Bone density may be determined in the gut

Serotonin produced in the gut may have a major role in bone formation. Too much of the gut-derived hormone in mice leads to weak bones, while too little causes  bones to be too dense, a new study shows. The results, published in the Nov. 28 Cell, may lead to new treatments for  bone diseases, such as osteoporosis.

The finding that serotonin may regulate bone mass is “a fabulous discovery,” comments Matthew Warman, a physician researcher at Children’s Hospital Boston who studies bone diseases. “It was completely unexpected that a  gut hormone would have such a strong effect on bone mass.”  Serotonin is known for its role inside the human brain: The small hormone regulates mood, learning and sleep. But 95 percent of the body’s serotonin is produced in the gut and never crosses the blood-brain barrier. This massive supply of serotonin regulates the day-to-day operations of the gut, including the rhythmic contractions that move food through the digestive tract. But this new research shows that gut-derived  serotonin may have an important job after it leaves the gut — building bones.   The link between serotonin and bone density came from studying Lrp5, a gene that regulates bone formation. Rare mutations in the Lrp5 gene can cause it to make Lrp5 protein that is either more or less active than normal. People with mutations in Lrp5 that cause the protein to be less active suffer from bone-weakening osteoporosis,  while people with mutations that increase Lrp5 protein activity have high bone mass syndrome. To study how Lrp5 might be regulating bone density in humans, the researchers turned to mice, whose bones are affected by Lrp5 mutations in the same way as humans.   The scientists found that in mice, the Lrp5 gene regulates yet another gene that in turn controls serotonin production in the gut. This finding hinted at a connection among Lrp5 , its associated bone diseases and serotonin produced in the gut. To test the link between Lrp5 and serotonin in the gut, the researchers gave mice mutations that caused reduced Lrp5 protein activity. These mice had much higher levels of gut-derived serotonin than did mice without the mutation. The same was true of three human patients who had osteoporosis caused by the mutations in the Lrp5 gene: The patients had three to  five times more gut-derived serotonin than control subjects. The opposite was also true: Mice with mutations that cause an increase in Lrp5 protein activity, which causes dense bones, had lower levels of gut-derived serotonin.  What’s more, two human patients with high bone mass syndrome caused by similar  mutations showed 50 percent less gut-derived serotonin than control subjects.   Not only did researchers correlate serotonin levels with bone mass, they also changed the density of the mice’s bones by tinkering with serotonin levels in the gut. The mice were fed a diet low in tryptophan — a serotonin precursor  found in turkey — as a way to lower the levels of gut-derived serotonin. On this low-tryptophan diet, mice with the mutation that would have caused weak bones instead had normal bone density. Mutated mice who received a drug that prevents serotonin synthesis in the gut showed the same healthy bones as the mice on the low-tryptophan diet.  Coauthor Patricia Ducy of Columbia University said that the link between the gut and bone was a surprise. “We were not looking into this direction when we started our work, but the results we obtained in vivo in mice were compelling and we listened to them.” The new connection between bone and gut-derived serotonin will likely spur  many new types of experiments on bone formation. “It’s what you’d call a landmark study,” researcher Bjorn Olsen of Harvard  Medical School  in Boston says. “It opens new doors.” Although the role of the gut in bone formation is potentially paradigm-shifting, Warman cautions that, “like any paradigm-shifting result, it requires additional confirmation.”