Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice

Abstract

Postmenopausal osteoporosis is characterized by excess osteoclastogenesis which leads to net bone loss and brittle fractures. Studies have demonstrated that estrogen deficiency-associated bone loss is microbiotadependent and could be prevented by probiotics and prebiotics. In this study, we report that orally administered lactulose (20 g/kg, 6 weeks) orally administered significantly inhibited osteoclastogenesis, bone resorption, and prevented ovariectomy (OVX)-induced bone loss in mice. Lactulose increased intestinal Claudin 2, 3 and 15, compared to the OVX group, and lowered pro-osteoclastogenic cytokines levels including tumor necrosis factorα, interleukin(IL)-6, receptor activator of nuclear factor kappa-Β ligand (RANKL), and IL-17 as well as increased the anti-inflammatory cytokine IL-10 in the intestine, peripheral blood, and bone marrow. Lactulose significantly preserved the number of Foxp3 + Treg cells in the intestines compared with that in OVX mice. Lactulose altered the composition of intestinal microbiota measured by 16s rDNA sequencing and increased intestinal and serum short-chain fatty acids (SCFAs) levels including acetate, propionate and butyrate which were decreased in OVX mice as measured by gas chromatography. Oral administration of lactulose for 2 weeks significantly lowered the level of bone resorption marker C-telopeptide of type 1 collagen-1 in healthy male young volunteers (aging 20-25 years). In conclusion, lactulose inhibited osteoclastogenesis and bone resorption by altering the intestinal microbiota and increasing SCFAs. Lactulose could serve as an ideal therapeutic agent for postmenopausal osteoporosis.

Prebiotic Food Intake may Improve Bone Resorption in Japanese Female Athletes

“…Several studies have reported that short-term administration of inulin or lactulose increased Bi dobacterium spp. in the gut microbiota [10,20,21], which reduced bone resorption markers in postmenopausal women and healthy young men [22][23][24]; however, only limited studies have demonstrated that supplemented prebiotics change the gut microbiota and bone turnover metabolism markers in humans [24]. According to a consensus statement, prebiotics were recognized to particularly stimulate Bi dobacterium spp.…”

Gut microbiota and bone metabolism

“…Prebiotics, the substrates that promote the proliferation and metabolism of beneficial bacteria in the gut, also have a positive regulatory effect on calcium absorption and bone mass in postmenopausal women 96,97 . In OVX mice, prebiotics can normalize intestinal permeability, thereby decreasing exposure to GM, as well as inhibit the OVX‐induced, immune inflammation‐associated osteoclastogenesis via lowering the levels of pro‐osteoclastogenic cytokines, including TNF‐α, IL‐6, RANKL, and IL‐17, and increasing that of the anti‐inflammatory cytokine IL‐10 98 …”

“…96,97 In OVX mice, prebiotics can normalize intestinal permeability, thereby decreasing exposure to GM, as well as inhibit the OVX-induced, immune inflammation-associated osteoclastogenesis via lowering the levels of pro-osteoclastogenic cytokines, including TNF-α, IL-6, RANKL, and IL-17, and increasing that of the antiinflammatory cytokine IL-10. 98 Diabetes is a common endocrine-related disease closely linked with osteoporosis. 99,100 The GM plays a critical linking role between the two diseases.…”

MiR-486-3p promotes osteogenic differentiation of BMSCs by targeting CTNNBIP1 and activating Wnt/β-catenin pathway

“…Twenty mice were randomly allocated into sham surgery (Control, Con) and ovariectomy (OVX) group according to their weight and random numbers were generated by Excel software. The procedure of OVX has been described previously [17]. Brie y, shave hair off the ank area of mice after its anesthesia with pentobarbital.…”