Thesis title: Host-microorganism interactions in obesity and colorectal cancer
Nowadays colorectal cancer (CRC) is a threat to global health. The data collected by the Global Cancer Observatory (GCO) report that CRC is the third most common cancer and the second cause of tumor-associated mortality in the world. The early diagnosis of CRC is very hard and the screening methods currently used in the clinical practise have several limitations. This has stimulated intense research aimed to find sensitive, non-invasive and early biomarkers in easily collectable matrices. Both non-modifiable and modifiable factors can increase the risk of developing CRC. Among lifestyle-related factors obesity, as result of excessive caloric intake and sedentary life, is a predominant risk factor for colorectal carcinogenesis. The progressive increase in CRC incidence correlates with overweight and obesity epidemic proportion, consistently with the evidence of a positive correlation between body mass index (BMI) and CRC risk. A decrease of cancer incidence is recorded after bariatric surgery (BS) that is considered the most efficient treatment to lose weight in case of severe obesity.
White adipose tissue (AT) is the first target organ in obesity being characterised by metabolic derangements, a low-grade of chronic inflammation and oxidative stress. By phosphoproteomics analysis, we investigated the profile of DNA damage response (DDR) and senescence markers in AT of subjects with severe obesity, compared to the normal weight controls. A higher protein activation/expression of DDR players and senescence markers was found in AT of patients affected by obesity. Notably, the concurrent DDR and cellular senescence activation was observed in visceral AT (VAT), but not in subcutaneous AT (SAT), in agreement with the known association between VAT expansion and comorbidities development. All these data, associated to the elevated systemic levels of inflammatory and oxidative markers, observed in the plasma of our patients, align with the onset of a senescent-associated secretory phenotype (SASP). Interestingly, after BS, a significant reduction of systemic pro-inflammatory cytokines, a restoration of adipokines secretion and a significant reduction of plasmatic ccf-mtDNA, as a damage-associated molecular pattern (DAMP), have been recorded thus testifying the achievement of a healthier profile of subjects affected by severe obesity.
Dysbiosis, commonly observed in obesity, concurs to CRC development and could be proposed as a potential therapeutic target and biomarker with both predictive and prognostic value. We characterized both gut and oral bacterial microbiomes in individuals affected by obesity and CRC patients with the aim to identify common and distinct microbial profiles. In parallel, the prevalence of specific oral human DNA viruses, potentially associated with CRC, was analyzed in CRC patients and in subject groups at high CRC risk, such as individuals with obesity or with nonfamilial colon adenomatous polyposis (AP). The prevalence of the same infections was also analyzed in obese individuals after BS to investigate whether weight loss could affect the oral viral profile. We found the same trend of modulation in obesity and CRC for most bacterial genera, both in the gut and in the oral cavity. Our results also show a significantly higher prevalence of oral beta-Human Papilloma Viruses (HPV) and beta-HPV multiple infections in CRC patients, and a trend of increase in high-risk groups. Furthermore, the prevalence of specific beta HPV genotypes was found associated to both BMI and pathological conditions. Notably, a lower prevalence of all beta HPVs and of specific genotypes was observed in obese patients after bariatric surgery suggesting that the surgery-related benefits can reduce the persistence of viral agents potentially involved in CRC risk increase.
Given the increase of Proteobacteria (such as E. coli or S. enterica) and the reduction of Verrucomicrobiota (such as A. muciniphila) found in the gut microbiome of both subjects with obesity and CRC patients, we investigated the effects of endotoxins from pathogenic and commensal/probiotic bacteria on the generation and function of human dendritic cells (DC) and DC/γδ T lymphocyte crosstalk in an in vitro study on healthy donors. We found that A. muciniphila LPS can promote the differentiation of DC with full immunostimulatory properties, in contrast to comparable concentrations of LPS derived from E. coli and S. enterica, which can create an immunosuppressive environment.
According to the obtained results, alterations of oral and intestinal microbiome seem to be a causative bridge between obesity and CRC, but larger cohorts and deeper analysis are necessary to draw a definitive link.