CDLD Research Project 3: Impact of the Gut Microbiome on Liver Innate Immunity and Skeletal Function
Chad Novince Ph.D., D.D.S. – Department of Oral Health Science
Novince Lab Webpage
Bone remodeling is the continuous process in which the skeleton is dynamically renewed. In this process myeloid-derived osteoclastic cells resorb old bone and mesenchymal-derived osteoblastic cells subsequently form new bone. Skeletal deterioration occurs when the action of the osteoclasts exceeds those of the osteoblasts and there is a net loss of osseous tissue. In humans, the adult skeleton begins a state of slow continuous deterioration at around 25-30 years of age. We have shown that the commensal gut microbiota enhances osteoclastogenesis and suppresses osteoblastogenesis, thereby promoting skeletal bone loss.
Innate immunity helps maintain a balanced homeostatic relationship with the commensal gut microbiota and has potent effects on host physiology. Our preliminary data imply that stimulation of MyD88-dependent toll-like receptor (TLR) signaling by commensal gut microbiota causes bone loss. We have shown that young-adult germfree (GF) mice have increased bone mass, which is reversed upon colonization with intestinal microbiota. The commensal microbiota in specific pathogen free (SPF) mice were found to enhance osteoclastogenesis and suppress osteoblastogenesis resulting in bone loss. Surprisingly, the impact of the gut microbiota on bone remodeling was not due to immune responses within the gut, but rather reflected communication between the gut and liver. When compared to GF mice, SPF control mice were found to have increased cytokines (Il1b, Il6, Tnf, Csf1, Ccl2, Cxcl1) in the liver, but not in the ileum. In SPF mice, inflammatory monocytes were enhanced in the lymph nodes draining the liver, but not the mesenteric lymph nodes. Collectively these findings support a novel signaling axis between the gut, liver, and bone that regulates bone remodeling. In support of our model, we demonstrated that expression of MyD88-dependent TLR signaling components (Tlr2, Myd88, Mal, Irak4) were increased and hepatocyte-associated innate immune factors (Hamp, Saa1, Lcn2, Lbp) were upregulated in SPF livers. Serum lipocalin-2 (LCN2) was increased in SPF compared to GF mice and in MyD88 wildtype compared to MyD88 knockout mice. Liver-derived LCN2 is, therefore, a candidate innate immune factor that controls bone remodeling.
Overall Hypothesis: Circulating gut microbiota-derived ligands stimulate liver cell MyD88-dependent synthesis of innate immune serum factors that regulate bone remodeling (Figure 1).