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.

Colorectal cancer (CRC) is a multifaceted disease influenced by both environmental and genetic factors. A large body of literature has demonstrated the role of gut microbes in promoting inflammatory responses, creating a suitable microenvironment for the development of skewed interactions between the host and the gut microbiota and cancer initiation. Even if surgery is the primary therapeutic strategy, patients with advanced disease or cancer recurrence after surgery remain difficult to cure. Therefore, the gut microbiota has been proposed as a novel therapeutic target in light of recent promising data in which it seems to modulate the response to cancer immunotherapy. The use of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics, and fecal microbiota transplantation, is therefore considered to support current therapies in CRC management. In this review, we will discuss the importance of host−microbe interactions in CRC and how promoting homeostatic immune responses through microbe-targeted therapies may be useful in preventing/treating CRC development.

No abstract

AbstractiNKT cells account for a relevant fraction of effector T-cells in the intestine. Although iNKT cells are cytotoxic lymphocytes, their role in colorectal cancer (CRC) remains controversial. From the analysis of colonic LPMCs of human and murine CRC specimens we report that tumor-infiltrating iNKT cells are characterized by an IL17/GM-CSF pro-tumorigenic phenotype, while maintaining cytotoxic properties in the adjacent non-tumoral tissue. Exposure of iNKT cells to the tumor-associated pathobiontFusobacterium nucleatumblunted their cytotoxic capability and enhanced iNKT cell-mediated neutrophils chemotaxis, which upregulated PMN-MDSC gene signatures and functions. Importantly,in vivostimulation of iNKT cells with αGalCer restored their anti-tumorigenic functions. Survival analyses demonstrated that human CRC co-infiltration by iNKT cells and tumor-associated neutrophils correlates with negative outcomes.Our results reveal a functional plasticity of human intestinal iNKT cells with pro- and anti-tumorigenic activities in CRC, suggesting an iNKT pivotal role in shaping the cancer developmental trajectory.

IFNγ-producing ex-Th17-cells (“Th1/17”) were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterized a novel, potentially colitogenic subset of Th17-cells in the intestine of patients with Crohn’s Disease (CD). Human Th17-cells expressing CCR5 (“pTh17”) co-expressed T-bet and RORC/γt and produced very high levels of IL-17, together with IFN-γ. They had a gene signature of Th17 effector cells and were distinct from established Th1/17-cells. pTh17-cells, but not Th1/17-cells, were associated with intestinal inflammation in CD, and decreased upon successful anti-TNF therapy with infliximab. Conventional CCR5(-)Th17-cells differentiated to pTh17 cells with IL-23 in vitro. Moreover, anti-IL-23 therapy with risankizumab strongly reduced pTh17-cells in the intestine. Importantly, intestinal pTh17-cells were selectively activated by adherent-invasive Escherichia coli (AIEC), but not by a commensal/probiotic E. coli strain. AIEC induced high levels of IL-23 and RANTES from DC. Intestinal CCR5 +Th1/17-cells responded instead to Cytomegalovirus and were reduced in UC, suggesting an unexpected protective role. In conclusion, we identified an IL-23-inducible subset of human intestinal Th17-cells. pTh17 cells produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC, suggesting a key colitogenic role.