A large number of microorganisms, such as bacteria and fungi, coexist in the digestive tract and they play an essential role in the maintenance of homeostasis in the body. Gut microbiota in the gastrointestinal tract affect the host cells directly or indirectly through their metabolites. They also support the development of the host immune system and modify functions of the host. Bacteria coexist not only in the gastrointestinal lumen but also inside mucosa-associated lymphoid tissue (MALT), such as Peyer’s patches of the small intestine which have also been shown to affect the immune function of the host. Dietary components can alter the composition of intestinal flora and affect the gastrointestinal mucosal barrier and host immune function. Intestinal bacteria, the host-immune system, and diet influence each other to create and maintain homeostasis, and they also have critical roles in various pathological conditions. Molecules modified by glycosylation and metabolites produced by bacteria such as short-chain fatty acids act as mediators between host cells and microorganisms, playing a major role in determining the composition of gut microorganisms as well as mediating biological functions of the host.

The intestinal tract is a unique organ that is constitutively exposed to countless antigens, including dietary antigens and commensal microorganisms. A large number of immune cells are accumulated in the gut. It is known that T helper 17 (Th17) cells, a subset of CD4 positive T helper cells, are constitutively present in the intestinal lamina propria. This is because microorganisms such as segmented filamentous bacteria (SFB) induce the differentiation and proliferation of Th17 cells. Interestingly, Th17 cells induced by commensal bacteria contribute to protection against pathogenic bacteria and the construction of the epithelial barrier system, and they also play an important role in maintaining intestinal homeostasis. Therefore, Th17 cells in the gut have different phenotypes from Th17 cells that induce pathological inflammation in the systemic compartment. SFB-induced Th17 cells have been reported to promote disease aggravation in rheumatoid arthritis and multiple sclerosis mouse models. Since intestinal Th17 cells are critical to the induction and regulation of host diseases, Th17 cells may be an important target for the treatment of diseases. It is expected that clarifying the detailed mechanism of the differentiation and control of intestinal Th17 cells will lead to the development of novel therapeutic approaches for various diseases.

The immune system exhibits individual variations which are involved in the development of allergic inflammatory diseases and infectious diseases. Accumulating evidence suggests that the immune system is not only regulated by the genetic background, but also by gut environmental factors, including dietary nutrition and intestinal microbes. This article reviews our new findings that essential fatty acid metabolites regulate the immune system. α-Linolenic acid and linoleic acid are representative essential fatty acids in dietary oils, and they are classified as ω3 and ω6 fatty acids, respectively. In mice, we found that a diet containing linseed oil, which is high in α-linolenic acid, led to the suppression of the development of food allergy when compared with mice fed a conventional diet containing soybean oil. Lipidomic analysis revealed that the amount of 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) was markedly increased in the gut of mice fed with linseed oil. We also found that 17,18-EpETE exerts anti-allergic activity in food allergy. We then extended our analysis by investigating the role of 17,18-EpETE in skin inflammation, and found that 17,18-EpETE was effective at ameliorating contact hypersensitivity in mice and cynomolgus macaques. Mechanistically, 17,18-EpETE inhibited neutrophil infiltration of the skin by suppressing chemoattractant-induced Rac activation and pseudopod formation in a GPR40-dependent manner. Moreover, we established a bacterial production system by introducing bacterial CYP BM3 to E. coli for stereospecific production of 17(S),18(R)-EpETE which exerts a potent anti-inflammatory activity. Regarding the metabolites of ω6 fatty acid, we found that a high affinity receptor for leukotriene B4 (BLT1) was expressed on IgA+ B cells and plasma cells in the gut. We further found that a BLT1-mediated pathway played an essential role in oral vaccines by enhancing the production of antigen-specific secretory IgA in the feces through the promotion of plasma cell proliferation. Indeed, we found that the BLT1-mediated pathway elevated the gene expression level of MyD88 which transmits innate immune signals from commensal bacteria for plasma cell proliferation. These findings suggest that nutrition and intestinal microbes in vaccine recipients are key factors for the success of oral vaccines. This evidence will lead to the development of personalized/stratified medicine and nutrition, tailored to individual dietary habits, metabolism and intestinal microbiota.

We collected fecal samples from laboratory mice kept at 13 universities in Japan, and analyzed the DNA samples extracted from these fecal samples using quantitative PCR (qPCR), which has been reported elsewhere to be able to analyze the phylum-level analysis of mouse fecal microbiota almost as precisely as next-generation sequencers do. In addition, we conducted qPCR assays targeting the family to species level, which has been used by many researchers as a useful molecular tool, to evaluate the effects of food ingredients on the gut microbiota of mice. These qPCR results were subjected to multivariate analysis, which showed that different phylogenetic clusters had formed at the phylum and family/genus levels of the taxonomic hierarchy at each breeding facility. The chi-square test was used to determine whether the formation of these strain clusters was correlated with internal factors such as mouse strain, sex, and age, or external factors such as water supply, bedding, and feed. The results show a significant correlation between differences in feed. These results indicate that the fecal microbiota of laboratory mice in Japan is affected by exogenous factors, as has been reported in other countries, and indicate the need for standardization of the mouse bacterial microbiota, or the consideration of alternative methods that do not rely on laboratory animals for accurately evaluating the functionality of orally consumed foods.