Increased urinary indoxyl sulfate (indican): New insights into gut dysbiosis in Parkinson's disease Erica Cassani a, * , Michela Barichella a , Raffaella Cancello b , Ferruccio Cavanna a , Laura Iorio a , Emanuele Cereda c , Carlotta Bolliri a , Paola Zampella Maria a , Francesca Bianchi a , Benvenuto Cestaro d , Gianni Pezzoli a a Parkinson InstituteeIstituti Clinici di Perfezionamento, Milano, Italy b Istituto Auxologico Italiano, IRCCS, Milano, Italy c Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy d Department of Biomedical and Clinical Sciences L. Sacco, School of Clinical Nutrition, Faculty of Medicine and Surgery-University of Milan, Milano, Italy article info Article history: Received 19 September 2014 Received in revised form 21 December 2014 Accepted 4 February 2015 Keywords: Parkinson disease Gut dysbiosis Urinary indoxyl sulfate Constipation Small intestinal bacterial overgrowth (SIBO) abstract Introduction: Changes in the composition of gut microflora have been associated with an increase in chronic diseases. Indican urinary concentration is one of the most common and easily assessable markers of intestinal dysbiosis. Little information is available on intestinal dysbiosis in Parkinson's disease (PD). We decided to investigate indican urinary concentrations in a cohort of PD patients. Methods: A caseecontrol study including PD patients (N ¼ 68) on treatment with levodopa (PD) or on no pharmacological treatment (De Novo, DPD; N ¼ 34) and an age and gender-matched healthy control group (CTR; N ¼ 50). Main confounders, such as nutritional habits and constipation diagnosed according to Rome III criteria, were also investigated. Results: Indican urinary concentrations were significantly higher in PD and DPD than in CTR (P < 0.001 and P < 0.01, respectively). In PD patients the concentrations were unrelated to the presence of con- stipation, whereas this symptom was associated with higher concentrations in controls (P ¼ 0.043). The frequency of dairy product consumption was also positively associated with increased concentrations (P ¼ 0.008). Predictors of indican concentrations were sought by multivariate linear regression analysis. The higher indican urinary concentrations found in both DPD (P ¼ 0.045) and PD (P ¼ 0.023) patients persisted after adjustment for age, gender, BMI, constipation and consumption of dairy products. Conclusions: Gut dysbiosis seems to be an important issue in PD, independently of the presence of constipation and starting from the early stages of the disease. The role of gut dysbiosis in the pathogenesis of PD deserves further investigation. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction The human colon hosts about 10 11 e 10 12 bacteria/ml of lumen content [1]. These microorganisms include thousands of different bacteria, but 90% belong to only two families: Bacterioidetes and Firmicutes [1]. The composition of the bacterial flora of the gut changes throughout life according to a number of variables related both to the host and the environment [2]. The formation of bacterial flora is influenced by a number of factors, such as diet, antibiotic treatment, type of delivery and breast-feeding [2]. Inter-individual variability of microbiota is considerable among adults and even intra-individual variability is fairly high. Gut microbiota have a number of beneficial functions in the human body: they prevent colonization by pathogens, synthesize useful substances (e.g. short-chain fatty acids and vitamins), and modulate the local immune response [3]. Moreover, changes in the composition of gut microflora have been associated with an in- crease in chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome and atherosclerosis [4e7]. In particular, it appears that the gut microflora may be able to exert pro- inflammatory and pro-atherogenic effects. Indeed, it promotes increased absorption of lipopolysaccharides by enterocytes, resulting in their increase in the bloodstream. This phenomenon * Corresponding author. Parkinson Institute e Istituti Clinici di Perfezionamento, Via Bignami 1, 20126 Milan, Italy. Tel.: þ39 02 57993222; fax: þ39 02 57993322. E-mail address: erica.cassani@live.it (E. Cassani). Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis http://dx.doi.org/10.1016/j.parkreldis.2015.02.004 1353-8020/© 2015 Elsevier Ltd. All rights reserved. Parkinsonism and Related Disorders 21 (2015) 389e393