Fructus Ligustri Lucidi preserves bone quality through the regulation of gut microbiota diversity, oxidative stress, TMAO and Sirt6 levels in aging mice

Abstract

Gut dysbiosis and oxidative stress may trigger senile osteoporosis. Fructus Ligustri Lucidi (FLL) has bone-preserving properties and affects the intestinal microecology. However, the mechanism of the anti-osteoporotic effect of FLL and its link to the gut microbiota remains to be elucidated. Here, we demonstrated that sustained exposure of ICR mice to D-galactose / sodium nitrite for 90 days causes aging-related osteoporosis and reduced cognitive performance. The aging phenotype is also characterized by increased oxidative stress in serum. This is likely triggered by abnormal changes in the gut microbiota population of Bifidobacterium and the ratio of Firmicutes/ Bacteroidetes that resulted in increased levels of flavin-containing monooxygenase-3 and trimethylamine-N-oxide (TMAO). Moreover, the increased oxidative stress further accelerated aging by increasing tumor necrosis factor-α levels in serum and reducing Sirtuin 6 (Sirt6) expression in long bones, which prompted nuclear factor kappa-B acetylation as well as over-expression and activation of cathepsin K. FLL-treated aging mice revealed a non-osteoporotic bone phenotype and an improvement on the cognitive function. The mechanism underlying these effects may be linked to the regulation of gut microbiota diversity, antioxidant activity, and the levels of TMAO and Sirt6. FLL may represent a potential source for identifying anti-senile osteoporotic drug candidates.

The role of gut microbiota in bone homeostasis

“…Mice were used in 23 studies including C57BL6 in 15 studies, 33 - 47 CB6F1 in one study, 48 BALB/c in three studies, 39 , 48 , 49 Swiss Webster in one study, 17 ddY in one study, 50 senescence-accelerated mouse prone 6 (SAMP6) and senescence-accelerated mouse resistant 1 (SAMR1) in two studies, 51 , 52 and Institute of Cancer Research (ICR) mice in two studies. 53 , 54 Germ-free mice were used in six studies 33 , 34 , 36 , 38 , 45 , 48 and rats were used in six studies, including four Sprague-Dawley 55 - 58 and two Wistar. 59 , 60 Genetically modified animals were used in five studies.…”

“… 51 , 52 One study used D-galactose (D-gal) and sodium nitrite (NaNO 2 ) to induce age-related bone loss. 54 …”

“… 45 Nine studies had antibiotics treatment with different protocols. 35 , 41 - 43 , 46 - 48 , 61 , 63 Other supplements include short-chain fatty acid (SCFA), 39 , 48 sialoglycoprotein (SGP), 59 nitrate, 56 vitamin D, 37 vitamin E, 54 Duck Egg White-Derived Peptide VSEE (Val-Ser-Glu-Glu), 57 and tuna bone powder (TBP). 53 Two studies used traditional Chinese medicine (TCM) herb including Eclipta prostrata 51 and Fructus Ligustri Lucidi (FLL).…”

“… 53 Two studies used traditional Chinese medicine (TCM) herb including Eclipta prostrata 51 and Fructus Ligustri Lucidi (FLL). 54 One study had neuropeptide Y1 receptor (Y1R) antagonist intervention. 58 Two studies had a high-weight polymer (MDY) mucus supplement to repair the intestinal barrier function.…”

“…Gut microbiota was determined in 24 studies, and 19 studies performed 16S ribosomal RNA (rRNA) sequencing. 35 , 38 - 40 , 42 , 43 , 45 , 46 , 49 - 51 , 53 , 54 , 56 - 59 , 61 , 63 One study performed metagenomic analysis. 41 Two studies used culture-dependent analysis, 52 , 55 and six studies performed quantitative polymerase chain reaction (qPCR) analysis to quantify bacteria load.…”