Microbiota and Bone - Treatment Studies of Probiotics and Synbiotics on Osteoporosis in Mice

Abstract

Osteoporosis is a disease with low bone mass and an increased fracture risk. One in two women and one in four men in Sweden will experience an osteoporotic fracture. The aim of this thesis is to identify new gut microbiota-based preventive treatments for osteoporosis. The gut microbiota can regulate bone and lean mass and be manipulated by prebiotics, probiotics, and synbiotics (probiotics and prebiotics combined). Traditional probiotics may provide overall health benefits, while tailored next-generation probiotics target specific diseases. The traditional probiotic L. mix protects against bone loss induced by estrogen deficiency in females. There is a medical need to develop more efficient probiotics and treatments with bone sparing effects both in females and in males. In paper I, we investigated the effect of the probiotic L. mix to prevent bone loss in male mice. In paper II and III, we studied next-generation probiotics and synbiotics to identify novel preventive treatments for bone loss induced by estrogen deficiency in female mice. In paper IV, we transplanted gut microbiota from young and old female mice to germ-free female mice in order to investigate the impact on age-related changes of bone and/or lean mass, with the aim to identify next-generation probiotics. In paper I we showed that treatment with L. mix protected bone in orchidectomized (orx)-male mice, a model used to study sex steroid deficiency-induced bone loss in male mice. Pasteurized Akkermansia muciniphila (A. muciniphila) is considered a next-generation probiotic. Unexpectedly, in paper II, we demonstrated that pasteurized A. muciniphila caused bone loss in gonadally intact female mice and did not protect against ovariectomy (ovx)-induced bone loss. In paper III, we developed a next-generation synbiotic and confirmed its ability to produce the bone-protective product acetate both in silico and in vitro. Our study demonstrated that the synbiotic offered protection against ovx-induced bone loss in mice in a dose-dependent manner. In paper IV, we showed that the low lean mass, but not the low bone mass, in old mice can be transferred by gut microbiota transplantation to young growing germ-free mice. In conclusion, this thesis shows the potential of probiotics in preventing bone loss in men. It also demonstrated that it is possible to develop tailored next-generation synbiotics with the aim of producing specific products, but new probiotics and synbiotics need to be carefully evaluated for their safety. Finally, it shows that the low lean mass, but not low bone mass, of old mice can be transferred to young mice by microbiota transplantation