Abstract| Volume 28, SUPPLEMENT 1, S21-S22, April 2020

Gut microbiota dysregulation of fatty acid metabolism accelerates ages-mediated knee joint degeneration

      Purpose: Joint degeneration is a prominent feature of skeletal deterioration and disability in senile people. Gut microbiota dysregulation is shown to disturb host immune reaction and metabolic activity, augmenting tissue deterioration in various pathological contexts. Little has been verified what biological role of gut microbiota may play during age-mediated joint damage. The study is aimed to investigate whether gut microbiome was relevant to joint integrity in senile mice.
      Methods: Articular cartilage and subchondral bone microstructure in young (3 months old) and old (9 months old) male mice were quantified using μCT arthrography and histomorphometry. 16S sequences of gut microbiota in feces were probed using next generation sequencing Illumine HiSeq analysis platform. Microbiota operational taxonomy was verified using UPARSE algorithm. Annotation and classification hierarchy were analyzed using RDP classifier, PyNAST and GreenGenes database. Serum lipidomic profiles were characterized using gas chromatography along with tandem mass spectrometry. Chondrocytes and calvarial osteoblasts were isolated from 3-day-old mice. Chondrocytic makers and osteogenic gene expression were quantified using RT-quantitative PCR.
      Results: Old mice showed severe articular cartilage erosion and sparse subchondral bone microstructure. Likewise, OARSI scores of articular compartment were increased together with significant reductions in bone mineral density (BMD), trabecular volume (BV/TV, %) and thickness (Tb.Th/mm) of subchondral bone. Microorganisms-derived short-chain fatty acids, like butyric acid, caproic acid, and caprylic acid, etc. were significantly decreased in age mice, whereas long-chain fatty acid levels were higher than young mice. Microbiome profiles of 28 families of microorganisms were significantly altered in aged mice. Of them, microorganisms related to probiotics, like Lactobacillacea, were reduced, whereas bacteria relevant to metabolic syndrome, like Lachnospiraceae, were upregulated. In vitro, butyrate treatment attenuated extracellular matrix proteoglycan underproduction and aggrecan expression loss in inflamed chondrocytes, as well as ameliorated mineralized matrix accumulation and osteogenic gene expression in inflamed osteoblasts.
      Conclusions: Gut microbiome is correlated with age-mediated articular cartilage and subchondral bone loss. Dysbiosis alters short-chain fatty acid metabolism, which is important to stabilize extracellular matrix production in chondrocytes and osteoblasts to sustain cartilage and subchondral bone integrity. This study offers a productive insight into the communication of gut microbiome to host chondrocytes and osteoblasts in the development of joint degeneration. Control of short-chain fatty acid metabolism in joint microenvironment has the perspective of remedial effects to ameliorate age-induced joint damage.