The Role of Gut Microbiota Biomodulators on Mucosal Immunity and Intestinal Inflammation

Abstract

Alterations of the gut microbiota may cause dysregulated mucosal immune responses leading to the onset of inflammatory bowel diseases (IBD) in genetically susceptible hosts. Restoring immune homeostasis through the normalization of the gut microbiota is now considered a valuable therapeutic approach to treat IBD patients. The customization of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation, is therefore considered to support current therapies in IBD management. In this review, we will discuss recent advancements in the understanding of host-microbe interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. By considering gut microbiota dysbiosis as a key feature for the establishment of chronic inflammatory events, in the near future it will be suitable to design new cost-effective, physiologic, and patient-oriented therapeutic strategies for the treatment of IBD that can be applied in a personalized manner.

Keywords: FMT; gut microbiome; inflammatory bowel diseases; live biotherapeutic products.

Figure 1

Homeostatic and pro-inflammatory role of the gut microbiota and microbe-targeted therapies for IBD management. During homeostasis (left panel), the recognition of specific PAMPs from the gut microbiota induces antigen presenting cells (APCs) like macrophages and dendritic cells (DC) to produce IL1β and IL23. Subsequently, different cell-types such as neutrophils, Th17 and ILC3 cells express cytokines (e.g., IL17 and IL22) that control the expansion of commensals and the potential invasion of microbes that could be harmful (pathobionts). The production of short-chain fatty acids (SCFAs), by the gut microbiota, in concert with IL22, enhances intestinal epithelial cell barrier function. Furthermore, commensals such as bifidobacteria, PSA+ B. fragilis and Clostridium spp. stimulates APCs to promote anti-inflammatory IL10 Treg responses regulating iNKT, Th1 and Th17 responses. In inflammatory bowel disease (IBD) (central panel) a combination of genetic and environmental factors lead to depletion of protective bacteria and the enrichment of colitogenic pathobionts, resulting in chronic inflammation due to hyper-activation of T helper 1 (Th1) and Th17 cells as well as aberrant innate, pro-inflammatory responses. Dashed lines show impaired responses. The use of microbe-targeted therapies (right panel) to restore homeostatic immune responses contribute to the expansion of anti-inflammatory responses by Treg cells and the modulation of pro-inflammatory cytokines release.