The gut microbiota has emerged as a key modulator of cancer treatment responses in terms of both efficacy and toxicity. This effect is clearly mediated by processes impacting the activation and modulation of immune responses. More recently, the ability to regulate chemotherapeutic drug metabolism has also emerged as a key driver of response, although the direct mechanisms have yet to be fully elucidated. Through fermentation, the gut microbiota can produce several types of metabolites, including short-chain fatty acids (SCFAs). SCFAs play an important role in maintaining epithelial barrier functions and intestinal homeostasis, with recent work suggesting that SCFAs can modulate response to cancer treatments and influence both anti-tumor immune response and inflammatory-related side effects. In this review, we will discuss the importance of SCFAs and their implications for cancer treatment response and toxicities.

Introduction: Radiotherapy is a mainstay of solid tumor management but can be associated with unacceptable levels of off-target tissue toxicity which impact treatment outcomes and patients’ quality of life. Tumour response to radiotherapy and the frequency and severity of radiotherapy-induced toxicities, especially mucositis, varies among patients. Gut microbiota has been found to modulate both the efficacy and toxicity of some types of cancer chemotherapies and immunotherapies but has yet to be investigated thoroughly in the setting of radiotherapy. Area covered: In this review, we discuss the potential role of gut microbiota on modulating radiotherapy-induced oral and gastrointestinal mucositis and the anti-tumor response to radiotherapy through modulation of immune responses. Expert opinion: The gut microbiota plays a major role in the modulation of systemic immune responses, which influence both radiotherapy response and gastrointestinal toxicities such as mucositis. Hence, investigating the gut microbiota link to the variation in radiotherapy responses and toxicities among patients is warranted. Future targeting of these responses with a patient-tailored restoration of optimal microbial composition could lead to a new era of mucositis prevention and enhanced tumor responses.

Oral mucositis (OM) is one of the most common and debilitating oral complications of cancer treatments including chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. It is associated with severe pain and difficulties in chewing, swallowing, and speech. This leads to impairment of basic oral functions and could result in unplanned treatment interruption or modification. As such, OM negatively impacts both patients' quality of life as well as tumor prognostic outcomes. Understanding pathways underlying OM pathogenesis help identify new targets for intervention or prevention. The pathophysiology of OM has been widely studied over past decades with several pathways related to oxidative stress, inflammation, and molecular and cellular signaling being implicated. In this mini-review, we will discuss the emerging role of the oral-gut microbiome axis in the development of OM. Particularly, we will elaborate on how the alterations in the oral and gut microbiota as well as intestinal dysfunction caused by cancer treatments could contribute to the pathogenesis of OM. Further, we will briefly discuss the potential methods for targeting the oral-gut microbiome axis to improve OM outcomes.

Purpose Mounting evidence suggests the gut microbiome influences radiotherapy efficacy and toxicity by modulating immune signalling. However, its contribution to radiotherapy outcomes in head and neck cancer (HNC) is yet to be investigated. This study, therefore, aimed to uncover associations between an individual’s pre-therapy gut microbiota and i) severity of radiotherapy-induced oral mucositis (OM), and ii) recurrence risk in patients with HNC. Methods In this prospective pilot study, 20 patients with HNC scheduled to receive radiotherapy or chemoradiotherapy were recruited. Stool samples were collected before treatment and microbial composition was analysed using 16S rRNA gene sequencing. OM severity was assessed using the NCI-CTCAE scoring system. Patients were also followed for 12 months of treatment completion to assess tumour recurrence. Results Overall, 80% of the patients were male with a median age of 65.5 years. 53% experienced mild/moderate OM while 47% developed severe OM. Further, 18% experienced tumour relapse within 1 year of treatment completion. A pre-treatment microbiota enriched of Eubacterium, Victivallis, and Ruminococcus was associated with severe OM. Conversely, a higher relative abundance of immunomodulatory microbes Faecalibacterium, Prevotella, and Phascolarctobacterium was associated with a lower risk of tumour recurrence. Conclusion Our results indicate that a patient’s gut microbiota composition at the start of treatment is linked to OM severity and recurrence risk. We now seek to validate these findings to determine their ability to predict treatment outcomes in HNC, with the goal of using this data to inform second-generation microbial therapeutics to optimise treatment outcomes for patients with HNC.