• Gut-skin axis (GSA)
• cutaneous diseases
• gastrointestinal diseases
• gut and skin microbiota
• ultraviolet B-light exposure

• Humans
• Skin/microbiology
• Gastrointestinal Microbiome/physiology
• Animals
• Dysbiosis/microbiology
• Gastrointestinal Tract/microbiology
• Homeostasis
• Skin Diseases/microbiology
• Skin Diseases/therapy

• Congenital anomalies
• Human yolk sac
• Nutrient bioavailability

• Humans
• Yolk Sac/metabolism
• Embryonic Development/genetics
• Gene Regulatory Networks
• Nutrients/metabolism
• Gene Expression Regulation, Developmental
• Female
• Transcriptome

• 310489/2023-7 Conselho Nacional de Desenvolvimento Científico e Tecnológico
• APQ-00338-18 Fundação de Amparo à Pesquisa do Estado de Minas Gerais
• PJT-175161 CIHR

• Appendix
• Caecum
• Congenital anomalies
• Development
• Histomorphometry

• Humans
• Appendix/embryology
• Appendix/abnormalities
• Female
• Cecum/embryology
• Pregnancy
• Fetus
• Appendicitis/embryology
• Fetal Development
• Anatomic Variation

• Manipal Academy of Higher Education, Manipal

• 16S rRNA gene
• biomarker
• colorectal cancer
• gut microbiota
• left-sided CRC
• rectal CRC
• right-sided CRC

• Colonic duplication
• Mayer–Rokitansky–Küster–Hauser
• enteric duplication

• Xenopus
• Atrazine
• Electron transport chain
• Elongation
• Intestine
• Metabolism
• Rotation

• Atrazine
• Rotation
• Herbicides/toxicity
• Oxidation-Reduction
• Gene Expression Profiling

• P30 ES025128 NIEHS NIH HHS
• T32 GM133366 NIGMS NIH HHS
• R03 HD111763 NICHD NIH HHS
• T32 ES007046 NIEHS NIH HHS
• R03HD111763 NIH HHS
• National Institutes of Health
• Center for Human Heath and the Environment, North Carolina State University

• Bowel immaturity
• Colonic atresia
• Duodenal atresia
• Intestinal embryology
• Jejunoileal atresia
• Necrotizing enterocolitis

IL-38, an anti-inflammatory cytokine, is a key regulator of homeostasis in host immunity. Intestinal immunity plays a critical role in defence against pathogenic invasion, as it is the largest surface organ and the most common entry point for micro-organisms. Dysregulated IL-38 activity is observed in several autoimmune diseases including systemic lupus erythematosus and atherosclerosis. The protective role of IL-38 is well illustrated in experimental colitis models, showing significantly worse colitis in IL-38 deficient mice, compared to wildtype mice. Moreover, exogenous IL-38 has been shown to ameliorate experimental colitis. Surprisingly, upregulated IL-38 is detected in inflamed tissue from inflammatory bowel disease patients, consistent with increased circulating cytokine levels, demonstrating the complex nature of host immunity in vivo. However, colonic IL-38 is significantly reduced in malignant tissues from patients with colorectal cancer (CRC), compared to adjacent non-cancerous tissue. Additionally, IL-38 expression in CRC correlates with 5-year survival, tumour size and differentiation, suggesting IL-38 plays a protective role during the development of CRC. IL-38 is also an independent biomarker for the prognosis of CRC, offering useful information in the management of CRC. Taken together, these data demonstrate the role of IL-38 in the maintenance of normal intestinal mucosal homeostasis, but that dysregulation of IL-38 contributes to initiation of chronic inflammatory bowel disease (resulting from persistent local inflammation), and that IL-38 provides protection during the development of colorectal cancer. Such data provide useful information for the development of novel therapeutic targets in the management of intestinal diseases for more precise medicine.

