title: Clostridium difficile heterogeneously impacts intestinal community architecture but drives stable metabolome responses.
abstract: Clostridium difficile-associated diarrhoea (CDAD) is caused by C. difficile toxins A and B and represents a serious emerging health problem. Yet, its progression and functional consequences are unclear. We hypothesised that C. difficile can drive major measurable metabolic changes in the gut microbiota and that a relationship with the production or absence of toxins may be established. We tested this hypothesis by performing metabolic profiling on the gut microbiota of patients with C. difficile that produced (n=6) or did not produce (n=4) toxins and on non-colonised control patients (n=6), all of whom were experiencing diarrhoea. We report a statistically significant separation (P-value <0.05) among the three groups, regardless of patient characteristics, duration of the disease, antibiotic therapy and medical history. This classification is associated with differences in the production of distinct molecules with presumptive global importance in the gut environment, disease progression and inflammation. Moreover, although severe impaired metabolite production and biological deficits were associated with the carriage of C. difficile that did not produce toxins, only previously unrecognised selective features, namely, choline- and acetylputrescine-deficient gut environments, characterised the carriage of toxin-producing C. difficile. Additional results showed that the changes induced by C. difficile become marked at the highest level of the functional hierarchy, namely the metabolic activity exemplified by the gut microbial metabolome regardless of heterogeneities that commonly appear below the functional level (gut bacterial composition). We discuss possible explanations for this effect and suggest that the changes imposed by CDAD are much more defined and predictable than previously thought.
authors.affiliation: Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Campus Montepríncipe, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Rojo
authors.affiliation: Unidad Mixta de Investigación en Genómica y Salud de la Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) and Instituto Cavanilles de Biodiversidad y Biología Evolutiva de la Universidad de Valencia, Valencia, Spain.|CIBER en Epidemiología y Salud Pública (CIBEResp), Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Gosalbes
authors.affiliation: Unidad Mixta de Investigación en Genómica y Salud de la Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) and Instituto Cavanilles de Biodiversidad y Biología Evolutiva de la Universidad de Valencia, Valencia, Spain.|CIBER en Epidemiología y Salud Pública (CIBEResp), Madrid, Spain.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Unidad Mixta de Investigación en Genómica y Salud de la Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) and Instituto Cavanilles de Biodiversidad y Biología Evolutiva de la Universidad de Valencia, Valencia, Spain.|CIBER en Epidemiología y Salud Pública (CIBEResp), Madrid, Spain.
authors.forename: Ana E
authors.initials: AE
authors.lastname: Pérez-Cobas
authors.affiliation: CSIC, Institute of Catalysis, Madrid, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Hernández
authors.affiliation: Unidad Enfermedades Infecciosas, Servicio Medicina Interna, Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Oltra
authors.affiliation: Departamento de Microbiología, Facultad de Medicina, Universidad de Valencia and Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Buesa
authors.affiliation: Unidad Mixta de Investigación en Genómica y Salud de la Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) and Instituto Cavanilles de Biodiversidad y Biología Evolutiva de la Universidad de Valencia, Valencia, Spain.|CIBER en Epidemiología y Salud Pública (CIBEResp), Madrid, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Latorre
authors.affiliation: Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Campus Montepríncipe, Madrid, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Barbas
authors.affiliation: CSIC, Institute of Catalysis, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Unidad Mixta de Investigación en Genómica y Salud de la Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) and Instituto Cavanilles de Biodiversidad y Biología Evolutiva de la Universidad de Valencia, Valencia, Spain.|CIBER en Epidemiología y Salud Pública (CIBEResp), Madrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Moya
mesh_terms: D001427:Bacterial Toxins; D016360:Clostridioides difficile / Q000502:physiology*; D003015:Clostridium Infections / Q000378:metabolism / Q000382:microbiology*; D003967:Diarrhea / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D005260:Female; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D008297:Male; D055442:Metabolome / Q000502:physiology*; D055432:Metabolomics / Q000379:methods; D012329:RNA, Bacterial / Q000032:analysis; D012336:RNA, Ribosomal, 16S / Q000235:genetics
chemical_list: D001427:Bacterial Toxins; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S