To investigate the role of metabolic dysfunction in the absence of overt obesity on gut-joint associations and the involvement of individual taxa in this context, Guss et al. used a murine genetic model of metabolic syndrome (Toll-like receptor-5 deficiency) in combination with osteoarthritis-inducing mechanical overloading (2 or 6 weeks). The authors compared the impact of the metabolic disorder in this context to previously studied HFD-induced osteoarthritis models. Evaluation of histological changes in the cartilage indicated more severe osteoarthritis in the HFD-fed group; in this group they detected metabolic irregularities, increased body fat, systemic inflammation and the expected gut microbiome dysbiosis which included an increased abundance of Firmicutes. They concluded that while metabolic irregularities were observed in Toll-like receptor-5 deficient mice, alone they were not sufficient to induce osteoarthritis. Rather, they showed that increased levels of LPS in HFD-fed mice was associated with higher OARSI scores and a dysbiosis involving expansion of Firmicutes, suggesting an association between microbial components and development of osteoarthritis .
16S sequencing of DNA extracted from fecal pellets harvested from these mice revealed changes in the abundance of Bacteroidetes, Actinobacteria, and Firmicutes, among others (Fig. 2a). Firmicutes and Bacteroidetes are typically the dominant phyla of the vertebrate microbiome , and an increase in Firmicutes and decrease in Bacteroidetes has been associated with proinflammatory states in both humans and mice [62,63]. The change in the ratio may be linked with inflammation as an effect of both different responses to caloric intake and increased ability to extract calories from food [64,65]. Related to this, we found an increased Bacteroidetes/Firmicutes ratio in the microbiome of mice fed either glucosamine or UT2C compared with the vehicle control (Fig. 2a), consistent with a potential anti-inflammatory shift.
Numerous differences at the level of individual operational taxonomic units (OTUs) were found when either glucosamine or UT2C supplemented mice were compared with the vehicle control (Fig. 2b). The family Rikenellaceae and the Bacteroidales family S24–7 were significantly increased in mice fed glucosamine, while the supplement caused the opposite trend in an Oscillospira species (Fig. 3a). Dietary supplementation with UT2C produced even more changes in the abundance of individual OTUs than glucosamine when compared with the vehicle control. As with glucosamine, UT2C increased the abundance of S24-7 and decreased the amount of Oscillospira (Fig. 3b). Both Lactobacillus and Turicibacter levels were increased in mice given UT2C compared with vehicle control, and certain Clostridiales taxa decreased as well (Fig. 3b). Significantly, Rikenellaceae family members are reduced in proinflammatory models of induced colitis . Their increased abundance in mice fed glucosamine may suggest that this family can contribute to a lower inflammatory state. The absence of a change in Rikenellaceae in the UT2C-fed mice may indicate a glucosamine-specific effect. We also found Turicibacter to be significantly increased in mice fed UT2C compared with vehicle control or glucosamine. This genus has been found to be expanded in RA  although it has also been shown to be reduced in HFDs .
Nutraceuticals are long standing supplements implicated in joint health whose efficacy has been difficult to define with biological measures. Defining the mechanism of action has been problematic due to their relative inability to reach the joint. New findings presented here reveal that mice fed either glucosamine or UT2C supplements demonstrate changes in both joint health and microbiome. Tibia cartilage, uncalcified cartilage, and Safranin O+ chondrocytes are all increased in supplemented mice compared with vehicle controls. Global changes in phyla, Bacteroidetes/Firmicutes ratio, and individual OTUs in mice given supplements mirror improvements in the joint. Together, these parallel phenotypes suggest that nutraceuticals may exert beneficial action on joint health through modulation of the gut microbiome; further proof of causal links will require deeper investigation.
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* Lacey J. Favazzo, Honey Hendesi and David A. Villani contributed equally to the article.