Nutrients 2023 , 15 , 2688
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Another hypothesis for the important variability in response observed in this trial could be the inter-individual variation in prenylflavonoids metabolism that was reported previously [20–22]. The final level of 8-PN absorbed does not only depend on the presence of 8-PN itself in the HE but also on the transformation of its precursor IX into 8-PN by the intestinal bacteria E. limosum [21]. However, important inter-individual variability was observed for conversion efficacy with reported low, moderate, and high 8-PN producers in humans [19]. E. limosum levels were not statistically different between the HE and placebo group at baseline and after 48 weeks. Furthermore, subset analysis based on responsiveness to HE supplementation did not indicate any difference in E. limosum levels at baseline and after 48 weeks between the women with an increase in their total body BMD ≥ 1% vs. <1%. Likewise, the 8-PN levels detected in blood or urine in women who took the HE supplementation were not correlated with the magnitude of responsiveness. Altogether, these results suggest that conversion capability of the women included in this trial was not the primary cause of efficacy. Furthermore, it is likely that a plateau effect was reached with the dose of 100 µ g of 8-PN and that any additional amount brought by the conversion was not responsible for additional bone health effect. Interestingly, in the study conducted by Heyerick et al., using the same extract, 100 µ g of 8-PN was sufficient to relieve women from postmenopausal symptoms, and no additional benefit was observed with the higher dosage of 250 µ g of 8-PN [17]. A novel aspect of this trial was the analysis of the participants’ gut microbiome and its relationship to the responsiveness of treatment. No difference between HE and placebo was observed for overall association parameters, alpha-diversity indices, and SCFA levels throughout the study, hence indicating no major shift in the gut microbiome composition and function. However, the explorative multivariate analysis indicated that after 48 weeks among the taxa identified as the most relevant to discriminate the two groups, there was notably a higher abundance of the genera Turicibacter and Escherichia Shigella in the HE group. In a recent animal study, positive correlations between the genera Turicibacter and total BMD were observed in ovariectomized mice supplemented with new antidepressant drug (R)-ketamine [58]. (R)-ketamine significantly attenuated the reduced abundance of Turicibacter observed after ovariectomy compared to sham control. Moreover, Escherichia Shigella was found to be more abundant in individuals with osteopenia compared to those with osteoporosis in a cohort of 181 older adults (including 150 women) [59]. Conversely, with the latter study and our results, Escherichia Shigella was also found negatively associated with L1-L4 BMD, total BMD, and femur total BMD in the UK biobank cohort study including middle-aged adults [60]. These results suggest that there may be an association between Escherichia Shigella and BMD modulation, but causal relationship needs to be further investigated. Other species identified as discriminating the two groups have not yet been related to bone health and disease. Strengths of this study include the sample size calculation, the robust design (random- ized, placebo-controlled, double-blind), the good adherence rate, the low drop-out rate, and the integrated analysis, including the impact of treatment on the microbiome and HE metabolites. The main limitation is the relatively short duration considering bone loss, as a duration of at least 2 years would incorporate more complete bone remodeling cycles and further strengthen the evidence provided by DXA in this trial. However, the bone remodelling cycle is known to last 120–200 days [61]; therefore, a duration of 48 weeks has allowed 1.5 to 2 bone remodelling cycles to happen. To conclude, in postmenopausal women with osteopenia, daily consumption of a standardized hop extract with 100 µ g of 8-PN during 48 weeks was found to have a beneficial increase of 1% of the total body BMD compared to placebo, above and beyond an increase associated with a calcium and vitamin D supplementation. Furthermore, even if no major shift of the gut microbiota composition was observed, modulation of some taxa previously identified as associated with bone loss was noted in the HE group and deserves further investigation. New clinical trials with notably a longer duration are needed to confirm the beneficial effect of standardized hop extract on bone health.
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