The intestinal tract is an ecosystem in which the resident microbiota lives in symbiosis with its host. This symbiotic relationship is key to maintaining overall health, with dietary habits of the host representing one of the main external factors shaping the microbiome-host relationship. Diets high in fiber and low in fat and sugars, as opposed to Western and high-fat diets, have been shown to have a beneficial effect on intestinal health by promoting the growth of beneficial bacteria, improve mucus barrier function and immune tolerance, while inhibiting pro-inflammatory responses and their downstream effects. On the contrary, diets low in fiber and high in fat and sugars have been associated with alterations in microbiota composition/functionality and the subsequent development of chronic diseases such as food allergies, inflammatory bowel disease, and metabolic disease. In this review, we provided an updated overview of the current understanding of the connection between diet, microbiota, and health, with a special focus on the role of Western and high-fat diets in shaping intestinal homeostasis by modulating the gut microbiota.

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis – in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances.

Bacterial translocation is defined as the passage of live bacteria from the gut lumen to distant sites. Gut commensal bacteria translocation has been attributed to ‘leakiness’, or ‘barrier breach’ of the intestinal epithelium, allowing live bacteria to cross an inappropriately permeable barrier and disseminate to distant sites. Alternatively, studies suggest dendritic cells directly capture luminal commensal bacteria and transport them to distant sites in the steady-state by extending dendrites between epithelial cells into the lumen. Recently we identified translocation of commensal gut bacteria following antibiotics was associated with the formation of goblet cell associated antigen passages (GAPs) in the colon and dependent upon goblet cells (GCs). The translocation of native gut commensal bacteria resulted in low-level inflammatory responses and potentiated mucosal damage in response to concurrent epithelial injury. Here we extend these observations and demonstrate properties of colonic GAPs and observations supporting their priority in the translocation of colonic commensal bacteria.

The mucosal surfaces of the body are the most vulnerable points for infection because they are lined by single or multiple layers of very active epithelial cells. The main protector of these cells is the mucus system generated by the specialized goblet cell secreting its main components, the gel-forming mucins. The organization of the mucus varies from an attached mucus that is impenetrable to bacteria in the large intestine to a nonattached, more penetrable mucus in the small intestine. The respiratory tract mucus system clears particles and microorganisms from healthy lungs but causes disease if reorganized to an attached mucus that cannot be efficiently transported. Similarly, transformation of large intestine mucus from impenetrable to penetrable causes chronic inflammation directed toward the intestinal microbiota. Mucus-producing goblet cells are regulated by and responsive to signals from immune cells, and at the same time signal back to the immune system. In this review we focus on the relationship of immune cells with intestinal goblet cells and mucus, making parallels to the respiratory tract.

Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-γ and TNF-α decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-γ and TNF-α treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor α, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-α and IFN-γ. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.