Cindy Boer

Microbiome Composition, Joint Pain and Inflammation | 231 5.2 Introduction Osteoarthritis (OA) is a degenerative joint disease and the most common form of arthri- tis: an estimated 22% of the adult population has at least one joint affected by osteoar- thritis and this prevalence increases to 49% in individuals over 65 years of age[1]. The hallmark clinical symptom of OA is pain, which is one of the leading causes of disability in OA[2]. Pathological changes in OA affect all joint tissues: degradation of cartilage and bone, abnormal bone formation (osteophytes), and inflammation of the synovial mem- brane, (synovitis). Although OA is often described as predominantly caused by mechan- ical factors and genetic predisposition, the existence of inflammation in OA, locally or systemic, is widespread[3-5]. In addition, it has become apparent that, by promoting or exacerbating OA symptoms, predominantly OA joint pain[4-7] this local or systemic inflammation has a causal role in OA pathology[3-5]. Obesity, a well-known risk factor for OA, is thought to increase OA risk through increased mechanical loading on weight-bearing joints. However, obesity also increases the risk for OA in non-weight-bearing joints[5,8]. The increased risk of OA in non-weight- bearing joints seen in obese individuals might be directed through low-grade systemic inflammation[9,10]. The gastrointestinal microbiome has emerged as one of the factors triggering obesity associated low-grade systemic inflammation[10-13]. Obesity is associated with changes in gastrointestinal-microbiome composition, which can lead to an increased intestinal absorption of immunogenic bacterial products[12,14,15]. Gastrointestinal bacteria produce a wide range of biologically active molecules, such as metabolites, short-chain fatty acids, proteins and enzymes, of which some are secreted in, outer membrane or membrane vesicles (OMVs/MVs). All gram-negative bacteria, archaea, fungi and several gram-positive bacteria can constitutively produce these vesicles[16-18]. These vesicles are insensitive to proteases, suggesting they can transport their content over long distances from their sites of origin. The content of these vesicles can be delivered to different organs in a concentrated manner[19]. Also, some of these biologically active molecules can affect intestinal mucosal permeability (short-chain fatty acids) or activate the immune system (lipopolysaccharide)[20]. Specifically, these molecules can affect macrophage activation and Toll-like-receptor (TLR) pathways[16,21], which have recently been shown to be the predominant inflammatory responses seen in OA[4]. Indeed, elevated levels of the bacterial endotoxin LPS (lipopolysaccharide), in the blood or in the synovium of OA patients, is associated with more severe knee OA, knee pain and inflammation[22]. This and other studies link gut-microbiome composition to low-grade systemic and local inflammation seen in OA[23-25].