The intestinal barrier orchestrates selective permeability to nutrients and metabolites while excluding noxious stimuli. Recent scientific advances establishing a causal role for the gut microbiota in human health outcomes have generated a resurgent interest toward intestinal permeability. Considering the well-established role of the gut barrier in protection against foreign antigens, there is mounting evidence for a causal link between gut permeability and the microbiome in regulating human health. However, an understanding of the dynamic host–microbiota interactions that govern intestinal barrier functions remains poorly defined. Furthermore, the system-level mechanisms by which microbiome-targeted therapies, such as probiotics and prebiotics, simultaneously promote intestinal barrier function and host health remain an area of active investigation. This review summarizes the recent advances in understanding the dynamics of intestinal permeability in human health and its integration with gut microbiota. We further summarize mechanisms by which probiotics/prebiotics influence the gut microbiota and intestinal barrier functions.

Background: Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. Methods: A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. Results: PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. Conclusions: PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer.

Stabilin-1 (STAB1) is a multifunctional scavenger receptor expressed by endothelial cells of the liver, spleen, lymph nodes, bone marrow and a subset of macrophages. STAB1 interacts with different ligands and modulates a wide range of functions including cell trafficking, endocytosis, homeostasis, angiogenesis, and tumor vascularization. The role of STAB1 in cancer progression and metastasis first became evident in Stab1 knockout (KO) mice, which developed smaller primary tumors and metastatic foci for some cancers. To date, various clinical cohorts and preclinical rodent studies have shown that STAB1 inhibition is associated with elevated anti-tumor T-cell responses. Moreover, human trials using anti-STAB1 antibody treatment indicate a shift towards immune activation and the potential to overcome cancer treatment resistance experienced with other immunotherapies. Although the role of STAB1 in cancer development and metastasis remains to be defined, STAB1 signaling in tumor-associated macrophages and downstream immune modulation are thought to be crucial mechanisms. Herein, we discuss the role of STAB1 in tumor-associated macrophages in relationship to disease progression and patient outcome.

The conventional orthotopic/xenograft models or genetically engineered murine models of colon cancer (CRC) are limited in their scope for a true understanding of tumor growth, progression and event... Method summary This study describes a procedure for murine modeling of CRC progression and metastasis to the lungs by colonoscopic-guided implantation of colon cancer cells into the host colonic mu... Graphical abstract