Updated perspectives on the contribution of the microbiome to the pathogenesis of mucositis using the MASCC/ISOO framework

Abstract

Advances in the treatment of cancer have significantly improved mortality rates; however, this has come at a cost, with many treatments still limited by their toxic side effects. Mucositis in both the mouth and gastrointestinal tract is common following many anti-cancer agents, manifesting as ulcerative lesions and associated symptoms throughout the alimentary tract. The pathogenesis of mucositis was first defined in 2004 by Sonis, and almost 20 years on, the model continues to be updated reflecting ongoing research initiatives and more sophisticated analytical techniques. The most recent update, published by the Multinational Association for Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO), highlights the numerous co-occurring events that underpin mucositis development. Most notably, a role for the ecosystem of microorganisms that reside throughout the alimentary tract (the oral and gut microbiota) was explored, building on initial concepts proposed by Sonis. However, many questions remain regarding the true causal contribution of the microbiota and associated metabolome. This review aims to provide an overview of this rapidly evolving area, synthesizing current evidence on the microbiota's contribution to mucositis development and progression, highlighting (i) components of the 5-phase model where the microbiome may be involved, (ii) methodological challenges that have hindered advances in this area, and (iii) opportunities for intervention.

Keywords: Cancer therapy; Dysbiosis; Gut microbiota; Mucositis; Oral microbiome.

Fig. 1

The severity of irinotecan-induced gastrointestinal mucositis is modulated by the gut microbiota through reactivation of SN38 by β-glucuronidase. Irinotecan (CPT-11) undergoes first-pass hepatic metabolism by carboxylesterase enzymes in the liver to form the active cytotoxic metabolite SN38. SN38 is conjugated to a glucuronide molecule to form the secondary non-toxic metabolite, SN38G, which is excreted into the GIT lumen via the bile duct. A In the absence of β-glucuronidase producing bacteria, SN38G is excreted without initiating mucositis. B Gastrointestinal mucositis is exacerbated through the conversion of SN38G to SN38 by bacterial β-glucuronidase enzymes, exposing intestinal tissue and mucosa to the cytotoxic drug

Fig. 2

5-phase pathogenesis of mucositis and involvement of the microbiota