Understanding how the host gut microbiota influences distant immunological niches

Abstract

The host gut microbiota has long been associated with improved health, however these associations have been historically hard to evaluate objectively. In the last decade, the advent of high throughput sequencing has enabled the field to examine the specific members of this ecosystem that are contributing to health. This has seen adoption of probiotic based treatments in several disorders including asthma, allergy and gastrointestinal diseases. However, an entirely unexpected association has been that between the gut microbiome and cancer. Modulation of the gut microbiota has been shown to influence primary tumour growth across multiple diseases; however, despite breast cancer being the most common in the western world, there have not been any studies addressing the role of the microbiome. This thesis intends to fill this gap in the field’s knowledge and determine the mechanistic role of the gut microbiota in breast cancer immune responses. We have shown that antibiotic induced dysbiosis accelerates primary tumour growth. However, to our surprise this appears to be driven by metabolic changes rather than immunological modulation. Additionally, we have shown that by supplementing the microbiota with species from a probiotic genus of bacteria, we can improve anti-cancer immune responses by modulating intratumoural cytokine production. Finally, we have shown that the microbiome also plays a role in guiding and controlling metastatic breast cancer by influencing the metastatic niche. Overall, these findings have demonstrated a key role for the microbiome in breast cancer growth and progression. Our data suggests that antibiotic use in BC patients should be examined closely and re-evaluated to avoid comprising treatment efficacy. Furthermore, the use of probiotics show potential for clinical use but should be followed up with robust mechanistic studies before clinical trials are considered