SUMMARY
Nutritional supplementation with probiotics can prevent pathologic bone
loss. Here we examined the impact of supplementation with Lactobacillus
rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice.
Micro-computed tomography revealed that LGG increased trabecular bone volume in
mice, which was due to increased bone formation. Butyrate produced in the gut
following LGG ingestion, or butyrate fed directly to germ-free mice, induced the
expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells.
Interaction of BM CD8+ T cells with Treg cells resulted in increased
secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells
promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+
cells, which drove expression of
Wnt10b−/−. Reducing Treg cell
numbers, or reconstitution of TCRβ−/− mice with
CD8+ T cells from
Wnt10b−/− mice, prevented
butyrate-induced bone formation and bone mass acquisition. Thus, butyrate
concentrations regulate bone anabolism via Treg cell-mediated regulation of
CD8+ T cell Wnt10b production.
It is well established that physiological generation of low levels of ROS act as critical second messengers in multiple signaling pathways. These include the regulatory networks that control growth and differentiation in disparate biological systems, including the gut of many metazoans. However, the molecular mechanism of ROS production within the intestine is unknown. Recent reports have shown that the ROS‐generating enzyme NADPH oxidase 1 (Nox1) is highly expressed by colon epithelia. We report that Lactobacillus spp. are potent inducers of endogenous ROS generation, and of ROS‐dependent cellular proliferation within intestines of two metazoan models, namely the fruitfly Drosophila melanogaster, and the mouse. Moreover, we show that these induced responses are diminished in mice or Drosophila that are selectively deficient for Nox1 within intestinal epithelial cells. Together, these results implicate Nox1 in epithelial cell homeostasis and reveal a novel mechanism for the maintenance of intestinal tissue structure.
Salmonellae are bacterial pathogens that have evolved sophisticated strategies to evade host immune defenses. These strategies include the secretion of effector proteins into mammalian cells so as to subvert innate immune and apoptotic signaling pathways, thereby allowing Salmonella to avoid elimination. Here, we show that the secreted Salmonella typhimurium effector protein AvrA possesses acetyltransferase activity toward specific mitogen-activated protein kinase kinases (MAPKKs) and potently inhibits c-Jun N-terminal kinase (JNK) and NF-kappaB signaling pathways in both transgenic Drosophila and murine models. Furthermore, we show that AvrA dampens the proapoptotic innate immune response to Salmonella at the mouse intestinal mucosa. This activity is consistent with the natural history of Salmonella in mammalian hosts, where the bacteria elicit transient inflammation but do not destroy epithelial cells. Our findings suggest that targeting JNK signaling to dampen apoptosis may be a conserved strategy for intracellular pathogens.
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