Faecal microbiota transplantation from metabolically compromised human donors accelerates osteoarthritis in mice

Abstract

ObjectivesEmerging evidence suggests that the microbiome plays an important role in the pathogenesis of osteoarthritis (OA). We aimed to test the two-hit model of OA pathogenesis and potentiation in which one ‘hit’ is provided by an adverse gut microbiome that activates innate immunity; the other ‘hit’ is underlying joint damage.MethodsMedical history, faecal and blood samples were collected from human healthy controls (OA-METS-, n=4), knee OA without metabolic syndrome (OA+METS-, n=7) and knee OA with metabolic syndrome (OA+METS+, n=9). Each group of human faecal samples, whose microbial composition was identified by 16S rRNA sequencing, was pooled and transplanted into germ-free mice 2 weeks prior to meniscal/ligamentous injury (MLI) (n≥6 per group). Eight weeks after MLI, mice were evaluated for histological OA severity and synovitis, systemic inflammation and gut permeability.ResultsHistological OA severity following MLI was minimal in germ-free mice. Compared with the other groups, transplantation with the OA+METS+ microbiome was associated with higher mean systemic concentrations of inflammatory biomarkers (interleukin-1β, interleukin-6 and macrophage inflammatory protein-1α), higher gut permeability and worse OA severity. A greater abundance of Fusobacterium and Faecalibaterium and lesser abundance of Ruminococcaceae in transplanted mice were consistently correlated with OA severity and systemic biomarkers concentrations.ConclusionThe study clearly establishes a direct gut microbiome-OA connection that sets the stage for a new means of exploring OA pathogenesis and potentially new OA therapeutics. Alterations of Fusobacterium, Faecalibaterium and Ruminococcaceae suggest a role of these particular microbes in exacerbating OA.

Gut Microbiota Dysbiosis in High-Risk Individuals For Rheumatoid Arthritis Triggers Mucosal Immunity Perturbation and Promotes Arthritis in Mice

“…Fusobacterium were enriched in Pre-RA group of mice compared with HC, while Akkermansia and Staphylococcus were enriched in both Pre-RA and RA groups. Interestingly, Fusobacterium has been implicated in metabolic disorder [33,34], osteoarthritis [35] and Behcet's disease [36]. One of the most well-known pathogenic species within the Fusobacterium genus, Fusobacterium nucleatum, are associated with the occurrence of multiple conditions including colorectal carcinoma [37], IBD [38], and RA [39].…”

The gut microbiota in osteoarthritis: where do we stand and what can we do?

“…Huang et al designed a study to collect fecal samples from human healthy controls, knee OA without metabolic syndrome, and knee OA with metabolic syndrome groups, then transplant pooled samples into germ-free OA mice induced by meniscal/ligamentous injury (MLI). Interestingly, only the microbiota transplantation from the knee OA with metabolic syndrome and MLI resulted in an increase in the severity of OA, which was also consistently associated with elevated inflammatory biomarkers and gut permeability [ 21 ]. These findings support that an adverse microbiome would exacerbate the histopathological severity of OA induced by joint injury in a murine model.…”

“…The combinative treatments increased the abundance of Bifidobacterium and Roseburia and decreased Clostridium leptum and Akkermansia muciniphila . Huang et al, 2020 [ 21 ] MLI-induced OA germ-free mice model FMT (fecal samples collected from human healthy controls, knee OA without metabolic syndrome and knee OA with metabolic syndrome) 10 weeks OA severity was minimal in GF mice following MLI. Compared with the other groups, transplantation with the knee OA with metabolic syndrome groups, microbiome was associated with higher systemic levels of inflammatory biomarkers, higher gut permeability and worse OA severity.…”

Cross-Talk between Diet-Associated Dysbiosis and Hand Osteoarthritis

“…They transplanted faecal microbiota from healthy and from metabolically compromised human donors into germ-free mice, 2 weeks before articular knee injury. Compared with the other groups, transplantation with the microbiome from metabolically compromised donors was associated with higher mean systemic concentrations of inflammatory biomarkers, higher gut permeability, and worse OA severity [ 72 ].…”