were studied on their effects on host physiology and gut microbiota in mice with HFD-induced MetS. We found that both FuL and FuA profoundly attenuated body weight gain, improved glucose homeostasis and reduced systematic inflammation in diseased mice. Interestingly, combined with ameliorated MetS, both fucoidans altered the gut microbiota in a direction that favored the host. Altogether, our study provides a fresh perspective into the role of gut microbiota modulation during the treatment of MetS by fucoidan.
Section snippets
Chemicals and materials
The brown algae Ascophyllum nodosum and Laminaria japonica were sourced from Antofagasta (Chile) and Weihai (China) respectively. Both seaweeds were obtained from Gather Great Ocean Algae Industry Group Co., Ltd. (Qingdao, China) and authenticated by Prof. Xiang zhong Gong at Ocean University of China based on histological and morphological features. FuA and FuL were extracted and further purified as previously reported (Shan et al., 2016). Chemical compositions of FuA and FuL were determined
Chemical characterization of fucoidan
FuA from Ascophyllum nodosum with type II chain was found to have a molecular weight (MW) of 1330 kDa and sulfate content (SC) of 21.0% (Supplementary Table S2). In contrast, the MW and SC of FuL from Laminaria japonica with type I chain were found only to be 310 kDa and 18.4%, respectively (Supplementary Table S2). As for monosaccharide composition, expectedly, both FuA and FuL were dominated by fucose (Supplementary Table S2). However, FuA had a higher amount of GlcA (24.1%) while Gal (19.3%)
Discussion
Fucoidan has long been championed as a multifunctional marine polysaccharide with versatile activities (Li et al., 2008, Fitton, 2011, Fitton et al., 2015). However, its precise mechanism of action remains largely unclear although several different ones have been proposed. In light of the fact that gut microbiota can be manipulated by drugs and functional foods to improve human health and to treat disease (Chang et al., 2015, Jia et al., 2008), we extrapolate that fucoidan may have gut
Conclusions
In conclusion, our study demonstrated that fucoidan intervention can reduce MetS probably through its modulations of gut microbiota by selectively promote the growth of benign bacteria including Akkermansia and SCFA-producers. Based on preceding studies, we characterized a novel potential therapeutic role of fucoidan and for the first time we provided a deep analysis of gut microbiota alterations that occurred after fucoidan supplementation in the context of metabolic inflammation, obesity and
Conflict of interest
The authors declare no competing financial interests.
Acknowledgements
This work was supported in part by National Natural Science Foundation of China (31670811), NSFC-Shandong Joint Fund for Marine Science Research Centers (U1406402), National Science & Technology Support Program of China (2013BAB01B02), Special Fund for Marine Scientific Research in the Public Interest (201005024), Taishan scholar project special funds and Major Science and Technology projects in Shandong Province (2015ZDJS04002), Qingdao Basic & Applied Reaarch Project (165115JCH).
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