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 microbiota-dependent 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 factor-α, 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.
Highlights
Bone is continuously remodeling through bone formation by osteoblasts and resorption by osteoclasts [1]
Lactulose prevents bone loss induced by ovariectomy in mice
Trabecular area, as shown by H&E staining and bone volume/total volume (BV/TV), bone surface area/total volume (BS/TV), Tb.N, and bone mineral density (BMD) increased significantly (Supplementary Fig. 2). These results indicate that lactulose affects bone metabolism independently of estrogen
Summary
Bone is continuously remodeling through bone formation by osteoblasts and resorption by osteoclasts [1]. Osteoclastogenesis is overactivated and the bone turnover rate increases, which leads to net bone loss [2, 3]. Lactulose suppresses osteoclastogenesis available probiotic supplement VSL#3 twice weekly reduces gut permeability and intestinal and bone marrow inflammation, and completely protects against bone loss. Short-chain fatty acids (SCFAs), which are primary gut flora metabolites, have been reported to directly inhibit osteoclastogenesis and prevent postmenopausal and inflammation-induced bone loss [9, 10]. Lactulose is a synthetic derivative of lactose with one galactose and one fructose It cannot be digested by enzymes in the mammalian digestive tract but can be used by colonic microflora [12]. The results show that lactulose protected against ovariectomy (OVX)-induced bone loss in mice and significantly suppressed osteoclastogenesis. Lactulose maintained the intestinal epithelial barrier permeability that decreased after OVX, preserved the number of intestinal Treg cells that decreased significantly after OVX and lowered the pro-inflammatory and osteoclastogenic cytokine levels
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