Exposure of Colon-Derived Epithelial Monolayers to Fecal Luminal Factors from Patients with Colon Cancer and Ulcerative Colitis Results in Distinct Gene Expression Patterns
<p>Fecal metabolite profiles and characterization of the RepliGut<sup>®</sup> Planar monolayers treated with fecal supernatants (FS). (<b>A</b>) A principal component analysis based on 9699 spectral features detected in FS, analyzed by untargeted liquid chromatography/mass spectrometry, for healthy subjects (HS, <span class="html-italic">n</span> = 6, green dots), patients with ulcerative colitis (UC, <span class="html-italic">n</span> = 6, red dots) and colon cancer patients (CC, <span class="html-italic">n</span> = 6, blue dots). (<b>B</b>) Primary human intestinal cells in the RepliGut<sup>®</sup> Planar system form a polarized monolayer with an apical membrane morphologically comparable with that of human intestine, as visualized by apical localization of phospho-ezrin (green), and actin filaments as detected by fluorescent phalloidin (magenta). Nuclei are visualized in blue color. The right hand and bottom panels show the orthographic view of the region, where “XY” and “XZ” indicate different cross-sections. The image was acquired with LSM700 inverted confocal microscope; 63× magnification. (<b>C</b>) Transepithelial electrical resistance was measured before and at 24 h and 48 h after addition of FS (HS: green dots, UC: red dots, CC: blue dots), TNFα (black triangles) or untreated (Media, gray triangles).</p> "> Figure 2
<p>Gene expression of RepliGut<sup>®</sup> Planar monolayers stimulated with fecal supernatants (FS) from healthy subjects (HS), patients with ulcerative colitis (UC), and patients with colon cancer (CC). Differentiated monolayers were stimulated apically with FS, TNFα, or left untreated (Media), for 48 h. Gene expression was analyzed by mRNA sequencing. (<b>A</b>) Principal component analysis (PCA) for monolayers treated with FS from HS, UC, CC, or with TNFα or media. (<b>B</b>) PCA for monolayers treated with FS from HS, UC, or CC. (<b>C</b>) Heatmap of distances between samples for monolayers treated with FS from HS, UC, or CC. HS <span class="html-italic">n</span> = 6 (green dots), UC <span class="html-italic">n</span> = 6 (red dots), CC <span class="html-italic">n</span> = 6 (blue dots), TNFα <span class="html-italic">n</span> = 2 (black triangles), and media <span class="html-italic">n</span> = 2 (gray triangles).</p> "> Figure 3
<p>Comparison of gene expression of RepliGut<sup>®</sup> Planar monolayers stimulated with fecal supernatants (FS) from patients with colon cancer (CC) and healthy subjects (HS). Differentiated monolayers were stimulated apically with FS for 48 h. Gene expression was analyzed by mRNA sequencing. (<b>A</b>) Volcano plot showing log2 fold change vs. significance. Wald test and false discovery rate analysis using the Benjamini−Hochberg method were used. Downregulated genes are shown in blue, upregulated genes in red and all the other genes in black. Horizontal dotted lines show cut-off for significance (q < 0.05) and vertical dotted lines show two-fold up- and downregulation. (<b>B</b>) Gene expression of the four most significant genes from (<b>A</b>). HS <span class="html-italic">n</span> = 6 (green dots) and CC <span class="html-italic">n</span> = 6 (blue dots). Results for patients with ulcerative colitis (UC) <span class="html-italic">n</span> = 6 (pale red dots) are shown to the right of the dotted line for reference.</p> "> Figure 4
