The Role of The Gut Microbiome In Mediating Lactose Intolerance Symptoms M.F. Brandao Gois1, A. Vich Vila1,2, T. Sinha1, L. Bolte1,2, C. Wijmenga1, J. Fu1, R.K. Weersma2, A. Kurilshikov1, A. Zhernakova1. 1 University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 2 University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands. Key words: diet, gut microbiome, lactose intolerance Lactose Intolerance (LI) is defined by the low expression of lactase enzymes, thus resulting in a difficulty or inability to digest lactose throughout adulthood. Upon lactose ingestion, LI patients can experience the appearance of gastrointestinal complaints. However, the occurrence and type of such symptoms varies greatly. Recent studies have demonstrated the potential influence of genetics, microbiome, and diet in lactose metabolism. However, the lack of an analysis performed in a single large cohort limits the understanding of the potential relatedness among each and other influencing factors in lactose metabolism, such as the occurrence of gut symptoms. Here, we investigate the interplay between genetics, gut microbiome, diet and gastrointestinal complaints in lactose intolerance. We assessed the microbiome composition, genetic variants associated with LI, dairy intake and occurrence of gastrointestinal complaints in 959 participants from the Dutch general population cohort Lifelines Deep. Individuals with the genetic variant previously reported to be associated with LI were identified as LI individuals. We performed correlation tests, linear regressions, and mediation analyses. As observed in other studies, LI individuals displayed positive associations between Bifidobacterium genus abundance and dairy intake (P-value: 0.05). Here, we also report a positive correlation between Bifidobacterium abundance and the occurrence of gut complaints (P-value: 0.003). Through an in-depth analysis of the gut symptoms, we identified that bloating (P-value= 0.01, cor= 0.27), abdominal pain (P-value=0.04, cor=0.23) and abdominal discomfort (P-value=0.02, cor=0.34) are positively correlated with Bifidobacterium abundance. Lastly, we found that the association between dairy intake and gastrointestinal complaints is partly mediated by Bifidobacterium abundance (P-val: 0.054, proportion mediated= 43%). Altogether, our results indicate that the gut microbiome plays an important role in lactose metabolism. Thus, through large cohort analysis, we elucidate the complexity among the influencing factors in lactose metabolism and gut complaints occurrence.