Table 1.
Candidate biomarkers for gut barrier damage in colorectal carcinogenesis.
| Candidate biomarkers | Putative function | Evidence as biomarkers | Reference | |
|---|---|---|---|---|
| D-lactate and diamine oxidase (DAO) | Intestinal permeability | Plasma levels of D-lactate and DAO were found to be increased in CRC patients (n=53) compared to control (n=45) | (89) | |
| Direct measurement of intestinal damage | iFABP | Intestinal permeability | Plasma concentration levels increased in patients with severe ulcerative colitis (n = 42) | (90) |
| Zonulin | Intestinal permeability | Faecal levels increased in patients with Crohn’s disease (n=37) compared to control (n=40) Mice gavaged with zonulin showed increased both small intestinal and gastroduodenal permeability compared with bovine serum albumine-treated controls |
(91) (92) |
|
| ZO1 | Tight Junction integrity | Lower levels in colonic mucosa of IBD patients (n=50) compared to controls (n=31) Knock out in mouse epithelial cell lines result in a loss of tight junction strands |
(93) (94) |
|
| CLDN1 | Tight Junction integrity | CLDN1 expression was increased in both high-grade dysplasia and ulcerative colitis-associated CRC tissue (n=6) when compared with ulcerative colitis and normal tissue (n=39) The upregulation of claudin-1 in transgenic mice induces MMP-9 and p-ERK signalling to activate Notch-signalling pathway |
(95) (96) |
|
| JAM2 | Tight Junction structure | JAM-2 expression was decreased in colorectal cell lines and CRC tissue (n=94) compared to controls (75) | (97) | |
| MLCK | Tight Junction regulation | Upregulated in IBD in human intestinal resection and biopsy specimens | (98) | |
| Indirect measurement of intestinal damage | LPS and flagellin | Intestinal permeability | Serum LPS- and flagellin-specific immunoglobulin levels positively associated to CRC risk among men in a prospective cohort study. A borderline statistically significant inverse association was observed for women. Levels of LPS were found to be increased in CRC patients (n=53) compared to control (n=45) |
(99) (89) |
| Soluble CD14 | Response to LPS exposure | Increased TLR4-CD14 expression were found in Caco-2 cell lines Plasma levels of sCD14 were positively associated with a Western diet (n=1198) in a cross-sectional study |
(100) (101) |
|
| LPS-binding protein (LBP) | Exposure to LPS | Levels of serum LBP were higher in CRC patients with cachexia (n=74) than in CRC patients without cachexia (n=78) | (102) | |
| Cytokine markers (e.g., IFNgamma, IL10, IL12p70, IL13, IL1beta, IL2, IL4, IL6, IL8, TNFalfa) | Inflammation | Early barrier loss and activation of IL23/IL17-driven tumour-elicited inflammation act additively and sequentially to genetically controlled events that govern CRC development and progression in ApcF/WTmice IFNgamma and TNFalfa alter barrier properties of the intestinal epithelium increasing epithelial paracellular permeability human in cell lines |
(103) (104) |
|
| Short chain fatty acids (SCFA) | Intestinal permeability | A cross sectional study observed that faecal levels of SCFA was significantly lower in CRC patients (n=19) compared to healthy control (n=16) Levels of bacteria producing SCFA assessed in stool samples were lower in CRC patient (n=15) compared to control (n=12) |
(105) (106) |
|
| Secondary bile acids | Intestinal permeability | Apc min/+ mice treated with cholic acid (n=10) showed an increased intestinal permeability compared to control (n=10) | (107) | |
| Vitamin D and VDR | Intestinal damage | In vivo model of infectious colitis showed that vitamin D deficiency increased colonic hyperplasia and epithelial barrier dysfunction | (108) | |
| Calprotectin | Inflammation | Elevated faecal calprotectin levels associated with intestinal inflammation and IBD | (109) |
CRC, colorectal cancer; iFABP, intestinal fatty acid binding protein; LPS, Lipopolysaccharide; ZO1, Zonula Occludens 1; IBD, irritable bowel syndrome; CLDN1, claudin 1; CLDN2, claudin2; JAM2, Junctional adhesive molecule 2; MLCK, myosin ligase chain kinase.