The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance.

Background & Aims Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBD), but the mechanisms that lead to such a defect are not fully understood. This study was aimed at characterizing the factors involved in the defective barrier function in IBD. Methods Transcriptome analysis was performed on colon samples taken from healthy controls (CTR) and IBD patients. Expression of GATA-binding factor 6 (GATA6), a transcription factor involved in intestinal epithelial cell differentiation, was evaluated in colon samples taken from CTR and IBD patients by real-time PCR and immunohistochemistry. Intestinal sections of wild-type and Gata6del mice, which exhibit a conditional Gata6 deletion in intestinal epithelial cells, either left untreated or receiving subcutaneous indomethacin or rectal trinitrobenzene sulfonic acid, were stained with hematoxylin and eosin. In parallel, some Gata6del mice received antibiotics to deplete intestinal flora. Mucosal inflammatory cell infiltration and cytokine production were evaluated by flow cytometry and real-time PCR respectively while tight junction proteins were examined by immunofluorescence. Intestinal barrier integrity was assessed by FITC-dextran assay. Results Multiple genes involved in cell commitment/proliferation and wound healing were differentially expressed in IBD compared to CTR. Among these, GATA6 was significantly decreased in the IBD epithelium compared to CTR. In mice, conditional deletion of GATA6 in the intestinal epithelium induced primarily epithelial damage, diminished Zonula Occludens-1 expression and enhanced intestinal permeability, ultimately resulting in bacteria-driven local immune response and enhanced susceptibility to gut inflammation. Conclusions Reduced expression of GATA6 promotes intestinal barrier dysfunction thus amplifying intestinal inflammatory pathology.

Colorectal carcinoma (CRC) is one of the most common neoplasias in the Western world and it is still one of the most deadly cancers worldwide mainly due to the fact that metastatic CRC is not responsive to current pharmacologic treatment. Identification of pathways that sustain CRC cell behaviour could help develop effective therapeutic compounds. A large body of evidence indicates that colon carcinogenesis is a dynamic process in which multiple cell types present in the tumor microenvironment either stimulate or suppress CRC cell growth, survival, and diffusion mainly via the production of cytokines. Interleukin-34 (IL-34), a cytokine initially known for its ability to regulate monocyte/macrophage survival and function, is highly produced in human CRC by both cancer cells and non-tumoral cells. IL-34 function is mainly mediated by interaction with the macrophage colony-stimulating factor-1 receptor (MCSF-1R), which is also over-expressed by CRC cells as well as by tumour-associated macrophages (TAMs) and cancer-associated fibroblasts. IL-34-driven MCSF-1R activation triggers several pro-tumoral functions in the colon. In this article, we review the current understanding of the involvement of IL-34 and its receptor in CRC, with particular attention to the available evidence about the IL-34/MCSF-1R axis-mediated regulation of TAMs and the role of IL-34 and MCSF-1R in promoting cancer resistance to chemotherapy and immunotherapyManuscript Contribution to the FieldIn this review, we highlight the multiple effects of IL-34 and its receptor, macrophage colony-stimulating factor-1 receptor, on the activity of colorectal cancer (CRC) cells and non-tumoral cells, with particular attention to the available data supporting the role of IL-34/MCSF-1R axis in the control of tumor-associated macrophages. The findings summarized in this manuscript could help understand whether targeting IL-34/MCSF-1R can be exploited for therapeutic intervention in CRC.

Initially known as a cytokine produced by and regulating the function of monocytes and macrophages, interleukin-34 (IL-34) can be synthesized by many cell types and interacts with receptors expressed by multiple immune and non-immune cells. IL-34 is constitutively expressed in the healthy human small intestine and colon and its production is markedly increased in damaged gut of patients with Crohn’s disease and patients with ulcerative colitis, the main forms of chronic inflammatory bowel diseases (IBD) in human beings. Circumstantial evidence suggests that, in these pathologies, IL-34 plays a crucial role in mediating cross-talk between immune cells and stromal cells, thereby promoting activation of signalling pathways, which amplify the ongoing mucosal inflammation as well as production of fibrogenic molecules. In this article, we summarize the available data supporting the multiple effects of IL-34 in human IBD with particular attention to the role of the cytokine in immune and stromal cell interactions.

Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC.