Studies on gut microbiome-joint connections in arthritis

点击翻译按钮获取中文摘要

ABSTRACT [Parent R01 Grant - Attached for System-to-System (S2S) Requirements] Although mechanical overloading of joints has been implicated in the comorbid association between obesity and osteoarthritis (OA) [1, 2], we and others have established a pathogenic role for obesity-associated inflammation [3-6]. Our work to further study inflammation in this context has led to new data implicating dysbiosis of the gut microbiome as a root cause of inflammation in the colon, circulation, and synovium that culminates in accelerated OA degeneration in joints [7]. Changes include colonic, serum, and synovial upregulation of inflammatory cytokines, which parallel the expansion of Peptococcaceae and Peptostreptococcaceae family members in the obese gut. Correction of this dysbiosis via dietary supplementation with the indigestible prebiotic fiber oligofructose ablates these proinflammatory communities while restoring an Actinobacteria taxa that is lost in obesity, Bifidobacterium pseudolongum (B. pseudolongum). This correction leads to reduced inflammation in niches spanning from the colon to the joint, reduced numbers of macrophages and B cells in the synovium, and protection against the development of OA in the knee [7]. Moreover, we have discovered that oral delivery of a B. pseudolongum probiotic is joint protective and the B. pseudolongum metabolome itself contains molecules that directly inhibit inflammation. Based on these findings, we propose that 1) the OA of obesity is caused by a gut microbiome dysbiosis that triggers an inflammatory cascade starting in the intestine and radiating to the joint, and 2) obesity-related OA can be mitigated either by correcting the obese gut dysbiosis using methods to expand B. pseudolongum or by commandeering its metabolites to reduce inflammation in the colonic epithelium where the obesity-related inflammatory signature initiates. To investigate these concepts, we propose to address the following two Specific Aims. Aim 1 is to establish that gut microbiome dysbiosis is causal in the OA of obesity, with the hypothesis that the obese dysbiotic gut microbiome is the initiator of a systemic inflammatory cascade that initiates in the colon, radiates to joints, and accelerates OA. Aim 2 is to study how B. pseudolongum protects against joint degeneration in obesity, with experiments designed to test the hypothesis that B. pseudolongum mitigates inflammation and is joint protective in the context of obesity and its metabolome contains inflammation-suppressing agents. Completion of these aims will establish that the OA of obesity is an inflammatory process driven by gut microbiome dysbiosis. Expansion of B. pseudolongum or delivery of its metabolites could represent novel therapeutic approaches to address a disease of global scope that is currently only treated palliatively.