Hannah R Wardill1, Stijn A R van der Aa2, Ana R da Silva Ferreira3, Rick Havinga2, Wim J E Tissing4, Hermie J M Harmsen3. 1. Department of Pediatrics, University Medical Centre Groningen, The University of Groningen, Groningen, the Netherlands; Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Precision Medicine Theme (Cancer), South Australian Health and Medical Research Institute, South Australia, Australia. Electronic address: hannah.wardill@adelaide.edu.au. 2. Department of Pediatrics, University Medical Centre Groningen, The University of Groningen, Groningen, the Netherlands. 3. Department of Medical Microbiology, University Medical Centre Groningen, The University of Groningen, Groningen, the Netherlands. 4. Department of Pediatrics, University Medical Centre Groningen, The University of Groningen, Groningen, the Netherlands; Princess Maxima Center for Paediatric Oncology, Utrecht, the Netherlands.
Abstract
BACKGROUND: Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them. METHODS/ RESULTS: Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae. CONCLUSIONS: These are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.
BACKGROUND: Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them. METHODS/ RESULTS: Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae. CONCLUSIONS: These are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.
Authors: H R Wardill; C E M de Mooij; A R Da Silva Ferreira; H Havinga; H J M Harmsen; W J F M van der Velden; L F J van Groningen; W J E Tissing; N M A Blijlevens Journal: Sci Rep Date: 2022-05-11 Impact factor: 4.996