Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice

Antibiotic exposure in children has been associated with the risk of inflammatory bowel disease (IBD). Antibiotic use in children or in their pregnant mother can affect how the intestinal microbiome develops, so we asked whether the transfer of an antibiotic-perturbed microbiota from mothers to their children could affect their risk of developing IBD. Here we demonstrate that germ-free adult pregnant mice inoculated with a gut microbial community shaped by antibiotic exposure transmitted their perturbed microbiota to their offspring with high fidelity. Without any direct or continued exposure to antibiotics, this dysbiotic microbiota in the offspring remained distinct from controls for at least 21 weeks. By using both IL-10-deficient and wild-type mothers, we showed that both inoculum and genotype shape microbiota populations in the offspring. Because IL10−/− mice are genetically susceptible to colitis, we could assess the risk due to maternal transmission of an antibiotic-perturbed microbiota. We found that the IL10−/− offspring that had received the perturbed gut microbiota developed markedly increased colitis. Taken together, our findings indicate that antibiotic exposure shaping the maternal gut microbiota has effects that extend to the offspring, with both ecological and long-term disease consequences.Inoculation of pregnant dams with an antibiotic-perturbed microbiota resulted in vertical transmission to the offspring in the absence of antibiotics and increased colitis in IL10–/– mice, indicating that antibiotic treatment has long-term effects.

[1]  S. Schrag,et al.  US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  Dan Knights,et al.  Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice , 2016, Nature Microbiology.

[3]  M. Azad,et al.  Infant antibiotic exposure and the development of childhood overweight and central adiposity , 2014, International Journal of Obesity.

[4]  Robert C. Edgar,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2001 .

[5]  A. Young,et al.  Fecal Lipocalin 2, a Sensitive and Broadly Dynamic Non-Invasive Biomarker for Intestinal Inflammation , 2012, PloS one.

[6]  J. Willis,et al.  Distinct inflammatory mechanisms mediate early versus late colitis in mice. , 2002, Gastroenterology.

[7]  M. Attene-Ramos,et al.  DNA damage and toxicogenomic analyses of hydrogen sulfide in human intestinal epithelial FHs 74 Int cells , 2010, Environmental and molecular mutagenesis.

[8]  Lisa M Bramer,et al.  Dynamics of the human gut microbiome in Inflammatory Bowel Disease , 2017, Nature Microbiology.

[9]  Christoph Beglinger,et al.  The role and utility of faecal markers in inflammatory bowel disease , 2015, Therapeutic advances in gastroenterology.

[10]  Robert L Davis,et al.  Prescription drug use in pregnancy. , 2004, American journal of obstetrics and gynecology.

[11]  Zachary D. Kurtz,et al.  Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet , 2016, Genome Medicine.

[12]  K. Bønnelykke,et al.  Prevalence and Predictors of Antibiotic Administration during Pregnancy and Birth , 2013, PloS one.

[13]  A. Berrebi,et al.  Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database , 2009, European Journal of Clinical Pharmacology.

[14]  Se Jin Song,et al.  The treatment-naive microbiome in new-onset Crohn's disease. , 2014, Cell host & microbe.

[15]  R. Sartor,et al.  Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. , 2017, Gastroenterology.

[16]  I. Petersen,et al.  Oral antibiotic prescribing during pregnancy in primary care: UK population-based study. , 2010, The Journal of antimicrobial chemotherapy.

[17]  C. Manichanh,et al.  Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach , 2005, Gut.

[18]  J. Hansen,et al.  Gene expression patterns in experimental colitis in IL‐10‐deficient mice , 2009, Inflammatory bowel diseases.

[19]  Erik Aronesty,et al.  Comparison of Sequencing Utility Programs , 2013 .

[20]  Olli Simell,et al.  Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes , 2008, The Journal of experimental medicine.

[21]  Angela C. Poole,et al.  Human Genetics Shape the Gut Microbiome , 2014, Cell.

[22]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[23]  Howard Ochman,et al.  Cospeciation of gut microbiota with hominids , 2016, Science.

[24]  S. Coffin,et al.  Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study , 2012, Pediatrics.

[25]  U. Sauer,et al.  The maternal microbiota drives early postnatal innate immune development , 2016, Science.

[26]  Harry Sokol,et al.  A microbial signature for Crohn's disease , 2017, Gut.

[27]  C. Bernstein,et al.  Association Between the Use of Antibiotics and New Diagnoses of Crohn's Disease and Ulcerative Colitis , 2011, The American Journal of Gastroenterology.

