Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Aug 24, 2023; 14(4): 71-85
Published online Aug 24, 2023. doi: 10.4291/wjgp.v14.i4.71
Novel, non-colonizing, single-strain live biotherapeutic product ADS024 protects against Clostridioides difficile infection challenge in vivo
Christopher K Murphy, Michelle M O’Donnell, James W Hegarty, Sarah Schulz, Colin Hill, R Paul Ross, Mary C Rea, Ronald Farquhar, Laurent Chesnel
Christopher K Murphy, Laurent Chesnel, Research and Development, Adiso Therapeutics Inc., Concord, MA 01742, United States
Michelle M O’Donnell, Sarah Schulz, Colin Hill, R Paul Ross, APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland
James W Hegarty, Mary C Rea, Teagasc Food Research Centre, Moorepark Fermoy, Cork P61 C996, Ireland
Ronald Farquhar, Executive Leadership Team, Adiso Therapeutics Inc., Concord, MA 01742, United States
Author contributions: Murphy CK, O’Donnell MM, Hill C, Ross RP, Rea MC, Farquhar R, and Chesnel L designed the experiments; O’Donnell MM, Hegarty JW, and Schulz S conducted the research; data was acquired and interpreted by O’Donnell MM, Hegarty JW, Schulz S, and Chesnel L; Chesnel L drafted the manuscript; all authors reviewed the manuscript and approved the final version.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of NeoSome Life Sciences (IACUC Protocol No. NLS17-002).
Conflict-of-interest statement: Hill C, Ross RP, and Rea MC received consulting fees from Adiso Therapeutics, Inc. Murphy CK, Farquhar R, and Chesnel L are employees of Adiso Therapeutics, Inc. O’Donnell MM, Hegarty JW, and Schulz S are supported by an Adiso Therapeutics, Inc., research grant to UCC/APC.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Laurent Chesnel, PhD, Research and Development, Adiso Therapeutics, Inc., 530 Virginia Road, Suite 300, Concord, MA 01742, United States.
Received: June 1, 2023
Peer-review started: June 1, 2023
First decision: July 19, 2023
Revised: August 2, 2023
Accepted: August 7, 2023
Article in press: August 7, 2023
Published online: August 24, 2023
Research background

Clostridioides difficile (C. difficile) is a Gram positive pathogen that causes C. difficile infection (CDI). It infects millions of people worldwide, causing potentially life-threatening gastrointestinal disease in individuals with disrupted gut microbiomes. Following successful antibiotic treatment, recurrent CDI (rCDI) can occur in cured patients. Therefore, development of a therapeutic product for preventing rCDI following successful standard-of-care antibiotic therapy is of vital importance.

Research motivation

C. difficile, a major cause of infectious disease death in the United States, causes inflammation of the colon and potentially deadly diarrhea. ADS024, a Bacillus velezensis strain, has previously demonstrated direct in vitro bactericidal activity against C. difficile, without affecting other members of the gut microbiota. In this study, we investigated the efficacy of ADS024 against CDI challenge in vivo. Following our findings, further investigation of ADS024 as a single-strain, live biotherapeutic product (SS-LBP) for prevention of rCDI following successful standard-of-care antibiotic therapy is warranted.

Research objectives

The objectives of the research were to investigate: (1) The in vivo efficacy of B. velezensis ADS024 in protecting against CDI challenge in mouse models; (2) the capability of ADS024 to colonize the GI tract; and (3) the impact of ADS024 on the gut microbiome, finding that it was efficacious against CDI challenge without colonization, and with minimal effects on the gut microbiome, thus supporting further development of ADS024 as an SS-LBP for prevention of rCDI.

Research methods

Mouse models were used to determine: (1) The in vivo efficacy against CDI challenge; and (2) colonization status of ADS024 (in conjunction with miniature swine). Human distal colon model and miniature swine were utilized to determine the effects of ADS024 on the gut microbiome. To mimic disruption of the gut microbiota, the mice and miniature swine were exposed to vancomycin prior to dosing with ADS024. To model the human distal colon, an anerobic fecal fermentation system was used.

Research results

Single oral daily doses of ADS024, similarly to multiple doses, demonstrated efficacy in protecting against subsequent challenge by C. difficile in a mouse model of CDI challenge. ADS024 showed no colonization based on lack of recovery ADS024 colonies in fecal samples 24 h after single doses in mice, 72 h after single doses in miniature swine, or a 28-d repeat-dose study in miniature swine. Phylogenetic analysis in the human distal colon model and in vivo studies performed in miniature swine demonstrated a selective impact of ADS024 on the healthy human colonic microbiota.

Research conclusions

In vivo efficacy of ADS024 in protecting against CDI challenge and minimal effects on the gut microbiome support development of ADS024 as an SS-LBP in preventing rCDI following standard antibiotic treatment.

Research perspectives

In vivo investigation of ADS024 is compatible with previous in vitro studies that showed efficacy against C. difficile and maintenance of gut microbiota diversity. Altogether, findings from these studies support initiation of clinical trials to evaluate the safety and efficacy of ADS024 in patients recovering from CDI.