Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

Hannah R Wardill,Stijn A.R Van Der Aa,Ana R Da Silva Ferreira,Rick Havinga,Wim J.E Tissing,Hermie J.M Harmsen

doi:10.1016/j.ejca.2021.05.015

Hannah R Wardill, Stijn A.R Van Der Aa + Show 4 more

Open Access

https://doi.org/10.1016/j.ejca.2021.05.015

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Abstract

BackgroundChemotherapy 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/ResultsHere, 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. ConclusionsThese 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.

Highlights

Cancer therapy is well recognised for its detrimental effects on the host microbiota, causing profound and often chronic changes in the microbial community of the gastrointestinal tract [1]
We report the first phenotypic analysis of Faecal microbiome transplantation (FMT) delivered after cytotoxic chemotherapy (MTX) and antibiotics, identifying Muribaculaceae (S24-7) as a key regulator of mucosal injury and repair
A strong body of data shows microbial injury after chemotherapy drugs, including MTX [26], it remains hotly debated if these changes are directly mediated by chemotherapy or a form of collateral damage resulting from mucosal injury [27]

Summary

Introduction

Cancer therapy is well recognised for its detrimental effects on the host microbiota, causing profound and often chronic changes in the microbial community of the gastrointestinal tract [1]. Disruption of the host microbiota is considered a critical event in the initiation of various treatment complications, many of which are catalysed by breakdown of the mucosal barrier [3,4]. Mucosal barrier injury (MBI) is initiated by acute cytotoxic injury to the intestinal stem cell niche, it is perpetuated by innate immune responses that are thought to be dictated by hostmicrobe interactions at the mucosal interface [5]. These assumptions are largely based on associations between the gut microbiome composition and gastrointestinal symptoms, with robust causal data lacking [5]. It remains unclear if microbial changes that occur after chemotherapy truly contribute to symptoms or are a form of collateral damage resulting from breakdown of the mucosal barrier

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