[28]  Duy Tin Truong,et al.  Studying Vertical Microbiome Transmission from Mothers to Infants by Strain-Level Metagenomic Profiling , 2016, mSystems.

[29]  S. Virtanen,et al.  Prenatal and Post-natal Exposure to Antibiotics and Risk of Asthma in Childhood , 2015, Pediatrics.

[30]  M. Blaser,et al.  Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences , 2014, Cell.

[31]  P. Dixon.  VEGAN, a package of R functions for community ecology , 2003 .

[32]  A. Rogers,et al.  Helicobacter-based mouse models of digestive system carcinogenesis. , 2009, Methods in molecular biology.

[33]  P. Bork,et al.  Human gut microbes impact host serum metabolome and insulin sensitivity , 2016, Nature.

[34]  R. Sartor,et al.  Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice , 1998, Infection and Immunity.

[35]  D. Kasper,et al.  How colonization by microbiota in early life shapes the immune system , 2016, Science.

[36]  S. Ng,et al.  Geographical variability and environmental risk factors in inflammatory bowel disease , 2013, Gut.

[37]  J. Greenbaum,et al.  IL-10 producing intestinal macrophages prevent excessive anti-bacterial innate immunity by limiting IL-23 synthesis , 2015, Nature Communications.

[38]  Martin J. Blaser,et al.  Antibiotics, birth mode, and diet shape microbiome maturation during early life , 2016, Science Translational Medicine.

[39]  M. Reinshagen.  [Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease]. , 2015, Zeitschrift fur Gastroenterologie.

[40]  Eric P. Nawrocki,et al.  An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea , 2011, The ISME Journal.

[41]  Bernard Henrissat,et al.  Metabolic Reconstruction for Metagenomic Data and Its Application to the Human Microbiome , 2012, PLoS Comput. Biol..

[42]  Susan Holmes,et al.  phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data , 2013, PloS one.

[43]  S. Virtanen,et al.  Mother’s and Offspring’s Use of Antibiotics and Infant Allergy to Cow’s Milk , 2013, Epidemiology.

[44]  K. Pollard,et al.  An integrated metagenomics pipeline for strain profiling reveals novel patterns of bacterial transmission and biogeography , 2016, Genome research.

[45]  E. Zoetendal,et al.  The Genome of Akkermansia muciniphila, a Dedicated Intestinal Mucin Degrader, and Its Use in Exploring Intestinal Metagenomes , 2011, PloS one.

[46]  Tobias Kollmann,et al.  Early infancy microbial and metabolic alterations affect risk of childhood asthma , 2015, Science Translational Medicine.

[47]  Yava L Jones-Hall,et al.  Immunopathological characterization of selected mouse models of inflammatory bowel disease: Comparison to human disease. , 2014, Pathophysiology : the official journal of the International Society for Pathophysiology.

[48]  Bryan T Grenfell,et al.  Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. , 2014, The Lancet. Infectious diseases.

[49]  Björn Usadel,et al.  Trimmomatic: a flexible trimmer for Illumina sequence data , 2014, Bioinform..

[50]  Henrik Svanström,et al.  Antibiotic use and inflammatory bowel diseases in childhood , 2010, Gut.

[51]  K. Wada,et al.  Branched-chain amino acid intake and the risk of diabetes in a Japanese community: the Takayama study. , 2013, American journal of epidemiology.

[52]  M. Leach,et al.  Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. , 1996, The Journal of clinical investigation.

[53]  Andreas Wilke,et al.  The Biological Observation Matrix (BIOM) format or: how I learned to stop worrying and love the ome-ome , 2012, GigaScience.

[54]  William A. Walters,et al.  Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample , 2010, Proceedings of the National Academy of Sciences.

[55]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[56]  C. Lynch,et al.  Branched-chain amino acids in metabolic signalling and insulin resistance , 2014, Nature Reviews Endocrinology.

[57]  A. Moore,et al.  Interleukin-10 Knockout Mouse:: A Model for Studying Bone Metabolism During Intestinal Inflammation , 2004, Inflammatory bowel diseases.

[58]  Tom O. Delmont,et al.  Peripartum Antibiotics Promote Gut Dysbiosis, Loss of Immune Tolerance, and Inflammatory Bowel Disease in Genetically Prone Offspring. , 2017, Cell reports.

[59]  D. R. Cox,et al.  The analysis of binary data , 1971 .

[60]  C. Huttenhower,et al.  Metagenomic biomarker discovery and explanation , 2011, Genome Biology.