## 4 Discussion  
In this study, seven volatile compounds, namely benzaldehyde, ethylbenzene, indole, methylbenzene, phenol, octanal, and oxime methoxy-phenyl were the most significant VOCs detected by SPME and CG-MS, for the different levels and kinetic profiles, in normal colonic mucosa and adenomatous polypoid lesion tissue of the same patient in ex vivo condition. Furthermore, benzaldehyde and methylbenzene, which are produced by both tissues, can also be detected in the expired breath of the same patients. High levels of methylbenzene (concentration range: \(>\)50 pg*mL\({}^{-1}\)) and absence/traces of benzaldehyde (concentration range: n.d.-LOD) were found in the breath of patients affected by adenomatous polypoid lesions (see Table 4). On the other hand, ethylbenzene, indole, phenol, octanal, and oxime methoxy-phenyl were not found in the corresponding expired breath samples, suggesting that they do not cross the capillary-alveolar barrier to be exhaled or that different metabolic pathways involving the intestinal microbiota could contribute to their production.  
Comparing these data with those reported in another paper by our group, and performed with the same methodology, on CRC specimens, some of the VOCs highlighted in this study, such as benzaldehyde, ethylbenzene, methylbenzene, and octanal were identified in ex vivo CRC tissue samples [15]. When the kinetic profiles of these compounds are compared with those of CRC patients [15], it is evident that benzaldehyde, ethylbenzene, and methylbenzene levels are different, whereas the octanal profile looks the same. In addition, differences were also found between the concentration ranges of these compounds in polyps compared with colonic adenocarcinoma. Specifically, ethylbenzene and octanal concentrations were lower in adenomatous polypoid lesions compared to CRC, whereas methylbenzene values were comparable.  
Moreover, the kinetic analysis by DI-SPME has highlighted several differences between the VOCs produced by colonic polyps and CRC cancer tissues, probably correlated to differences in the metabolic pathways involved in tumor progression. A decrease in ethylbenzene production may be related to increased consumption or binding of this compound with protein or lipid [16]. In fact, as in the literature reported, ethylbenzene undergoes \(\alpha\)- and \(\omega\)-oxidation by microorganisms, whereas the octanal metabolism could be linked to oxidative stress [17]. [PERSON] et al. [16] showed that aldehydes, under different conditions, were consumed and/or bound by cultured human adipose tissue cells. In the case of benzaldehyde, [PERSON] et al. [18] described different metabolic pathways, such as tryptophan metabolism, in which this compound could be involved. Thanks to intestinal microbiota, tryptophan produces indole and a lot of its metabolites [19] precursors or signal molecules for many biologically active substances that play an important role in the \"gut-brain axis\" [20].  
Phenol was considered for the first time in this study and showed comparable levels between normal mucosa and adenomatous polypoid lesion tissues. Phenol and its derivate, in general, because of their peroxididative capacity, could result in hematotoxic and hepatotoxic effects, facilitating mutagenesis and carcinogenesis in humans and other living organisms. Phenol is also produced during the natural decomposition of organic materials [21].  
Furthermore, Oxime methoxy-phenyl is a typical chemical compound in body odor [22].  
Finally, a recent paper analyzing the VOC pattern exhaled by CRC patients suggests that low levels of ethylbenzene and tetradecane, coupled with high levels of methylbenzene, could be predictive of a CRC [15]. A similar VOC pattern was also found in patients affected by colonic polyps; therefore, it could be speculated that this breath analysis might play a role as a mass screening tool since high levels of methylbenzene with no or very low traces of benzaldehyde and tetradecane seem to suggest the presence of colon neoplasia (polyp or cancer).