<p>Comparison of gene expression of RepliGut<sup>®</sup> Planar monolayers stimulated with fecal supernatants (FS) from patients with ulcerative colitis (UC) and healthy subjects (HS). Differentiated monolayers were stimulated apically with FS for 48 h. Gene expression was analyzed by mRNA sequencing. (<b>A</b>) Volcano plot showing log2 fold change vs. significance. Wald test and false discovery rate analysis using the Benjamini−Hochberg method were used. Downregulated genes are shown in blue, upregulated genes in red and all the other genes in black. Horizontal dotted lines show cut-off for significance (q < 0.05) and vertical dotted lines show two-fold up- and downregulation. (<b>B</b>) Gene expression of the four significant genes from (<b>A</b>). HS <span class="html-italic">n</span> = 6 (green dots) and UC <span class="html-italic">n</span> = 6 (red dots). Results for patients with colon cancer (CC) <span class="html-italic">n</span> = 6 (pale blue dots) are shown to the right of the dotted line for reference.</p> "> Figure 5
<p>Comparison of gene expression of RepliGut<sup>®</sup> Planar monolayers stimulated with fecal supernatants (FS) from patients with ulcerative colitis (UC) and patients with colon cancer (CC). Differentiated monolayers were stimulated apically with FS for 48 h. Gene expression was analyzed by mRNA sequencing. (<b>A</b>) Volcano plot showing log2 fold change vs. significance. Wald test and false discovery rate analysis using the Benjamini−Hochberg method were used. Downregulated genes are shown in blue, upregulated genes in red and all the other genes in black. Horizontal dotted lines show cut-off for significance (q < 0.05) and vertical dotted lines show two-fold up- and downregulation. (<b>B</b>) Gene expression of the four most significant genes from (<b>A</b>). UC <span class="html-italic">n</span> = 6 (red dots) and CC <span class="html-italic">n</span> = 6 (blue dots). Results for healthy subjects (HS) <span class="html-italic">n</span> = 6 (pale green dots) are shown to the right of the dotted line for reference.</p> "> Figure 6
<p>Cytokine secretion from RepliGut<sup>®</sup> Planar monolayers stimulated with fecal supernatants (FS) from patients with ulcerative colitis (UC), patients with colon cancer (CC), and healthy subjects (HS). Differentiated monolayers were stimulated apically for 48 h with FS from HS, CC, UC, or media alone (<span class="html-italic">n</span> = 3). IL1β, IL8, and TNFα levels in the basolateral compartment were analyzed by MSD<sup>®</sup> V-PLEX platform system. (<b>A</b>) Levels of IL1β, IL8, and TNFα. Dashed lines represent median cytokine concentration from monolayers cultured with media alone. (<b>B</b>) Principal component analysis based on the levels of IL1β, IL8, and TNFα. HS <span class="html-italic">n</span> = 6 (green dots), UC <span class="html-italic">n</span> = 6 (red dots), CC <span class="html-italic">n</span> = 6 (blue dots), and media <span class="html-italic">n</span> = 3 (gray triangles).</p> ">
Abstract
:1. Introduction
2. Results
2.1. Study Subjects, Study Samples, and Assessment of Transepithelial Electrical Resistance (TEER) in the Colon-Derived Two-Dimensional Epithelial Monolayers
2.2. Gene Expression in Epithelial Monolayer Is Altered by Fecal Supernatants (FS) and Linked to Each Patient Group
2.3. Epithelial Monolayer Secretion of IL8 Is Altered by Fecal Supernatants
3. Discussion
4. Materials and Methods
4.1. Study Subjects and Sample Collection
4.2. Preparation of Fecal Supernatants
4.3. Liquid Chromatography−Mass Spectrometry
4.4. Stimulation of Colonoid Monolayers with Fecal Supernatants
4.5. Immunofluorescence and Imaging
4.6. Gene Expression Analysis
4.7. Cytokine Analysis
4.8. Data Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Ulcerative Colitis (n = 6) | Colon Cancer (n = 6) | Healthy (n = 6) | |
---|---|---|---|
Age, median (range) | 49 (40–67) | 81 (68–91) | 32 (25–44) |
Sex, female/male | 3/3 | 3/3 | 2/4 |
Mayo score, median (range) | 9 (6–11) | N/A | N/A |
Tumor stage 1, I/II/III/IV | N/A | 2/1/2/1 | N/A |
