title: The Monoclonal Antitoxin Antibodies (Actoxumab-Bezlotoxumab) Treatment Facilitates Normalization of the Gut Microbiota of Mice withClostridium difficileInfection.
abstract: Antibiotics have significant and long-lasting impacts on the intestinal microbiota and consequently reduce colonization resistance againstClostridium difficileinfection (CDI). Standard therapy using antibiotics is associated with a high rate of disease recurrence, highlighting the need for novel treatment strategies that target toxins, the major virulence factors, rather than the organism itself. Human monoclonal antibodies MK-3415A (actoxumab-bezlotoxumab) toC. difficiletoxin A and toxin B, as an emerging non-antibiotic approach, significantly reduced the recurrence of CDI in animal models and human clinical trials. Although the main mechanism of protection is through direct neutralization of the toxins, the impact of MK-3415A on gut microbiota and its restoration has not been examined. Using a CDI murine model, we compared the bacterial diversity of the gut microbiome of mice under different treatments including MK-3415A, vancomycin, or vancomycin combined with MK-3415A, sampled longitudinally. Here, we showed thatC. difficileinfection resulted in the prevalence ofEnterobacterspecies. Sixty percent of mice in the vehicle group died after 2 days and their microbiome was almost exclusively formed byEnterobacter. MK-3415A treatment resulted in lowerEnterobacterlevels and restoration ofBlautia, Akkermansia, andLactobacilluswhich were the core components of the original microbiota. Vancomycin treatment led to significantly lower survival rate than the combo treatment of MK-3415A and vancomycin. Vancomycin treatment decreased bacterial diversity with predominantEnterobacterandAkkermansia, whileStaphylococcusexpanded after vancomycin treatment was terminated. In contrast, mice treated by vancomycin combined with MK-3415A also experienced decreased bacterial diversity during vancomycin treatment. However, these animals were able to recover their initialBlautiaandLactobacillusproportions, even though episodes ofStaphylococcusovergrowth were detected by the end of the experiments. In conclusion, MK-3415A (actoxumab-bezlotoxumab) treatment facilitates normalization of the gut microbiota in CDI mice. It remains to be examined whether or not the prevention of recurrent CDI by the antitoxin antibodies observed in clinical trials occurs through modulation of microbiota.
authors.affiliation: Área de Genómica y Salud, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad ValencianaValencia, Spain; Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de ValènciaValencia, Spain; Centro de Investigación Biomédica en Red en Epidemoioloía y Salud PúblicaMadrid, Spain.
authors.forename: Mária
authors.initials: M
authors.lastname: Džunková
authors.affiliation: Área de Genómica y Salud, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad ValencianaValencia, Spain; Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de ValènciaValencia, Spain; Centro de Investigación Biomédica en Red en Epidemoioloía y Salud PúblicaMadrid, Spain.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Auria
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Área de Genómica y Salud, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad ValencianaValencia, Spain; Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universitat de ValènciaValencia, Spain; Centro de Investigación Biomédica en Red en Epidemoioloía y Salud PúblicaMadrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Moya
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA, USA.
authors.forename: Ciarán P
authors.initials: CP
authors.lastname: Kelly
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA, USA.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D000992:Antitoxins / Q000008:administration & dosage*; D000080908:Broadly Neutralizing Antibodies; D016360:Clostridioides difficile / Q000302:isolation & purification*; D003015:Clostridium Infections / Q000382:microbiology* / Q000628:therapy*; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D008137:Longitudinal Studies; D051379:Mice; D016019:Survival Analysis; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000992:Antitoxins; D000080908:Broadly Neutralizing Antibodies; C000613978:bezlotoxumab; D014640:Vancomycin; C000613979:actoxumab
keywords: 16S rDNA amplicon sequencing; Bayesian networks; C. difficile toxin antibody; Clostridium difficile infection; MK-3415A; actoxumab and bezlotoxumab; antibiotics; immune therapy