Fetal cardiac growth is associated with in utero gut colonization M.A. Guzzardi a, *, L. Ait Ali a,b , R. D’Aurizio c , F. Rizzo d,e , P. Saggese d , E. Sanguinetti a , A. Weisz d,e , M. Pellegrini c , P. Iozzo a, ** a Institute of Clinical Physiology, National Research Council (IFC-CNR), Pisa, Italy b Fondazione Toscana Gabriele Monasterio (FTGM), Pisa, Italy c Laboratory of Integrative System Medicine, Institute of Informatics and Telematics, National Research Council (IIT-CNR), Pisa, Italy d Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, Salerno, Italy e Genomix4Life srl, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy Received 23 July 2018; received in revised form 9 October 2018; accepted 11 October 2018 Handling Editor: Gian Luigi Russo Available online 19 October 2018 KEYWORDS Gut microbiota; Meconium; Echocardiography; Cardiac hypertrophy; Fetal growth; Inflammation Abstract Background and aims: Intra-uterine metabolic environment predicts newborns’ car- diac morphology, metabolism and future health. In adults, gut microbiota composition relates to altered cardiac structure and metabolism. We investigated the relationship between gut mi- crobiota colonization and fetal cardiac growth. Methods and results: Bacterial composition in meconium samples of 26 healthy, full-term new- borns was assessed by 16S rDNA gene sequencing. Its relationship with birth echocardiographic parameters, and the interaction with cord blood levels of inflammatory markers were investi- gated. Correlative and cluster analysis, linear discriminant analysis effect size and predictive functional analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied. Fetal left ventricle growth was related to gut microbiota composition at birth. Specif- ically, left ventricle posterior wall thickness (LVPW) greater than 4 mm was associated with lower microbiota beta and alpha diversity, depletion (LDA score > 3) of several bacteria at each taxonomic level, including Lactobacillales, and enrichment (LDA score > 5) in Enterobacteriales and Enterobacteriaceae . The latter was signi fi cantly related to cord blood gamma- glutamyltransferase levels (r Z 0.58, p Z 0.0057). Functionally, a thicker LVPW was related to up-regulation of pathways involved in lipopolysaccharide biosynthesis (þ50%, p Z 0.045 in correlative analysis) and energy metabolism (þ12%, p Z 0.028), and down-regulation of path- ways involved in xenobiotic biodegradation (À21 to À53%, p Z 0.0063e0.039), PPAR signaling (À24%, p Z 0.021) and cardiac muscle contraction (À100%, p Z 0.049). Conclusion: Fetal cardiac growth and gut colonization are associated. Greater neonatal LVPW thickness is related to lower diversity of the gut microbiota community, depletion of bacteria having anti-remodeling effects, and enrichment in bacteria functionally linked to inflammation. ª 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Feder- ico II University. Published by Elsevier B.V. All rights reserved. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body surface area; CCA, canonical correspondence analysis; EDD, end-diastolic diameter; EDV, end-diastolic volume; ESD, end-systolic diameter; ESV, end-systolic volume; GGT, gamma- glutamyltransferase; IL-6, interleukine-6; IVSd, interventricular septum diameter; LDA, linear discriminant analysis; KEG, Kyoto Ency- clopedia of Genes and Genomes; LPS, lipopolysaccharide; LVEF, left ventricle ejection fraction; LVPW, left ventricle posterior wall diameter; MCP-1, monocyte chemoattractan protein-1; OTU, operational taxonomic unit; PICRUSt, phylogenetic investigation of com- munities by reconstruction of unobserved states; PPAR, peroxisome proliferator-activated receptor; TNF-alpha, tumor necrosis factoralpha. * Corresponding author. Institute of Clinical Physiology, National Research Council (CNR), Via Moruzzi 1, 56124, Pisa, Italy. ** Corresponding author. Institute of Clinical Physiology, National Research Council (CNR), Via Moruzzi 1, 56124, Pisa, Italy. E-mail addresses: m.guzzardi@ifc.cnr.it (M.A. Guzzardi), patricia.iozzo@ifc.cnr.it (P. Iozzo). https://doi.org/10.1016/j.numecd.2018.10.005 0939-4753/ª 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. Nutrition, Metabolism & Cardiovascular Diseases (2019) 29, 170e176 Available online at www.sciencedirect.com Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd