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In previous studies we demonstrated that oral administration of <jats:italic>Lactobacillus reuteri<\/jats:italic> in healthy male mice increases bone density. The host and bacterial mechanisms of these effects however are not well understood. The objective of this study was to understand the role of lymphocytes in mediating the beneficial effects of <jats:italic>L. reuteri<\/jats:italic> on bone health in male mice. We administered <jats:italic>L. reuteri<\/jats:italic> in drinking water for 4 weeks to wild type or Rag knockout (lack mature T and B lymphocytes) male mice. While <jats:italic>L. reuteri<\/jats:italic> treatment increased bone density in wild type, no significant increases were seen in Rag knockout mice, suggesting that lymphocytes are critical for mediating the beneficial effects of <jats:italic>L. reuteri<\/jats:italic> on bone density. To understand the effect of <jats:italic>L. reuteri<\/jats:italic> on lymphocytes in the intestinal tissues, we isolated mesenteric lymph node (MLN) from na\u00efve wild type mice. In <jats:italic>ex vivo<\/jats:italic> studies using whole mesenteric lymph node (MLN) as well as CD3<jats:sup>+<\/jats:sup> T-cells, we demonstrate that live <jats:italic>L. reuteri<\/jats:italic> and its secreted factors have concentration-dependent effects on the expression of cytokines, including anti-inflammatory cytokine IL-10. Fractionation studies identified that the active component of <jats:italic>L. reuteri<\/jats:italic> is likely water soluble and small in size (&lt;3\u2009kDa) and its effects on lymphocytes are negatively regulated by a RIP2 inhibitor, suggesting a role for NOD signaling. Finally, we show that T-cells from MLNs treated with <jats:italic>L. reuteri<\/jats:italic> supernatants, secrete factors that enhance osterix (transcription factor involved in osteoblast differentiation) expression in MC3T3-E1 osteoblasts. Together, these data suggest that <jats:italic>L. reuteri<\/jats:italic> secreted factors regulate T-lymphocytes which play an important role in mediating the beneficial effects of <jats:italic>L. reuteri<\/jats:italic> on bone density.<\/jats:p>","DOI":"10.1038\/s41598-019-51293-8","type":"journal-article","created":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T10:04:04Z","timestamp":1570788244000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Beneficial effects of Lactobacillus reuteri 6475 on bone density in male mice is dependent on lymphocytes"],"prefix":"10.1038","volume":"9","author":[{"given":"Fraser L.","family":"Collins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naiomy Deliz","family":"Rios-Arce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Schepper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7408-6690","authenticated-orcid":false,"given":"A. 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