• Mice
• Animals
• Colitis
• Inflammatory Bowel Diseases
• Cytokines
• Colorectal Neoplasms/pathology

• colon cancer
• liver metastasis
• lung metastasis
• nomogram
• prognosis

• Humans
• Female
• Aged
• SEER Program
• Neoplasm Staging
• Prognosis
• Colonic Neoplasms/pathology
• Liver Neoplasms/pathology
• Lung Neoplasms/pathology

Colorectal cancer is one of the leading causes of global cancer-related mortality. Tumor-infiltrating effector immune cells play critical roles in tumor control, and their activity can dictate disease outcomes. In this study, we provide evidence of the associations between different CD8⁺ T cell subpopulations with disease-free survival (DFS) in CRC patients. We report associations between higher levels of certain circulating and tumor-infiltrating CD8⁺ T cell subsets and improved clinical outcomes in CRC patients.

T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3⁺CD4^- (CD8⁺) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8⁺ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8⁺ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8⁺ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8⁺ T cell subsets (TIM-3-expressing, FoxP3⁻Helios⁻TIM-3⁺ and FoxP3⁻Helios⁺TIM-3⁺ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25⁺ and TIM-3⁺ T cells, and FoxP3⁺Helios⁻TIM-3⁺ Tregs were associated with better DFS.

• IL-37
• IL-38
• TAM
• TAN
• colorectal cancer

• Hirschsprung Disease
• gastrointestinal malformations
• gastrointestinal tract
• intestinal atresia
• intestinal duplication

• Digestive System Abnormalities/diagnosis
• Digestive System Abnormalities/surgery
• Humans
• Intestinal Volvulus
• Meckel Diverticulum/diagnosis
• Meckel Diverticulum/surgery
• Prognosis

Colorectal cancer (CRC) accounts for 9.4% of overall cancer deaths, ranking second after lung cancer. Despite the large number of factors tested to predict their outcome, most patients with similar variables show big differences in survival. Moreover, right-sided CRC (RCRC) and left-sided CRC (LCRC) patients exhibit large differences in outcome after surgical intervention as assessed by preoperative blood leukocyte status. We hypothesised that stronger indexes than circulating (blood) leukocyte ratios to predict RCRC and LCRC patient outcomes will result from combining both circulating and infiltrated (tumour/peritumour fixed tissues) concentrations of leukocytes.

To seek variables involving leukocyte balances in peripheral blood and tumour tissues and to predict the outcome of CRC patients.

Sixty-five patients diagnosed with colon adenocarcinoma by the Digestive Surgery Service of the La Paz University Hospital (Madrid, Spain) were enrolled in this study: 43 with RCRC and 22 with LCRC. Patients were followed-up from January 2017 to March 2021 to record overall survival (OS) and recurrence-free survival (RFS) after surgical interventions. Leukocyte concentrations in peripheral blood were determined by routine laboratory protocols. Paraffin-fixed samples of tumour and peritumoural tissues were assessed for leukocyte concentrations by immunohistochemical detection of CD4, CD8, and CD14 marker expression. Ratios of leukocyte concentration in blood and tissues were calculated and evaluated for their predictor values for OS and RFS with Spearman correlations and Cox univariate and multivariate proportional hazards regression, followed by the calculation of the receiver-operating characteristic and area under the curve (AUC) and the determination of Youden’s optimal cutoff values for those variables that significantly correlated with either RCRC or LCRC patient outcomes. RCRC patients from the cohort were randomly assigned to modelling and validation sets, and clinician-friendly nomograms were developed to predict OS and RFS from the respective significant indexes. The accuracy of the model was evaluated using calibration and validation plots.

