Nutrients 2023 , 15 , 2688
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sweats [6]. Moreover, isoflavones from soy and red clover have received considerable atten- tion in the management of postmenopausal bone loss with an overall moderately beneficial effect against bone loss when consumed for at least twelve months [7,8]. There is limited literature regarding the effect of hops ( Humulus lupulus ) on bone metabolism although hops contain one of the most potent phytoestrogens known to date: 8-prenylnaringenin (8-PN). As a novel phytoestrogen, 8-PN is unique in that its receptor specificity and potency is higher than any other phytoestrogens investigated thus far [9,10]. In vitro, 8-PN was shown to enhance differentiation and maturation of osteoblast and inhibit differentiation of osteoclast with intensities of response stronger than that observed with soy isoflavones [11]. Several in vivo studies demonstrated that an oral supplementation with a standardized hop extract was able to prevent estrogen-deficiency-induced bone loss in osteoporotic rodent models [12–15]. Moreover, in ovariectomized rats, supplementation with 68.4 mg/kg of body weight (bw) per day of 8-PN during twelve weeks improved bone biomechanical properties to the same degree as 0.7 mg/kg bw per day of estradiol, while the two other phytoestrogens tested, genistein (60 mg/kg bw per day) and resveratrol (50 mg/kg bw per day), had no significant impact [15]. From a clinical point of view, a bioavailability study per- formed in menopausal women indicates that prenylflavonoids (8-PN, 6-prenylnaringenin, isoxanthohumol, and xanthohumol) from a standardized hop extract are absorbed slowly, undergo enterohepatic circulation, and have long half-lives exceeding 20 h [11]. Moreover, 8-prenylnaringenin seems to be significantly more bioavailable in healthy humans than its isomer 6-prenylnaringenin [12]. In terms of health effect, three clinical studies have demon- strated the efficiency of standardized hop extract in decreasing menopausal symptoms at a doseof 100 µ g of 8-PN per day during a minimum duration of 6 weeks [16–18]. However, to date, the potential impact of hop extract and 8-PN in the prevention of osteoporosis has not been assessed in humans. While the presence of 8-PN in hops is low, other more abundant prenylated phenols such as xanthohumol (X) and isoxanthohumol (IX) can be metabolically converted to 8-PN. The conversion of IX into 8-PN can be accomplished enzymatically by hepatic CYP1A2 or by the gut microbiome [19,20]. However, large inter-individual variability was found for IX conversion capacity by the human gut microbiome, with only about one- third of individuals exhibiting the capability to efficiently execute this transformation [20]. Eubacterium limosum has been identified as one intestinal bacterium capable of facilitating the conversion (O-demethylation) of IX into 8-PN [21,22]. Finally, the gut microbiome impact on host health has been increasingly studied over past decades. There is notably a growing body of evidence indicating that the gut microbiome plays a key role in bone metabolism and osteoporosis pathogenesis even though mechanisms of action have not been clearly elucidated yet [23–25]. Given the role of the gut microbiome in bone health maintenance and its importance in 8-PN generation potency, it is of great interest to investigate the gut microbiome as a potential key factor in the mechanism of action of hop extract. The present clinical trial aimed to determine whether one-year consumption of a hop extract standardized in 8-PN can moderate bone mineral density decreases in post- menopausal women with osteopenia and to explore potential mechanism of action via gut microbiome modulation.
2. Materials and Methods 2.1. Study Design and Participants
This study was a 48-week, parallel-design, placebo-controlled, double-blind, random- ized clinical trial. The clinical aspects of the study were carried out from August 2019 to December 2020 in Cork (Ireland), including screening, recruitment, and follow-up. Partici- pants were recruited through advertisements (local newspaper and social media platforms) or referred by local general practitioners in the area. A total of 221 participants were screened to identify 100 eligible participants, all of whom were postmenopausal women (>1-year post-menopause), between 50 and 85 years of age, with a body mass index (BMI)
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