#395 Gut dysbiosis in ADPKD patients: a controlled pilot study
Authors: Strubl Sebastian , Woestmann Fabian , Todorova Polina , Arjune Sita , Farowski Fedja , Baar Till , Brodesser Susanne , Grundmann Franziska , Vehreschild Maria Jgt , Mueller Roman-Ulrich 
Published: May 2024

Abstract

Background and Aims
Gut dysbiosis has been associated with chronic kidney disease (CKD) and nephrolithiasis and may thus be a factor explaining variability of outcome in autosomal dominant polycystic kidney disease (ADPKD). However, beside a single pilot study the gut microbiome has not been studied in ADPKD. Due to the implications of microbiota in inflammation and crystal formation, we hypothesized that gut dysbiosis could also negatively affect PKD. For this reason, we aimed to characterize the intestinal microbiome in a controlled pilot study of PKD patients and explore the potential impact of dysbiosis on PKD disease progression.

Method
This study was designed as an observational, cross-sectional controlled pilot study. 25 ADPKD patients were recruited from the AD(H)PKD patient cohort. 12 healthy control subjects were age- and sex matched. Patients with chronic bowel disease were excluded. Serum parameters including eGFR were analyzed around the timepoint of stool collection. The gut microbiome was analyzed by 16S rRNA gene profiling of stool samples. The sequencing data was processed using the DADA2 pipeline and QIIME version 2. Differentially abundant features were identified using linear discriminant analysis (LDA) effect size (LEfSe) analysis. Bacteria-derived serum uremic toxins (total and free Trimethylaminoxid, Indoxylsulfate, p-Cresyl-Sulfate) were measured using liquid chromatography coupled to tandem mass spectrometry (LC- MS/MS). Microbiome data was then correlated with age, kidney function, and markers of PKD disease progression like Mayo classification and early onset of arterial hypertension or urologic complications (&lt;35 years of age).

Results
Healthy control subjects revealed a significantly higher abundance Actinobacteria (LEfSe LDA score = 3.9, p = 0.025) including probiotic Bifidobacteriaceae (LEfSe LDA score = 3.9, p = 0.021). ADPKD patients displayed a significantly increased abundance of potentially dysbiotic Enterobacteriaceae (LEfSe LDA score = 3.6, p = 0.009). Those findings were independent of kidney function. Most notably, the abundance of Streptococcaceae were significantly overrepresented in PKD patients with Mayo Classes 1D and 1E compared to 1A-1C (p = 0.011). Additionally, early onset of hypertension (&lt; 35 years of age) was associated with an increased abundance of potentially dysbiotic Proteobacteria and a decreased abundance of potentially probiotic Tannerelleaceae. Furthermore, ADPKD patients revealed increased abundance of Peptococcaceae with increasing age and declining kidney function. Finally, serum uremic toxins were significantly increased in ADPKD patients and highly correlated with eGFR. Serum uremic toxins revealed a tendency of positive correlation with the abundance of Peptococcaceae which did not reach statistical significance.

Conclusion
This controlled pilot study confirms alterations of specific OTUs in PKD patients showing an increase of Enterobacteriaceae and decrease of probiotic Bifidobacteriaceae upon PKD. This suggests a potential shift towards gut dysbiosis. Most notably, the abundance of specific OTUs were observed to be associated with markers of rapid disease progression like Mayo classification 1D and 1E, as well as early onset of arterial hypertension. This suggests for the first time, that gut dysbiosis could affect PKD disease progression. However, it still remains unknown whether gut dysbiosis is caused by ADPKD itself or is a consequence of secondary circumstances such as antibiotic treatment which is common in ADPKD due to frequent urinary tract or cyst infections. Thus, further investigation in larger cohorts is warranted to elucidate the impact of gut microbiota on ADPKD.