Wnt signalling in the gut microbiota–bone axis

The probiotic strain Lactobacillus rhamnosus GG (LGG) can promote bone formation and increase bone density in mice. New findings published in Immunity provide insights into this gut microbiota–bone pathway, which might have therapeutic implications for diseases such as osteoporosis.

Credit: Panther Media GmbH/Alamy Stock Photo

According to the new findings, LGG-induced upregulation of the gut metabolite butyrate expands the regulatory T (T_reg) cell pool, which subsequently increases the production of the osteogenic Wnt ligand Wnt10b by CD8⁺ T cells to stimulate bone formation.

The researchers found that, as expected, dietary supplementation with LGG resulted in increased bone formation and bone mass in young mice. In the gut, LGG indirectly stimulated the production of butyrate by expanding strains of butyrate-producing bacteria.

Butyrate is known to promote the expansion of peripheral T_reg cells, and indeed in the new study LGG supplementation increased the numbers of T_reg cells in the gut and bone marrow. Further experiments using butyrate supplementation and T_reg cell depletion indicated that LGG affects bone mass through a butyrate-dependent T_reg cell-mediated pathway.

Both LGG and butyrate supplementation increased the expression of Wnt10b in the bone marrow, which was attributed to an increase in expression by CD8⁺ T cells. Further analysis revealed the pivotal role of Wnt10b in the LGG–bone pathway, and suggested that butyrate indirectly increases CD8⁺ T cell expression of Wnt10b via T_reg cells. Butyrate treatment resulted in a T_reg-cell dependent increase in binding of the transcription factors NFAT1 and SMAD3 to the Wnt10b promoter in CD8⁺ T cells, promoting Wnt10b expression.

butyrate indirectly increases CD8⁺ T cell expression of Wnt10b via T_reg cells

“Butyrate may, therefore, be used [as an] alternative to probiotics and may represent a novel treatment for osteoporosis,” explains Roberto Pacifici, corresponding author of the study. “There is a need for a clinical trial with LGG or butyrate to determine if these substances prevent bone loss and improve skeletal development.”