Akkermansia muciniphila May Determine Chondroitin Sulfate Ameliorating or Aggravating Osteoarthritis

Abstract

Chondroitin sulfate (CS) has shown either ameliorating or aggravating effects on osteoarthritis (OA) in separately conducted clinical trials. Because CS is usually administered orally, it should be affected by or would impact on the individual gut microbiota. Evidence is accumulating that CS can nourish sulfatase-secreting bacteria (SSB) and sulfate-reducing bacteria (SRB). To decipher how can an individual gut microbiota determine the clinical values of CS for treatment on OA, we suggest here that CS would give distinct outcomes for OA treatment depending on Akkermansia muciniphila, a gut commensal probiotic bacterial species as optimal presence albeit also behaving as mucus-eroding bacteria (MEB) when abundant presence. Briefly, CS would ameliorate OA if A. muciniphila is present due to without overgrowth of SSB and SRB, whereas CS would aggravate OA if A. muciniphila is absent because of failure in or lack of competition with abundant SSB and SRB. By noting such a frequently ignored phenomenon, we urge the development of non-orally administering CS to minimize its side-effects and extend it to other medicinal applications. Chondroitin sulfate (CS), also known as polysaccharide constituted of alternated residues of N-acetylgalactosamine and glucuronic acid, is a naturally O-sulfated glycan in cartilage and bones. CS extracted from cow or pig cartilage is prescribed as a symptomatic slow-acting drug for osteoarthritis (OA) in 22 countries, including the European Union, but it is still regulated in the USA as a dietary supplement for improving OA (Jordan, 2003). The United States Food and Drug Administration (FDA) denied a request that CS be labeled as reducing the risk of OA and OA-related joint pain, tenderness, and swelling (FDA, 2004). Despite compelling evidence that CS interferes with OA progression (Vergés and Castañeda-Hernández, 2004; Clegg et al., 2006; Reginster et al., 2007), a systematic review of 20 clinical trials concluded that CS had not demonstrated any symptomatic benefit and discouraged its use in routine clinical practice (Reichenbach et al., 2007). A recent Cochrane clinical trial review concluded that CS appeared to alleviate pain in the short term, but did not improve or maintain the health of joints affected by OA (Singh et al., 2015). Because of this shortcoming in pain relief, CS was not recommended for the symptomatic treatment of knee OA (Jevseva et al., 2013). Combined treatment with CS and glucosamine sulfate or glucosamine hydrochloride did not reduce joint damage in a rabbit model of knee OA (Roman-Blas et al., 2017b). CS plus glucosamine sulfate was not superior to placebo in alleviating articular lesions in a randomized, double-blind, placebo-controlled clinical trial in patients with knee OA (Roman-Blas et al., 2017a). The effectiveness, benefits, and harms of CS for treating OA are not fully understood, which is possibly attributed to a "good" or "bad" study design. Contamination of heparin with CS has been associated with adverse clinical events, such as allergy and hypertension (Kishimoto et al., 2008), and the potential effect of CS-mediated gut dysbiosis on the differential pharmaceutical outcomes of CS must be considered. Here we aim to give a perspective on the clinical assessment of the impact of CS on OA and other inflammatory disorders.