Regulating vitamin D-gut microbiota interactions to prevent chemotherapy-induced mucositis

About this project 

Chemotherapy side effects are a limiting factor in effective cancer treatment. Gastrointestinal mucositis (GM) is a debilitating side effect of chemotherapy affecting all patients having high dose chemotherapy, and up to 40% of those having standard doses. Compromised gut structure reduces gut function, leading to malnutrition, diarrhoea and dehydration. Current evidence implicates multiple damage pathways activated in the gut that lead to mucositis. Recent investigations also demonstrate many signalling pathways of active vitamin D (1,25D) exist in normal intestine, and maintaining adequate intestinal 1,25D would interfere with gastrointestinal mucositis. Many patients are vitamin D deficient when diagnosed with cancer or become deficient during treatment. Gut microbial diversity also declines following chemotherapy. The exact relationship between chemotherapy, vitamin D, gut microbiota, and chemotherapy-induced mucositis is unknown. Therefore, studies addressing specific relationships between vitamin D, gut microbiota, and chemotherapy-induced mucositis are necessary. Our novel compound (VD1-6) inhibits CYP24A1, responsible for vitamin D catabolism, resulting in increased 1,25D, and contribution to maintenance of gut microbiota. Probiotics (in addition to maintaining gut microbiota) will further increase 1,25D activity through VDR pathways, due to the bidirectional relationship between vitamin D and gut microbiota. 

HYPOTHESIS: Maintaining vitamin D and gut microbiota levels through co-administration of vitamin D therapy and probiotics during chemotherapy treatment will mitigate chemotherapy-induced GM. 

AIMS: We aim to determine the relationship of vitamin D and gut microbiota during clinical gastrointestinal mucositis in cancer patients, and assess mechanisms of vitamin D and gut microbiota interactions to co-administer vitamin D and gut microbiota therapies to prevent chemotherapy-induced mucositis.

What you’ll do 

The short-term outcomes of the project will be a significant contribution to the knowledge around the roles of both vitamin D and gut microbiota in maintaining gut health, leading to the development of improved therapies. In addition, novel data will be produced around the bidirectional and synergistic relationship between vitamin D and gut microbiota. Potentiating new therapeutic options for people with debilitating gastrointestinal conditions will be game-changing in terms of quality of life and ease of dealing with day-to-day activities. Diarrhoea is a key symptom of inflammatory gastrointestinal conditions and is a rate-limiting factor for many in terms of just leaving the house in extreme situations. Current therapies treat symptoms rather than the damage itself; most are ineffective. Patients report being unable to leave the house without spare clothing and a map of public toilets. It is becoming widely recognised that the gut interacts with almost all other body systems, and gut health significantly contributes to the health of these systems. Longer-term future impact may also include translating data into other fields, where optimizing gut health conditions and minimizing gastrointestinal inflammation will improve outcomes. Examples include, but are not limited to, improving livestock production and optimising the health and performance of people working under high stress and workload, such as defence personnel, and elite athletes. Data will be presented at relevant local and international conferences, and published in peer-reviewed journals in categories related to Gastroenterology and Hepatology, and Supportive Care in Cancer.

Where you’ll be based 

Project will be conducted in HB6 tissue culture facilities, and HB8 tissue culture laboratories for infection co-culture work. Animal work will be conducted in CAF in cytotoxic facility. Models have previously been used by supervisory team. Project is essential for Gut Research Group work in establishing the relationship between vitamin D and gut microbiota, and the combined roles in protecting gut environment against damage and inflammation. This work will either be funded by a current NHMRC Ideas Grant application, or will complement the current animal and clinical studies that are underway, funded by a current NHMRC Ideas Grant (2020169). The project aligns with the discovery research conducted within Health and Biomedical Innovation, and fits within the Gut Health Theme. Vitamin D is an emerging therapeutic target for gastrointestinal conditions. However the specific mechanisms for its protective capacity are not yet fully understood. This project will provide extensive knowledge into the specific role of vitamin D and gut microbiota combined in the gastrointestinal environment, building from cellular effects through to combined cellular and microbial effects, into animal effects. We have shown that vitamin D and gut microbiota have a protective gut effect individually, and with emerging evidence of a bidirectional relationship, the next step is to investigate this relationship to determine whether the combined effects are better than individual effects. End users include oncologists treating cancer patients with cancer treatment-induced gastrointestinal toxicities, and potentially gastroenterologists treating patients with other inflammatory bowel conditions. Financial Support  

This project is funded for reasonable research expenses. Additionally, a living allowance scholarship of $35,200 per annum is available to Australian and New Zealand citizens, and permanent residents of Australia, including permanent humanitarian visa holders. Australian Aboriginal and/or Torres Strait Islander applicants will be eligible to receive an increased stipend rate of $52,352 per annum (2025 rate). A fee-offset or waiver for the standard term of the program is also included. For full terms and benefits of the scholarship please refer to our scholarship information. International applicants are not invited to apply at this time.

Eligibility and Selection 

This project is open to applications from Australian or New Zealand citizens, and Australian permanent residents or permanent humanitarian visa holders. International applicants are not invited to apply at this time.

Applicants must meet the eligibility criteria for entrance into a Master of Research or a PhD. Additionally, applicants must meet the project selection criteria: 

• Honours or Masters by Research degree (or equivalent)
• Have an interest in gut structure and function.

All applications that meet the eligibility and selection criteria will be considered for this project. A merit selection process will be used to determine the successful candidate.

The successful applicant is expected to study full-time and to be based at our City West Campus in the heart of Adelaide. 

Essential Dates 

Applicants are expected to start in a timely fashion upon receipt of an offer. Extended deferral periods are not available. Applications close on Friday 7 March 2025.