Effects of Antibiotic Pretreatment of an Ulcerative Colitis-Derived Fecal Microbial Community on the Integration of Therapeutic Bacteria In Vitro

Abstract

Fecal microbiota transplantation (FMT) is a proposedly useful strategy for the treatment of gastrointestinal (GI) disorders through remediation of the patient gut microbiota. However, its therapeutic success has been variable, necessitating research to uncover mechanisms that improve patient response. Antibiotic pretreatment has been proposed as one method to enhance the success rate by increasing niche availability for introduced species. Several limitations hinder exploring this hypothesis in clinical studies, such as deleterious side effects and the development of antimicrobial resistance in patients. Thus, the purpose of this study was to evaluate the use of an in vitro, bioreactor-based, colonic ecosystem model as a form of preclinical testing by determining how pretreatment with the antibiotic rifaximin influenced engraftment of bacterial strains sourced from a healthy donor into an ulcerative colitis-derived defined microbial community. Distinct species integrated under the pretreated and untreated conditions, with the relative rifaximin resistance of the microbial strains being an important influencer. However, both conditions resulted in the integration of taxa from Clostridium clusters IV and XIVa, a concomitant reduction of Proteobacteria, and similar decreases in metabolites associated with poor health status. Our results agree with the findings of similar research in the clinic by others, which observed no difference in primary patient outcomes whether or not patients were given rifaximin prior to FMT. We therefore conclude that our model is useful for screening for antibiotics that could improve efficacy of FMT when used as a pretreatment. IMPORTANCE Patients with gastrointestinal disorders often exhibit derangements in their gut microbiota, which can exacerbate their symptoms. Replenishing these ecosystems with beneficial bacteria through fecal microbiota transplantation is thus a proposedly useful therapeutic; however, clinical success has varied, necessitating research into strategies to improve outcomes. Antibiotic pretreatment has been suggested as one such approach, but concerns over harmful side effects have hindered testing this hypothesis clinically. Here, we evaluate the use of bioreactors supporting defined microbial communities derived from human fecal samples as models of the colonic microbiota in determining the effectiveness of antibiotic pretreatment. We found that relative antimicrobial resistance was a key determinant of successful microbial engraftment with rifaximin (broad-spectrum antibiotic) pretreatment, despite careful timing of the application of the therapeutic agents, resulting in distinct species profiles from those of the control but with similar overall outcomes. Our model had results comparable to the clinical findings and thus can be used to screen for useful antibiotics.

Repeated Fecal Microbial Transplantations and Antibiotic Pre-Treatment Are Linked to Improved Clinical Response and Remission in Inflammatory Bowel Disease: A Systematic Review and Pooled Proportion Meta-Analysis

“…Ongoing debate exists regarding the pre-treatment of recipients with antibiotics prior to FMT to increase efficacy [ 71 , 72 ]. Conceptually, antibiotic pre-treatment helps provides a proverbial ecological clean slate for the engraftment of donor microbes by freeing up otherwise occupied niches.…”

Organoids and organs-on-chips: Insights into human gut-microbe interactions

“…In contrast, simplistic models of single-microbe effects can easily exaggerate the impact of individual gut microbiota (Walter et al, 2020), underscoring the benefit of investigating microbial communities. Growing complex intestinal bacterial communities in vitro is feasible (Oliphant et al, 2020;Van den Abbeele et al, 2010), but establishing media and oxygen conditions, under which both epithelial cells and bacteria with diverse requirements thrive, presents a formidable challenge. Consequently, the stable culture of complex microbial communities in lumen organoids has not been achieved to date.…”

Tumor-Associated Microbiome: Where Do We Stand?

“…The “Robogut” bioreactor has been established in the Allen-Vercoe laboratory to culture gut microbial ecosystems in vitro under physiologically relevant conditions [ 188 ]. The laboratory uses the bioreactors as a model of the colonic microbiota in determining the effectiveness of antibiotic pretreatment in ulcerative colitis caused by Clostridioides [ 189 ]. The goal of this technology is to culture novel and highly fastidious species that cannot be cultured using conventional methods of cell culture in static dishes [ 190 ].…”