Exposure to microgravity leads to alterations in multiple systems, but microgravity‐related changes in the gastrointestinal tract and its clinical significance have not been well studied. We used the hindlimb unloading (HU) mouse model to simulate a microgravity condition and investigated the changes in intestinal microbiota and colonic epithelial cells. Compared with ground‐based controls (Ctrls), HU affected fecal microbiota composition with a profile that was characterized by the expansion of Firmicutes and decrease of Bacteroidetes. The colon epithelium of HU mice showed decreased goblet cell numbers, reduced epithelial cell turnover, and decreased expression of genes that are involved in defense and inflammatory responses. As a result, increased susceptibility to dextran sulfate sodium–induced epithelial injury was observed in HU mice. Cohousing of Ctrl mice with HU mice resulted in HU‐like epithelial changes in Ctrl mice. Transplantation of feces from Ctrl to HU mice alleviated these epithelial changes in HU mice. Results indicate that HU changes intestinal microbiota, which leads to altered colonic epithelial cell homeostasis, impaired barrier function, and increased susceptibility to colitis. We further demonstrate that alteration in gastrointestinal motility may contribute to HU‐associated dysbiosis. These animal results emphasize the necessity of evaluating astronauts’ intestinal homeostasis during distant space travel.—Shi, J., Wang, Y., He, J., Li, P., Jin, R., Wang, K., Xu, X., Hao, J., Zhang, Y., Liu, H., Chen, X., Wu, H., Ge, Q. Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model. FASEB J . 31, 3695–3709 (2017). www.fasebj.org

The immune systems can be altered by spaceflight in many aspects, but microgravity-related mucosal immune changes and its clinical significance have not been well studied. The purpose of this study w...

After positive selection, the newly generated single positive (SP) thymocytes migrate to the thymic medulla, where they undergo negative selection to eliminate autoreactive T cells and functional maturation to acquire immune competence and egress capability. To elucidate the genetic program underlying this process, we analyzed changes in gene expression in four subsets of mouse TCRαβ⁺CD4⁺CD8^- thymocytes (SP1 to SP4) representative of sequential stages in a previously defined differentiation program. A genetic signature of the migration of thymocytes was thus revealed. CCR7 and PlexinD1 are believed to be important for the medullary positioning of SP thymocytes. Intriguingly, their expression remains at low levels in the newly generated thymocytes, suggesting that the cortex-medulla migration may not occur until the SP2 stage. SP2 and SP3 cells gradually up-regulate transcripts involved in T cell functions and the Foxo1-KLF2-S1P₁ axis, but a number of immune function-associated genes are not highly expressed until cells reach the SP4 stage. Consistent with their critical role in thymic emigration, the expression of S1P₁ and CD62L are much enhanced in SP4 cells. These results support at the molecular level that single positive thymocytes undergo a differentiation program and further demonstrate that SP4 is the stage at which thymocytes acquire the immunocompetence and the capability of emigration from the thymus.

Exposure to space environment induces alterations in glucose and lipid metabolism that contribute to muscular atrophy, bone loss, and cardiovascular disorders. Intestinal microbiota is also changed, but its impact on spaceflight‐related metabolic disorder is not clear. We investigated the relationship between glucose metabolic changes and gut dysbiosis in a hind limb‐unloading (HU) mouse model, a well‐accepted ground‐based spaceflight analog. Impaired body weight gain, glucose intolerance, and peripheral insulin resistance were found in 2–4‐wk HU mice. Reduced abundance of gut Bifidobacterium spp. and Akkermansia muciniphila was observed within 3 d of HU. The ground‐based control (Ctrl) mice that were cohoused with HU mice showed similar patterns of dysbiosis and metabolic changes. Compared with the Ctrls, higher levels of plasma LPS‐binding protein and altered transcription of Tnfa and glucose metabolism‐related genes in the liver were observed in HU mice. The supplementation of Bifidobacterium spp. suppressed endotoxemia and liver inflammation and improved glucose tolerance in HU mice. The results indicate a close relationship between dysbiosis and altered glucose metabolism in the HU model and also emphasize the importance of evaluating intestinal microbiota in astronauts and its effect on glucose metabolism.—Wang, Y., Zhao, W., Shi, J., Wang, J., Hao, J., Pang, X., Huang, X., Chen, X., Li, Y., Jin, R., Ge, Q. Intestinal microbiota contributes to altered glucose metabolism in simulated microgravity mouse model. FASEB J. 33, 10140–10151 (2019). www.fasebj.org

Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3