FECAL MICROBIOTA, SERUM BIOMARKERS, DIET AND LIFESTYLE: COLORECTAL CANCER RISK AND PROGNOSIS

Colorectal cancer (CRC) is the result of a complex interaction between non-modifiable and modifiable risk factors. The modifiable factors include obesity, diet, lifestyle choices, inflammatory markers, and vitamin D (vitD) status. Recent literature also suggests an important link between gut microbiota and CRC prognosis and progression, however assessing whether the relationship is causal is challenging. We conducted a comprehensive investigation of these factors to provide new insights on how their interplay affects CRC. We employed a multi-step approach. First, we designed a case-control study of CRC patients and healthy individuals. We found that several species, such as Parvimonas micra, Fusobacterium nucleatum and Bacteroides fragilis were significantly more abundant in cases. A poor lifestyle and a high-risk diet were significantly associated with CRC and mediation analysis suggested that the gut microbiota mediated the effect of diet on CRC risk. Then, we carried out a systematic review of the literature on human studies, to summarize the evidence published so far on the relationship between gut microbiota and vitD. We found that Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the most recurrent phyla increasing or decreasing following vitD supplementation and at increasing vitD serum levels or dietary intake. Finally, we designed a phase II randomized trial involving vitD supplementation or placebo for 1 year and including CRC survivors. Gut microbiota, circulating markers, diet and lifestyle were collected at baseline and at the end of the treatment. We found increased abundances of several probiotic taxa following vitD supplementation, including Faecalibacterium prausnitzii and Holdemanella biformis. We also found that the microbiota significantly mediated the effect of the supplementation on 25(OH)D levels. In the supplemented group, we found differences by sex/gender in the pathways involved in the biosynthesis of essential amino-acids. The weight status of the participants modulated the effect of the supplementation on both 25(OH)D levels and alpha diversity. In the supplemented group, 25(OH)D levels increased less at increasing Body Mass Index (BMI), while the change in alpha diversity was significantly and positively correlated with the change in 25(OH)D levels only in normal-weight individuals (BMI<25). For a subgroup of patients, we collected the gene expression (GE) profile evaluated on tumour tissue of a panel of 395 immuno-related genes. We identified three clusters of patients based solely on GE. One of the clusters was associated with a higher risk of colorectal and clinical events. Alpha diversity at baseline was also significantly and inversely associated with the risk of colorectal and clinical events, while vitD supplementation and Galactin-9 had a protective effect on both outcomes. Overall, our findings provide new insights on the complex interconnection between modifiable risk factors of CRC and highlight the importance of personalized strategies.