The relationship of leukocyte ratios in blood and peritumour resulted in six robust predictors of worse OS in RCRC: CD8⁺ lymphocyte content in peritumour (CD8_pt, AUC = 0.585, cutoff < 8.250, P = 0.0077); total lymphocyte content in peritumour (CD4CD8_pt, AUC = 0.550, cutoff < 10.160, P = 0.0188); lymphocyte-to-monocyte ratio in peritumour (LMR_pt, AUC = 0.807, cutoff < 3.185, P = 0.0028); CD8⁺ LMR in peritumour (CD8MR_pt, AUC = 0.757, cutoff < 1.650, P = 0.0007); the ratio of blood LMR to LMR in peritumour (LMR_b/LMR_pt, AUC = 0.672, cutoff > 0.985, P = 0.0244); and the ratio of blood LMR to CD8⁺ LMR in peritumour (LMR_b/CD8MR_pt, AUC = 0.601, cutoff > 1.485, P = 0.0101). In addition, three robust predictors of worse RFS in RCRC were found: LMR_pt (AUC = 0.737, cutoff < 3.185, P = 0.0046); LMR_b/LMR_pt (AUC = 0.678, cutoff > 0.985, P = 0.0155) and LMR_b/CD8MR_pt (AUC = 0.615, cutoff > 1.485, P = 0.0141). Furthermore, the ratio of blood LMR to CD4⁺ LMR in peritumour (LMR_b/CD4MR_pt, AUC = 0.786, cutoff > 10.570, P = 0.0416) was found to robustly predict poorer OS in LCRC patients. The nomograms showed moderate accuracy in predicting OS and RFS in RCRC patients, with concordance index of 0.600 and 0.605, respectively.

Easily obtainable variables at preoperative consultation, defining the status of leukocyte balances between peripheral blood and peritumoural tissues, are robust predictors for OS and RFS of both RCRC and LCRC patients.

• Left colorectal cancer
• Leukocyte ratios
• Prognostic variables
• Recurrence-free survival
• Right colorectal cancer
• Overall survival

The importance of the neuronal microenvironment has been recently highlighted in gut region-specific diabetic enteric neuropathy. Regionally distinct thickening of endothelial basement membrane (BM) of intestinal capillaries supplying the myenteric ganglia coincide with neuronal damage in different intestinal segments. Accelerated synthesis of matrix molecules and reduced degradation of matrix components may also contribute to the imbalance of extracellular matrix dynamics resulting in BM thickening. Among the matrix degrading proteinases, matrix metalloproteinase 9 (MMP9) and its tissue inhibitor (TIMP1) are essential in regulating extracellular matrix remodelling.

To evaluate the intestinal segment-specific effects of diabetes and insulin replacement on ganglionic BM thickness, MMP9 and TIMP1 expression.

Ten weeks after the onset of hyperglycaemia gut segments were taken from the duodenum and ileum of streptozotocin-induced diabetic, insulin-treated diabetic and sex- and age-matched control rats. The thickness of BM surrounding myenteric ganglia was measured by electron microscopic morphometry. Whole-mount preparations of myenteric plexus were prepared from the different gut regions for MMP9/TIMP1 double-labelling fluorescent immunohistochemistry. Post-embedding immunogold electron microscopy was applied on ultrathin sections to evaluate the MMP9 and TIMP1 expression in myenteric ganglia and their microenvironment from different gut segments and conditions. The MMP9 and TIMP1 messenger ribonucleic acid (mRNA) level was measured by quantitative polymerase chain reaction.

Ten weeks after the onset of hyperglycaemia, the ganglionic BM was significantly thickened in the diabetic ileum, while it remained intact in the duodenum. The immediate insulin treatment prevented the diabetes-related thickening of the BM surrounding the ileal myenteric ganglia. Quantification of particle density showed an increasing tendency for MMP9 and a decreasing tendency for TIMP1 from the proximal to the distal small intestine under control conditions. In the diabetic ileum, the number of MMP9-indicating gold particles decreased in myenteric ganglia, endothelial cells of capillaries and intestinal smooth muscle cells, however, it remained unchanged in all duodenal compartments. The MMP9/TIMP1 ratio was also decreased in ileal ganglia only. However, a marked segment-specific induction was revealed in MMP9 and TIMP1 at the mRNA levels.

These findings support that the regional decrease in MMP9 expression in myenteric ganglia and their microenvironment may contribute to extracellular matrix accumulation, resulting in a region-specific thickening of ganglionic BM.

• Type 1 diabetes
• Diabetic enteric neuropathy
• Neuronal microenvironment
• Basement membrane
• Matrix metalloproteinase 9
• Tissue inhibitor of metalloproteinase 1