Intestinal microbiota and colorectal carcinoma: Implications for pathogenesis, diagnosis, and therapy

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and leading cause of cancer-related deaths worldwide. In recent years, there has been a growing realisation that lifestyle plays a major role for CRC development and that intestinal microbiota, which are shaped by lifestyle and nutrition habits, may be critically involved in the pathogenesis of CRC. Although the precise mechanisms for how the microbiota contribute to CRC development and progression remain elusive, increasing evidence suggests a direct causative role for the intestinal microbiota in modulating signalling pathways, anti-tumour immune responses and cell proliferation. Recent advances in understanding host-microbe interactions have shed light onto the putative use of intestinal microbiota as a powerful tool in CRC diagnosis and therapy. Here, we will discuss the role of the intestinal microbiota in CRC pathogenesis, their potential utility as diagnostic markers, and consider how microbes could be used in therapeutic approaches for the treatment of CRC.

1. Introduction

Colorectal cancer (CRC) is the third most frequent cancer in the Western world and the second leading cause of cancer-related death worldwide. [1]. In recent years, despite improvements in screening and treatment options and approaches [2], CRC is still curable only in its early stages. This fact is demonstrated by the age standardised 5-year survival rates that vary between 70% in Korea to 60–69% in USA and Europe to less than 50% in Russia and India. In particular, 5-year survival rates in patients with UICC stage IV disease are still below 20% [3].

CRC aetiology has been linked to hereditary genetic syndromes, family history of CRC, inflammatory bowel disease (IBD), and, particularly, environmental and lifestyle risk factors, such as obesity, alcoholism, tobacco, and diet [4]. It is anticipated that the number of patients suffering from CRC will significantly rise within the next twenty years, associated with a rise in Western lifestyle practices and diet, particularly as these Western influences become more common also in Asia, Africa, and South America [5]. Clear associations have been demonstrated between the risk of developing CRC and consumption of certain food types, such as red meat, and nutrients, which act to either promote or reduce the risk of developing CRC [6]. Most of these environmental factors have been associated with an effect on the indigenous intestinal microbiota, causing a detrimental alteration known as dysbiosis [7]. Accordingly, the intestinal microbiota or its derived metabolites may be acting as the direct environmental modifiers for the risk to develop CRC, given the known associations of dietary habits on systemic immune responses, inflammation, intestinal immune responses to bacteria, as well as intestinal microbiota composition and functionality overall. This profound effect of microbiota on determining immune responses is exemplified by observations from the use of antibiotics in early childhood, which have been associated with increased colonic adenoma formation in later life, the precursor lesion to CRC [8,9].

Given recent technological and technical advances, there have been significant strides forward in our understanding of the relevance for intestinal microbiota in health and disease. In particular, through identification of several microbial signatures associated with CRC and related pathologies such as IBD. Despite these advances and the significant potential for modulating intestinal microbiota for the host benefit as part of a future personalised/precision medicine approach, our knowledge about how microbiota may be used as a diagnostic tool or which bacterium or mix of bacteria could treat or prevent CRC is still in its infancy. This highlights the need to move away from spurious, often retrospectively identified associations, greater scrutiny to prove causation and not just correlation, as well as highlighting the importance of functional data to better understand the complex microbiota-host interplay.

Keywords: Colorectal cancer (CRC), Intestinal microbiota, Nutrition, Pathogenesis, Diagnosis, Therapy

Read full Publication