Lactobacillus reuteri alleviates Glucocorticoid induced Avascular Necrosis of Femoral Head.

Abstract

Glucocorticoids (GC) are well‐known anti‐inflammatory drugs that are widely used to manage many diseases including autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. Chronic GC use can have significant side effects including 1) dysbiosis (an imbalance of gut microbiota composition), 2) increased intestinal permeability which is linked to increased serum endotoxin levels, 3) trabecular bone loss and 4) osteonecrosis (i.e., avascular necrosis of the femur head). Especially, patients with GC‐induced osteonecrosis of femur head suffer from pain and stiffness, resulting in long‐term disability. Our lab and others have shown that the gut (microbiome and barrier function) regulates bone density. Recently, we have also shown that the probiotic Lactobacillus reuteri 6475 (LR) prevented GC‐induced trabecular bone loss in male and female mice. Based on these findings, we examined if LR treatment can prevent GC‐induced osteonecrosis (GCON) of the femur head. Male C57BL/6J (16‐weeks‐old) mice were treated for 8‐weeks with GC (2.5 mg/kg/day, subcutaneously slow release pellet) and supplemented with or without 3.3×108 cfu/ml LR in their drinking water. Femur immunohistochemistry examining von Willebrand factor positive blood vessels revealed that GC‐induced avascularization of the femur head was prevented by LR supplementation. Specifically, compared to controls, GC treatment caused a 50% reduction in the number of blood vessels in the femur head – this was completely prevented by LR treatment. Similarly, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses determined that LR treatment prevented GC‐induced apoptosis of trabecular osteoblast and osteocytes. In addition, LR treatment prevented GC‐induced marrow adiposity. Consistent with these findings, microcomputed tomography indicated that femoral head bone loss was also prevented by LR treatment. Gene expression analysis of the femur head identified that GC‐induction of tumor necrosis factor alpha and Bcl‐2‐associated x protein (pro‐apoptotic) was prevented by LR. Together, these data indicate that probiotic LR supplementation prevents the pathological bone effects of GCs (avascularization, cell apoptosis, adiposity, bone loss) and may be a straightforward cost‐effective way to mitigate avascular necrosis of femoral head.Support or Funding InformationThese studies were supported by funding from the National Institute of Health, grants RO1 DK101050, AT007695 and by Michigan State University Foundation.