title: Gut-Microbiota-Metabolite Axis in Early Renal Function Decline.
abstract: BACKGROUND
  Several circulating metabolites derived from bacterial protein fermentation have been found to be inversely associated with renal function but the timing and disease severity is unclear. The aim of this study is to explore the relationship between indoxyl-sulfate, p-cresyl-sulfate, phenylacetylglutamine and gut-microbial profiles in early renal function decline.
  
  
  RESULTS
  Indoxyl-sulfate (Beta(SE) = -2.74(0.24); P = 8.8x10-29), p-cresyl-sulfate (-1.99(0.24), P = 4.6x10-16), and phenylacetylglutamine(-2.73 (0.25), P = 1.2x10-25) were inversely associated with eGFR in a large population base cohort (TwinsUK, n = 4439) with minimal renal function decline. In a sub-sample of 855 individuals, we analysed metabolite associations with 16S gut microbiome profiles (909 profiles, QIIME 1.7.0). Three Operational Taxonomic Units (OTUs) were significantly associated with indoxyl-sulfate and 52 with phenylacetylglutamine after multiple testing; while one OTU was nominally associated with p-cresyl sulfate. All 56 microbial members belong to the order Clostridiales and are represented by anaerobic Gram-positive families Christensenellaceae, Ruminococcaceae and Lachnospiraceae. Within these, three microbes were also associated with eGFR.
  
  
  CONCLUSIONS
  Our data suggest that indoxyl-sulfate, p-cresyl-sulfate and phenylacetylglutamine are early markers of renal function decline. Changes in the intestinal flora associated with these metabolites are detectable in early kidney disease. Future efforts should dissect this relationship to improve early diagnostics and therapeutics strategies.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; Department of Nephrology, Hospital del Mar, Institut Mar d'Investigacions Mediques, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Barrios
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Beaumont
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Tess
authors.initials: T
authors.lastname: Pallister
authors.affiliation: Department of Infectious Diseases, Hospital del Mar, Institut Mar d'Investigacions Mediques, Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Villar
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States of America.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Goodrich
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clark
authors.affiliation: Department of Nephrology, Hospital del Mar, Institut Mar d'Investigacions Mediques, Barcelona, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Pascual
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States of America.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Ley
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D000068016:Eubacteriales / Q000145:classification / Q000302:isolation & purification / Q000378:metabolism*; D003408:Cresols / Q000097:blood*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000382:microbiology; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics / Q000382:microbiology; D004200:Diseases in Twins / Q000097:blood / Q000235:genetics / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D005260:Female; D005285:Fermentation; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D005919:Glomerular Filtration Rate; D005973:Glutamine / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D007200:Indican / Q000097:blood*; D007674:Kidney Diseases / Q000097:blood / Q000235:genetics / Q000382:microbiology*; D008297:Male; D055442:Metabolome; D064307:Microbiota; D008875:Middle Aged; D021521:Ribotyping; D013463:Sulfuric Acid Esters / Q000097:blood*
chemical_list: D003408:Cresols; D013463:Sulfuric Acid Esters; D005973:Glutamine; C408690:4-cresol sulfate; C003089:phenylacetylglutamine; D007200:Indican