Investigating microbial therapies to combat gut microbiome dysbiosis during pelvic irradiation

Segers Charlotte

Promoter

Lebeer Sarah, (UA), sarah.lebeer@uantwerpen.be

SCK•CEN Mentor

Mastroleo Felice
felice.mastroleo@sckcen.be
+32 14 33 23 88

SCK•CEN Co-mentor

Verslegers Mieke
mieke.verslegers@sckcen.be
+32 14 33 28 67

Expert group

Microbiology

PhD started

2017-10-01

Short project description

Pelvic irradiation is one of the most frequently used forms of radiotherapy to treat patients diagnosed with different types of cancer (e.g. cervical cancer and colon cancer). During these irradiations patients are exposed to very high doses, up to 50Gy cumulated dose (Peters et al., 2000). Exposure to this magnitude of ionising radiations leads to severe side effects in the intestine which is rarely the primary target but is always affected. This disruption (also termed dysbiosis) will result in side effects like diarrhea enteritis and fatigue. These side effects can become so severe that they receive additional treatment or even that the cancer treatment has to be stopped prematurely (Wang et al., 2015).

Due to the side effects and disadvantages of commonly used treatment, novel microbial therapies are being developed using microbial food supplements like probiotics. These probiotics, which mainly consist of lactic acid bacteria such as live Lactobacillus and Bifidobacterium species, have shown promising results in treating diarrhea but their health benefits cannot always be univocally substantiated (Ciorba et al., 2015). There is thus clear need for selection of novel strains with added benefits.

Due to its ability to resist high doses of radiation and its anti-oxidative capacity (Badri et al., 2015), the cyanobacterium Arthrospira sp. seems promising to treat such side effects. Of interest, recent unpublished preliminary work from SCK•CEN microbiology and radiobiology units set-up a mouse model for pelvic irradiation and revealed changes in intestinal villi length when Arthrospira sp. was added to their diet.

Objective

The main objective of this project is to explore whether microbial food supplements can potentially be used as a therapeutic agent to prevent side effects that occur after exposure to pelvic irradiation in vivo.

To achieve this hypothesis, we set out the following main objectives based on the experience gained during a previous MSc thesis work: (1) The growth process and formulation of Arthrospira sp. to be delivered to the mice will be optimized, because Arthrospira sp. biomass composition can be fine-tuned based on the culture conditions. However, at present, these microbes cannot withstand common freeze-drying procedures. Therefore alternatives to obtain dry powder or alternative forms that can be stored and further processed will also have to be investigated. These challenges will be overcome due to the expertise of the promotors in cyanobacteria (SCK•CEN) and formulation and drying methods of probiotics (UAntwerpen), (2) A reproducible in-house available mouse model for pelvic irradiation and associated dysbiosis will be developed in which the clinical symptoms and side effects for human pelvic irradiation can be replicated (including diarrhea, oxidative stress, dysbiosis and impact on the microbiome composition). The development of such a model is challenging, but feasible due to the expertise of SCK•CEN mentors, where a large expertise with irradiation studies involving animal models do exist. In addition, the UAntwerpen promotor has expertise with animal models of colitis and microbiome studies. This innovative model of pelvic irradiation will be developed so that it will also be suitable to test the efficacy of any other treatments than the microbes described below, and (3) The effects of Arthrospira sp. on the side effects of pelvic radiotherapy will then be explored in the optimized mouse model. These effects will be compared at symptom level, as well as at histological and molecular level (for parameters related to inflammation, oxidative stress and the microbiome composition). Results will be compared with the effects of the model probiotic strain Lactobacillus rhamnosus GG for which previous studies have shown a protective effect. Because this protective effect has been shown to be at least partially mediated by Toll-like receptor -2 (TLR2), we will also investigate the efficacy of knock-out mutants with altered TLR2- signalling capacity, which are available in the lab of the promotor at UAntwerpen. In all, the combination of an innovative animal model and cutting-edge molecular approaches will enable us to validate the effects of Arthrospira sp. and L. rhamnosus GG on pelvic irradiation-induced side effects, and will reveal possible modes of action at the molecular level.