Gene Name | Fold Change | q-Value (CC vs. HS) |
---|---|---|
CCNY | −0.3857 | 0.006 |
CNST | −0.3386 | 0.033 |
DCAF8 | −7.8589 | 0.003 |
FAR1 | 0.3316 | 0.018 |
FGFR2 | −0.6135 | 0.018 |
FLRT3 | 0.9376 | 0.031 |
GLDC | 0.6479 | 0.033 |
GOPC | 0.2851 | 0.023 |
KCNK5 | −0.3865 | 0.042 |
LRP6 | −0.2310 | 0.006 |
MBD1 | −0.3579 | 0.027 |
MPZL3 | −0.3737 | 0.037 |
NABP1 | 0.3126 | 0.019 |
PCK1 | −1.0437 | 0.018 |
PELI2 | −0.2855 | 0.004 |
PNCK | −0.3762 | 0.037 |
PPAP2B | −0.4411 | 0.023 |
PTK2B | −0.1826 | 0.045 |
RIN2 | −0.2263 | 0.026 |
VEGFA | −0.3487 | 0.047 |
YPEL2 | −0.5200 | 0.016 |
ZFYVE27 | −0.2907 | 0.019 |
Gene Name | Fold Change | q-Value (UC vs. HS) |
---|---|---|
CERCAM | 0.7624 | 0.043 |
HSD17B2 | −0.4005 | 0.043 |
PBXIP1 | −0.2895 | 0.005 |
TUBA1B | −0.4825 | 0.043 |
Gene Name | Fold Change | q-Value (UC vs. CC) |
---|---|---|
AL139819.1 | 0.3827 | 0.044 |
ALDH1A3 | −0.5806 | 0.038 |
APLF | −0.7745 | 0.048 |
AVL9 | 0.1957 | 0.038 |
CCL2 | −1.0974 | 0.041 |
CCNY | 0.3068 | 0.041 |
CD63 | −0.1948 | 0.044 |
CHD4 | −0.2044 | 0.041 |
CLIP1 | 0.1637 | 0.038 |
CLN8 | 0.4625 | 0.046 |
CRHR1-IT1 | 0.4987 | 0.032 |
CTSL | −0.4901 | 0.025 |
DCAF8 | 8.1459 | 0.001 |
DNAJC11 | −0.4601 | 0.045 |
DNAJC3 | 0.1745 | 0.045 |
DPP3 | −0.4107 | 0.025 |
DYNC1LI1 | −0.5180 | 0.038 |
EDIL3 | −1.0717 | 0.041 |
EEF1A1P13 | 1.2351 | 0.025 |
ERN1 | 0.2983 | 0.041 |
F8A1 | −1.7489 | 0.021 |
FUCA2 | −0.3988 | 0.032 |
GAN | 0.4025 | 0.001 |
GBA | −0.3971 | 0.025 |
GLDC | −0.6223 | 0.038 |
GREM1 | −0.8350 | 0.038 |
GSTP1 | −0.3766 | 0.021 |
HPGD | −0.3718 | 0.044 |
INHBA | −1.0509 | 0.048 |
INSIG1 | 0.2298 | 0.038 |
KANSL1 | 0.2560 | 0.041 |
KLF7 | 0.2948 | 0.038 |
KLHL28 | 0.3201 | 0.044 |
LRIG1 | 0.5803 | 0.044 |
LRP6 | 0.1937 | 0.037 |
LXN | −0.4863 | 0.029 |
MLLT4 | 0.1303 | 0.031 |
MLXIPL | 0.6879 | 0.038 |
MSL1 | 0.2348 | 0.048 |
NCL | −0.4204 | 0.023 |
NEAT1 | 0.5613 | 0.038 |
PELI2 | 0.2772 | 0.006 |
PLA2G4C | −0.5980 | 0.041 |
PPP1R15B | 0.2462 | 0.026 |
PRAP1 | −0.4953 | 0.041 |
PTGES | −0.6840 | 0.036 |
RAPGEFL1 | 0.3226 | 0.044 |
RN7SL5P | 0.8572 | 0.026 |
RP11-34P13.13 | 0.8704 | 0.045 |
RP11-395B7.2 | 0.3212 | 0.038 |
SEPP1 | −0.4565 | 0.038 |
SH3D21 | 0.3871 | 0.025 |
SLC25A25 | 0.1949 | 0.042 |
SQSTM1 | −0.3686 | 0.041 |
TM4SF20 | −0.4150 | 0.032 |
TMEM176A | −0.4591 | 0.038 |
TMEM176B | −0.3301 | 0.046 |
TRIB3 | 0.3095 | 0.030 |
VEGFA | 0.3470 | 0.038 |
YPEL2 | 0.5035 | 0.023 |
ZNF330 | −0.6198 | 0.041 |
ZNF488 | 0.2957 | 0.047 |
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Magnusson, M.K.; Bas Forsberg, A.; Verveda, A.; Sapnara, M.; Lorent, J.; Savolainen, O.; Wettergren, Y.; Strid, H.; Simrén, M.; Öhman, L. Exposure of Colon-Derived Epithelial Monolayers to Fecal Luminal Factors from Patients with Colon Cancer and Ulcerative Colitis Results in Distinct Gene Expression Patterns. Int. J. Mol. Sci. 2024, 25, 9886. https://doi.org/10.3390/ijms25189886
Magnusson MK, Bas Forsberg A, Verveda A, Sapnara M, Lorent J, Savolainen O, Wettergren Y, Strid H, Simrén M, Öhman L. Exposure of Colon-Derived Epithelial Monolayers to Fecal Luminal Factors from Patients with Colon Cancer and Ulcerative Colitis Results in Distinct Gene Expression Patterns. International Journal of Molecular Sciences. 2024; 25(18):9886. https://doi.org/10.3390/ijms25189886
Chicago/Turabian StyleMagnusson, Maria K., Anna Bas Forsberg, Alexandra Verveda, Maria Sapnara, Julie Lorent, Otto Savolainen, Yvonne Wettergren, Hans Strid, Magnus Simrén, and Lena Öhman. 2024. "Exposure of Colon-Derived Epithelial Monolayers to Fecal Luminal Factors from Patients with Colon Cancer and Ulcerative Colitis Results in Distinct Gene Expression Patterns" International Journal of Molecular Sciences 25, no. 18: 9886. https://doi.org/10.3390/ijms25189886