Chitosan Oligosaccharides Regulate the Occurrence and Development of Enteritis in a Human Gut-On-a-Chip

Abstract

Past studies on the protective effects of chitosan oligosaccharides (COS) on inflammatory bowel disease (IBD) commonly rely on animal models, because traditional cell culture systems couldn’t faithfully mimic human intestinal physiology. Here a novel human gut-on-a-chip microsystem was established to further explore the regulatory effects of COS on the occurrence and development of human enteritis. By constructing an intestinal injury model caused by dextran sodium sulfate (DSS) on the chip, this study proved that COS can reduce intestinal epithelial injury by promoting the expression of the mucous layer for the first time. By establishing an inflammatory bowel disease model on the chip caused by E. coli 11775, this study demonstrated that COS can protect the intestinal epithelial barrier and vascular endothelial barrier by inhibiting the adhesion and invasion of E. coli 11775 for the first time. In addition, similar to the results in vivo, COS can decrease the inflammatory response by reducing the expression of toll-like receptor 4 protein and reducing the nuclear DNA binding rate of nuclear factor kappa-B protein on this chip. In summary, COS can be used as a potential drug to treat human IBD and the human gut-on-a-chip would be used as a platform for quick screening drugs to treat human IBD in future.

Intestine‐on‐a‐chip for intestinal disease study and pharmacological research

“…This intestine chip model is able to form intact intestinal F I G U R E 8 Mimicking treatment and therapy of intestinal disease using intestine chips. (A) Protective effect of gut bacteria and antibiotics in EIEC-induced and immune cell-associated intestinal injury, reproduced with permission of 45 Copyright 2016 PNAS and (B) protective effect of COS in intestine inflammation induced by DSS and pathogenic E. coli 11773, reproduced with permission of 94 Copyright 2022 Frontiers Media SA epithelium with barrier functions and normal blood vessels or lymph vessels and is also suitable for mimicking other organs such as the lung and brain. A comprehensive intestine emulation should comprise epithelial cells, endothelial cells, and all other cells present in the simulated target microenvironment.…”

“…Imaging characterization of the intestine chip. (A) Differential interference contrast (DIC) micrograph showing intestinal basal crypt (red arrow) and villi (white arrow) formed by human Caco‐2 intestinal epithelial cells and immunofluorescence image showing a horizontal cross‐section of F‐actin (green) and DAPI stained nuclei (blue), reproduced with permission of 45 Copyright 2016 PNAS; immunofluorescence images showing (B) a vertical cross‐section of MUC2 (red), F‐actin (yellow) and DAPI stained nuclei (blue), reproduced with permission of 60 Copyright 2019 Springer Nature; (C) a horizontal cross‐section and vertical cross‐sections of NHE3 (green), reproduced with permission of 61 Copyright 2021 Elsevier; (D) ZO‐1‐positive Caco‐2 cells (green) and PECAM‐1‐positive HUVECs (carmine), reproduced with permission of 72 Copyright 2022 Springer Nature; (E) WGA (left, green) and occluding on intestinal epithelial cells (right, red), reproduced with permission of 94 Copyright 2022 Frontiers Media SA and (F) the invasion of CRC cells (green) from epithelium into endothelium (red), reproduced with permission of 47 Copyright 2021 Elsevier…”

“…60 Intestinal mucin can also be stained by using wheat germ agglutinin (WGA) labeled with FITC. 94 NHE3 is expressed in the apical of intestinal epithelial cells and plays a major role in electroneutral sodium absorption, 95 which can also represent the apical polarization of the epithelial monolayers. The vertical and horizontal crosssection of NHE3 (green) detected by fluorescence confocal imaging demonstrated the intestinal apical polarization of differentiated cells (Figure 5C).…”

“…Kulthong et al established an intestine chip model with whole gut function to analyze the transport of individual dioxin congeners across epithelial monolayers. 97 By detecting the dioxin congeners 94 Copyright 2022 Frontiers Media SA and (F) the invasion of CRC cells (green) from epithelium into endothelium (red), reproduced with permission of 47 Copyright 2021 Elsevier in apical channels, perfused in basolateral channels, and absorbed into cells using gas chromatography-high resolution mass spectrometry (GC-HRMS), the transport and cellular accumulation of dioxins can be profiled. Microfluidic gut-on-a-chip model can also be combined with electrospray ionization MS (ESI-MS) and liquid chromatography coupled MS (LC-MS) to enable the measurement of drug transportation, delivery, and digestion.…”

Recent Research and Application Prospect of Functional Oligosaccharides on Intestinal Disease Treatment

“…Furthermore, some studies have found that functional oligosaccharides such as inulin-derived FOS can also increase the colonization sites of probiotics in the intestinal tract [ 33 ]. Our previous studies also found that COS promoted the growth, metabolic activity, and metabolite concentration changes of probiotics represented by Akkermansia muciniphila by affecting specific populations in microbial groups; reduced the adhesion, invasion, and colonization of intestinal pathogens represented by Escherichia coli ; and inhibited the occurrence and development of enteritis, thereby maintaining intestinal health [ 34 , 35 ].…”