Lignans from Sambucus williamsii Protect Bone Via Microbiome

The proportion of the world's population over 60 years will be nearly double from 12 to 22% between 2015 to 2050 [1]. It is anticipated that 21.2% of women and 6.3% of men globally will suffer from osteoporosis and might lead to almost 70 fragility fracture per minute [2]. Hormonal changes, especially estrogen deficiency associated with menopause, and aging are the major contributing factors to the pathogenesis of osteoporosis.

Phytoestrogens, which are classically defined as phytochemicals that possess similar chemical structures to endogenous estrogen, are considered to be potential alternatives to hormone replacement therapy for management of estrogen deficiency-induced symptoms in menopausal women [3]. Lignans, one of the three major classes of phytoestrogens, are widely present in a variety of plant foods, including seeds, beans, whole grains, bran, fruits, vegetables and beverages such as tea and coffee [4]. Although the epidemiological studies are inconclusive, numerous health benefits have been attributed to the intake of naturally lignan-rich foods, including the reduction of risk of heart disease, menopausal symptoms, breast cancer and osteoporosis [3, 5].

Flaxseed and sesame seeds, derived from Linum usitatissimum L. and Sesamum indicium, respectively, are the two richest known sources of lignans. The consumption of flaxseed in various forms including total extract, power, flour, and oil, exhibited positive effects on bone mineral density (BMD) and bone metabolism in different animal models and in several clinical studies [6]. From 2013 to 2022, six studies reported that sesame seeds intake only, or in combination with peanut seeds or black seeds, were beneficial for improving BMD and serum bone biochemical markers in postmenopausal animal models [7]. In contrast, a randomized, double-blind clinical trial including 199 healthy menopausal women consuming 40 flaxseed/d (n = 101) or wheat germ placebo (n = 98) for 12 months, revealed that flaxseed incorporation into the diet of healthy menopausal women did not alter the BMD in lumbar or femoral neck as compared with wheat germ placebo [8]. Due to the limited available clinical studies, the effects of lignans on bone health are inconclusive.

Several early studies revealed that ingested lignans were deglycosylated and converted to mammalian lignans enterolactone and enterodiol by gut microbiota, absorbed into blood, finally excreted in urine, bile and feces [9]. Lignans such as pinoresinol, lariciresinol, secoisolariciresinol diglucoside (SDG) and matairesinol which represented four different classes of lignans were converted to enterolignans through reduction, O-deglycosylation, O-demethylation, dehydrogenation and dihydroxylation by intestine bacteria [10]. However, only 55%, 62% and 72% of pinoresinol diglucoside, matairesinol and SDG were converted to enterolignans, respectively(11). A study showed that one hour after ingestion of sesame seeds, some lignans are quickly detected in the systemic circulation, such as pinoresinol, matairesinol, lariciresinol, secoisolariciresinol and sesamin, while other studies indicated that the enterolignans generally appeared in circulation 8–10 h after intake of dietary lignans [9]. Sacco et al. reported that after orally administering rats with trimer-labeled SDG for 7 days, 59.8% of the radioactivity, including the prototype and metabolites, was detected in the colon and cecum, while only 0.1% was detected in the entire skeletal tissue [12]. In addition, the fate of pure compounds does not invariably mirror the bioavailability of lignan within complex food or herbal medicines matrices. Therefore, the above publications suggest that the enterolignans or metabolites of lignans in the circulation might not be able to totally account for the beneficial actions of lignans on bone.

Sambucus williamsii Hance (SWH) belongs to Caprifoliaceae family and is widely distributed in China, Korea and Japan [13]. It is in the same genus as elderberry (also known as Sambucus nigra) which is popular in Europe to be used in products of syrup, gummies, soft drink, liqueur and eye gel. S. williamsii was first recorded in Tang Materia Medica (A.D. 659) for healing fractures and alleviating pain. Our previous studies have demonstrated that the SWH extract and its lignan-rich fraction increased BMD, improved trabecular bone micro-architecture, and promoted cortical bone strength in ovariectomized mouse and rat models [14‐17]. Fifty-six lignans were isolated and purified in the extract of SWH and were identified to be the bioactive components in SWH through the determination of the osteoblastic proliferation in vitro [18, 19].

The mechanism of actions of lignan derived from SWH were summarized in Fig. 1. In conclusion, lignans appear to exert protective effects on bone by modulating the composition of microbiota and suppressing the synthesis of gut-derived serotonin, without the need to be absorbed into the circulation. Microbiome, including microbiota, their metabolites and their living environment, is an indispensable factor for lignans to exert bone beneficial effects.

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