A widely used probiotic stimulates bone formation in mice, and could feasibly represent a new approach to preventing or treating osteoporosis in human patients, according to research by Emory University researchers. Studies by Roberto Pacifici, Ph.D., and colleagues showed that in young, healthy female mice, treatment using Latobacillus rhamnosus GG (LGG) prompted other intestinal bacteria to produce the short chain fatty acid (SCFA) butyrate, triggering the expansion and activation of T cells in the bone marrow, and ultimately stimulating Wnt signalling in osteoblasts, and bone formation.

“We were surprised by the potency of the gut microbiome in regulating bone and by the complexity of the mechanism of action of probiotics,” Dr. Pacifici said. “In general, there is a lot of interest in the concept that the gut bacteria regulate the function of distant organs. How this happens is largely unknown. We described a detailed mechanism by which changes in the composition of the gut microbiome induced by probiotics affect a distant system like the skeleton.”

The team’s research is published in Immunity, in a paper titled, “The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression.”

Immunity Graphical AbstractFractures due to osteoporosis can have serious consequences, with hip fracture complications leading to mortality rates of up to 24–30% in the first year following injury, and a 50% rate of permanent disability, the authors write. However, the costs and side effects of existing drugs that are used to treat osteoporosis mean that most cases are either poorly treated, or remain untreated.

Nutritional supplementation with probiotics represents an alternative potential strategy, and small-scale human studies have reported positive results with the use of probiotics to supplement the diets of osteoporosis patients. Despite these small studies, however, it is not really understood whether probiotics can improve postnatal skeletal development.

“Because their mechanism of action in bone is unknown, they are regarded as some kind of alternative, esoteric, unproven treatment,” Dr. Pacifici commented. “Our goal was to identify a biological mechanism of action of probiotics, a mechanism that makes sense to traditional scientists, hoping that this will make probiotics a mainstream treatment.”

The team’s previous studies had suggested that LGG supplementation could protect against bone resorption and bone loss in mice, and in certain cases drive bone formation and increase bone volume. Lactobacillus is among the most common of bacteria that are thought to have probiotic effects. Independent research has also separately indicated that LGG prompts the expansion of different types of intestinal bacteria that produce the short-chain fatty acid (SCFA) butyrate. SCFAs are known to support the development of peripheral regulatory T cells (Tregs), while studies have reported that Tregs play a role in stimulating bone formation.

For their latest work, the Emory University researchers investigated the effects of supplementing diet using LGG on bone homeostasis in young, healthy female mice. They found that adding the oral probiotic to the animals’ normal diet led to increased intestinal and serum butyrate levels, as well as increased bone formation. In these healthy animals LGG supplementation acted to stimulate the growth of other butyrate-producing gut bacteria, including Clostridia, which are recognized as the “central generators of butyrate in the intestine,” the authors state. The same effects on bone formation could be achieved by treatment using butyrate itself. And while butyrate treatment also led to increased bone mass in mice that were raised in a germ-free environment and so had no intact microbiome, LGG supplementation was ineffective in these animals. This supported the idea that the probiotic exerts its effects through the metabolic activity of other microbes that normally inhabit the intestines. “These findings indicated that a key mechanism whereby LGG-induced bone anabolism is by indirectly increasing production of butyrate in the small intestine,” the authors commented.

Further studies in experimental mouse models and in cultured cells demonstrated that supplementation using either LGG or butyrate induced the expansion of Tregs in the intestine and in the bone marrow. Treg expansion stimulated bone marrow CD8+ T cells to increase secretion of the Wnt ligand Wnt10b, which then activated Wnt signaling in the osteoblasts, stimulating bone formation. The bone-boosting effects of LGG or butyrate could be inhibited using antibodies that specifically blocked Treg expansion.

“The controversies about probiotics are: Do they work for real, and which one is the best?” Dr. Pacifici continued. “We show that they work for real in bone. Which one is the best remains unknown. However, the emerging concept is that the number of bacteria in a dose of probiotic may be as important or even more important than the type of probiotic used. It is possible that the response to probiotics might be influenced by mouse strain, gender, and age.”

The authors acknowledge that the potential benefits of LGG on bone mass in humans will need validation through clinical trials. “If successful, this research could substantiate the use of butyrate or probiotics as a novel, safe, and inexpensive treatment for optimizing skeletal development in young people and to prevent osteoporosis in older people,” noted Dr. Pacifici. The team suggests that using dietary supplements to boost Treg numbers may also have clinical benefits beyond bone diseases “… an increase in the number of Treg cells via nutritional supplementation may represent a therapeutic modality for increasing bone mass and preventing osteoporosis,” they write. “Moreover, the use of probiotics or butyrate to increase the number of Treg cells may find wider applications, such as in transplant medicine or as a treatment for inflammatory and autoimmune conditions.”

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