Cindy Boer

282 | Chapter 7 our digestive tract may play in osteoarthritis. Recent studies had shown an important role for the microbiome in obesity, and demonstrated that the microbiome changes with age. As, obesity and age are most well characterized risk factors for osteoarthritis. Chapter 5.1 we presented two novel large scale population bases microbiome data sets to be used for microbiome research: Generation R (n=2,111) and Rotterdam Study microbiome (n=1,427) datasets. Using these datasets we identified composition- al and functional differences in gut microbiome between children and adults. Moreover, we confirm that these microbiome profiles can serve as reference for future studies on specific human disease susceptibility in childhood, adulthood and specific diseased populations. Using the Rotterdam Study microbiome dataset as presented in the previous chapter, in Chapter 5.2 , the possible relationship between osteoarthritis, joint pain and gastrointestinal microbiome was investigated. Previous research had suggested that osteoarthritis-related joint pain and inflammation may be triggered or exacerbated by endotoxins produced by the gastrointestinal microbiome. Using the stool microbiome data set of the Rotterdam Study (n=1,427), an association between relative abundance of Streptococcus spp. and osteoarthritis-related knee pain was identified. These results were replicated in an independent cohort (Life-Lines Deep, n=867). Increased abun- dance of Streptococcus spp. in the gastro-intestinal microbiome was associated with increased knee joint pain, validated by absolute quantification of Streptococcus species. In addition, evidence was presented that this association is driven by local inflamma- tion in the knee joint. Indicating the microbiome as a possible therapeutic target for osteoarthritis-related knee pain. Last, in Chapter 6 , all the findings in this thesis are combined and put into a broader perspective. Finally, recommendations are given the next steps that need to be taken in order find preventive or curative treatments for one of the world’s oldest diseases. Despite the many advances in osteoarthritis genetics in the recent years, ~148 reported associated loci, much remains to be discovered. Many hundreds gene and thousands of genetics variants are probably involved in genetic osteoarthritis risk. Next, much of the interaction between genetics and the environment remains unknown in osteoarthritis pathology and risk, e.g., gut microbiome, osteoarthritis and genetics. In sum, much remains unknown about osteoarthritis pathology and risk. However, de- spite these missing pieces, many hopeful discoveries have been made, which in the fu- ture may lead to novel therapeutic and preventative strategies. This includes the novel