*Purpose: Chronic diarrhea is a common problem in renal transplant recipients (RTR) and can lead to a lower quality of life. However, in many patients the underlying etiology is unknown and they silently carry this burden. RTR suffer from dysbiosis, a disruption of the gut microbiome, which is associated with the occurrence of diarrhea. Therefore, we aimed to objectively identify the occurrence of diarrhea and characterize the composition and the functionality of the gut microbiome of RTR with diarrhea.

*Methods: Fecal microbiome data was generated using whole-genome metagenomic shotgun sequencing of 1000 fecal samples from the Transplantlines cohort study. Fecal samples were collected at different time points pre- and post-transplantation. Fecal dry matter analysis was used to objectively identify diarrhea. The occurrence of diarrhea was correlated to gut microbiota composition and functionality using MaAsLin.

*Results: We included 177 healthy controls (50% female, age: 57.5 ± 10.8 years), 465 RTR (42% female, age: 56.23 ± 13.0 years) more than 1 year post-transplantation with a median time after transplantation of 8 years and an IQR of [3.0:13.0] and 86 RTR (46% female, age: 57.8 ± 11.2 years) with multiple fecal samples less than 1 year post-transplantation. In total 23% of RTR suffered from diarrhea and had a significantly lower diversity of the gut microbiome (P<0.01). We identified multiple different bacteria that were different in RTR with diarrhea (false-discovery rate (FDR) <0.1). Metabolic pathways were significantly different in RTR with diarrhea (FDR<0.1).

*Conclusions: We combined gut microbiome composition with metabolic function, antibiotic resistance and bacterial growth rate analyses and concluded that the gut microbiome of RTR with diarrhea is different from RTR without diarrhea and healthy controls.

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