The inter-relationship between gut microbes and metabolic processing of nutrients is well appreciated. While intestinal microbes thrive in a safe and nutrient-rich niche, the host profits from their metabolic activity, which renders otherwise indigestible foods available. Exemplifying this, animals harbouring a microbiota require 30% less caloric intake to maintain their body weight than their germ-free counterparts. Emerging studies indicate that beyond its caloric contribution, diet plays a dynamic and previously unrecognized role in shaping both bacterial ecology and the immune system. Pattern recognition receptors including TLRs, inflammasomes, C-type lectins such as dectin-1 and RNA-sensing retinoic acid-inducible gene (RIG) -like helicases such as RIG-I and melanoma differentiation-associated gene-5 (MDA5), relay microbial cues to the immune system. Interestingly free fatty acids and ATP induce downstream signalling of TLR2/4 and the inflammasome, respectively.[122, 123] In addition to pattern recognition receptors other receptors expressed on immune cells can sense the metabolic environment including the serine/threonine kinase mammalian target of rapamycin (mTOR), double-stranded RNA-activated protein kinase (PKR), the aryl hydrocarbon receptor (AHR), and diverse nuclear hormone receptors. The metabolism from otherwise indigestible plant polysaccharides into short-chain fatty acids (SCFA) by the microbiota and its impact on immune system function has been extensively investigated (Fig. 1b). Intake of fibres dictates the amount of metabolized SCFA available in the lumen and this in turn shapes intestinal microbial ecology. Conversely, SCFA have an impact on the immune system. For example, low abundance of the SCFA butyrate diminishes T-cell derived cytokines and reinforces intestinal barrier integrity. Another microbial-processed SCFA, acetate binds to the G-protein coupled receptor 43 (GPR43), which is essential for resolution of intestinal inflammation. In another study, acetate has been linked to promote and maintain intestinal epithelial integrity and so protect against the enteropathogen Escherichia coli (O157 : H7). Experiments conducted in gnotobiotic mice associated with prototypic human microbes have demonstrated that dietary habits have a rapid, profound and predictable impact on the relative abundance of species and genes making up the microbiota and the microbial metagenome, respectively.[23, 132, 133] Supporting this, microbial communities were shared among mammalian species and humans with similar dietary habits. However, a direct relationship between dietary compounds and maturation of the immune system has only recently been shown. Physiological signalling through AHR, which was originally discovered for its role in detoxification processes in the liver, has been shown to be crucial for the formation of intra-epithelial lymphocytes and isolated lymphoid follicles and AHR signalling promotes the accumulation of innate lymphoid cells. Cruciferous vegetables, such as broccoli, contain a physiological ligand for the AHR and its deprivation recapitulated the phenotype observed in Ahr−/− mice. Defective AHR signalling resulted in impaired mucosal protective mechanisms as shown by exacerbated DSS-induced colitis or increased susceptibility to C. rodentium infection. Future studies should offer exciting new avenues into the cross-talk between the host, microbes, metabolism and immunity.
Autoimmune and allergic immune disorders such as inflammatory bowel disease, multiple sclerosis or asthma are rapidly increasing in westernized countries.[137-139] Genetic background certainly plays a role in disease predisposition in some individuals but genetics alone does not offer a satisfactory explanation for the observed increase in incidence. In 1989 Strachan formulated the hygiene hypothesis based on the observation that hay fever was less prevalent in children with older siblings. The hygiene hypothesis argues that increased sanitation in industrialized countries led to decreased infections with common pathogens and a concomitant rise in allergic disorders. In the last decades westernized countries undertook drastic measures to increase hygiene including water decontamination, food pasteurization and sterilization, uninterrupted cold chain, vaccination and wide-use of antibiotics. Accumulating evidence indicates a shift in the composition of indigenous intestinal microbes in westernized countries. Changes in lifestyle in industrialized countries such as antibiotic usage and dietary habits undoubtedly impact the microbiota composition. In line with this, the microbial communities of European children are dramatically dissimilar from those of rural Africans as demonstrated in a metagenomic study. In addition to a greater microbial diversity, the cellulose-hydrolysing and xylan-hydrolysing bacteria Prevotella and Xylanibacter were only detected in children from Africa and this was consistent with increased SCFA. However experimental evidence that changes in type and level of microbial stimulation can impact disease outcome, are mainly supported by animal models. The non-obese diabetic (NOD) mouse and the biobreeding diabetes-prone (BB-DP) rat develop a disease that shares many similarities with Type 1 diabetes and are therefore a good animal model for the study of Type 1 diabetes. Interestingly, the incidence of Type 1 diabetes in these animals was correlated to the hygiene conditions prevailing in the animal facility. The incidence of diabetes was lower in animals raised under conventional status compared with animals raised under specific pathogen-free (SPF) status.[143, 144] A direct link between microbiota and Type 1 diabetes was shown in NOD mice deficient for the TLR adaptor molecule MyD88. Whereas germ-free MyD88−/− NOD mice had a high diabetes incidence, their SPF counterparts were protected from disease. The authors concluded that the normal microbial stimuli protect from diabetes in a MyD88-independent manner. In a model of ovalbumin-induced asthma, an increased number of infiltrating lymphocytes and eosinophils with more pronounced secretion of Th2 cytokines was observed in airways of germ-free mice compared with SPF mice. Similarly, in a model of peanut allergy, mice treated with antibiotics or deficient in TLR4 underwent anaphylaxis, suggesting that bacterial-induced TLR4 signalling is critical in limiting inflammation. Clinical studies comparing the microbiota from healthy controls and patients suffering from allergic or autoimmune disease are in agreement with the animal models.[138, 148] For instance, patients suffering from Crohn's disease had a reduced diversity in the microbiota especially for the Firmicutes phylum.[149, 150] Administration of Faecalibacterium prausnitzii to mice, a species of Firmicutes that was markedly depleted in Crohn's disease patients, could ameliorate disease outcome in experimental 2,4,6-trinitrobenzenesulphonic acid-induced colitis. Although some studies comparing the microbial composition of atopic allergic individuals with that of healthy individuals observed differences,[152, 153] others could not reproduce this finding. Such comparative studies have to be interpreted with caution because dysbiosis could be a consequence rather than the cause of inflammatory disease. Nonetheless evidence provided from animal models and clinical studies is accumulating to support the concept that immune regulation can be influenced by the composition of intestinal microbes.