Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45HLA-DRCD14CD64) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11cCCR2CX3CR1 cells, a phenotype also shared by circulating CD14 monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11cCCR2CX3CR1 phenotype. CD11c monocyte-like cells produced IL-1β, both in resting conditions and after LPS stimulation, while CD11c Mϕ-like cells produced IL-10. CD11c pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14 monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11cCCR2CX3CR1) into tolerogenic tissue-resident (CD11cCCR2CX3CR1) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11c monocyte-like cells.

All animals develop in association with complex microbial communities. It is now well established that commensal microbiota is essential for the correct functionality of each organ in the host. Particularly, the commensal gastro-intestinal microbiota (CGIM) is a key factor for development, immunity and nutrient conversion, rendering them bio-available for various uses. Thus, nutritional inputs generate a positive loop in maintaining host health and are essential in shaping the composition of the CGIM communities. Probiotics, which are live exogenous microorganisms, selectively provided to the host, are a promising concept for manipulating the microbiota and thus for increasing the host health status. Nevertheless, most mechanisms induced by probiotics to fortify the immune system are still a matter of debate. Alternatively, prebiotics, which are non-digestible food ingredients, can favor the growth of specific target groups of CGIM. Several metabolites are produced by the CGIM, one of the most important are the short-chain fatty acids (SCFAs), which emerge from the fermentation of complex carbohydrates. SCFAs have been recognized as key players in triggering beneficial effects elicited by simple diffusion and by specific receptors present, thus, far only in epithelial cells of higher vertebrates at different gastro-intestinal locations. However, both strategies have shown to provide resistance against pathogens during periods of high stress. In fish, knowledge about the action of pro- and prebiotics and SCFAs is still limited. Thus, in this review, we briefly summarize the mechanisms described on this topic for higher vertebrates and discuss why many of them may operate in the fish gut representing a model for different mucosal tissues

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and leading cause of cancer-related deaths worldwide. In recent years, there has been a growing realisation that lifestyle plays a major role for CRC development and that intestinal microbiota, which are shaped by lifestyle and nutrition habits, may be critically involved in the pathogenesis of CRC. Although the precise mechanisms for how the microbiota contribute to CRC development and progression remain elusive, increasing evidence suggests a direct causative role for the intestinal microbiota in modulating signalling pathways, anti-tumour immune responses and cell proliferation. Recent advances in understanding host-microbe interactions have shed light onto the putative use of intestinal microbiota as a powerful tool in CRC diagnosis and therapy. Here, we will discuss the role of the intestinal microbiota in CRC pathogenesis, their potential utility as diagnostic markers, and consider how microbes could be used in therapeutic approaches for the treatment of CRC.

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Corpus‐dominant lymphocytic gastritis (LyG) is characterized by CD8 + T‐cell infiltration of the stomach epithelium by a so far uncharacterized mechanism. Although Helicobacter pylori is typically undetectable in LyG, patients respond to H. pylori antibiotic eradication therapy, suggesting a non‐H. pylori microbial trigger for the disease. Comparative microbiota analysis of specimens from LyG, H. pylori gastritis and healthy controls precluded involvement of H. pylori in LyG but identified Propionibacterium acnes as a possible disease trigger. In addition, the natural killer group 2 member D (NKG2D) system and the proinflammatory cytokine interleukin (IL)‐15 are significantly upregulated in the gastric mucosa of LyG patients, and gastric epithelial cells respond to microbe‐derived stimuli, including live P. acnes and the microbial products short‐chain fatty acids, with induction of NKG2D ligands. In contrast, H. pylori infection does not activate or even repress NKG2D ligands. Together, our findings identify P. acnes as a possible causative agent for LyG, which is dependent on the NKG2D system and IL‐15 activation. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The modulation of both IELs and ILCs to control intestinal inflammatory responses represents a major challenge, as they provide tight regulation among the epithelium, the microbiota, and the adaptive immune system. An improved understanding of the innate immunity mechanisms involved in gastrointestinal inflammation would therefore aid in the diagnosis and further treatment of gastrointestinal inflammatory disorders.

ObjectivesEsophageal microbiota and regulation of adaptive immunity are increasingly being investigated in eosinophilic esophagitis (EoE). Toll-like receptors (TLRs) play a central role in the initiation and maintenance of innate immune activity. Our objective was to characterize the esophageal and duodenal innate immune response in EoE and its modulation by dietary therapy.MethodsEsophageal and duodenal biopsy samples were collected from 10 adults with untreated EoE, before and after effective treatment with a six-food elimination diet (SFED), and 10 controls with normal esophagus. In all cases, bacterial load (by mRNA expression of 16S), TLRs, mucins, transcription factors, interleukins, components of the NKG2D system, and innate immunity effectors were assessed by qPCR. Protein expression of TLRs were also determined by immunofluorescence.ResultsBacterial load and TLR1, TLR2, TLR4, and TLR9 were overexpressed on biopsies with active EoE compared with controls. Muc1 and Muc5B genes were downregulated while Muc4 was overexpressed. Upregulation of MyD88 and NFκB was found together with IL-1β, IL-6, IL-8, and IL-10 mediators and PER-1, iNOS, and GRZA effectors. NG-K2D components (KLRK1, IL-15, MICB) were also upregulated. In all cases, changes in active EoE were normalized following SFED and mucosal healing. Duodenal samples also showed increased expressions of TLR-1, TLR-2, and TLR-4, but not 16S or any other mediators nor effectors of inflammation.ConclusionsEsophageal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease.

As an organism is exposed to pathogens during very early development, specific defense mechanisms must take effect. In this study, we used a germ-free zebrafish embryo model to show that osmotic stress regulates the activation of immunity and host protection in newly hatched embryos. Mechanistically, skin keratinocytes were responsible for both sensing the hyposmolarity of the aquatic environment and mediating immune effector mechanisms. This occurred through a transient potential receptor vanilloid 4/Ca2+/TGF-β–activated kinase 1/NF-κB signaling pathway. Surprisingly, the genes encoding antimicrobial effectors, which do not have the potential to cause tissue damage, are constitutively expressed during development, independently of both commensal microbes and osmotic stress. Our results reveal that osmotic stress is associated with the induction of developmental immunity in the absence of tissue damage and point out to the embryo skin as the first organ with full capacities to mount an innate immune response.