Standardization of the microbiota in mouse models ensures reproducibility of findings and avoids erroneous conclusions. Here, Robertson et al. demonstrate that the use of F2generation littermates is the superior method for standardization of the gut microbiota between experimental groups to minimize the influence of the microbiota in genotype-phenotype studies.
Defining the etiology of inflammatory bowel disease (IBD) continues to elude researchers, in part due to the possibility that there may be different triggers for a spectrum of disease phenotypes that are currently classified as either Crohn's disease (CD) or ulcerative colitis (UC). What is clear is that genetic susceptibility plays an important role in the development of IBD, and large genome-wide association studies using case-control approaches have identified more than 230 risk alleles. Many of these identified risk alleles are located in a variety of genes important in host-microbiome interactions. In spite of these major advances, the mechanisms behind the genetic influence on disease development remain unknown. In addition, the identified genetic risks have thus far failed to fully define the hereditability of IBD. Host genetics influence host interactions with the gut microbiota in maintaining health through a balance of regulated immune responses and coordinated microbial composition and function. What remains to be defined is how alterations in these interactions can lead to disease. The nature and cause of changes in the microbiota in patients with IBD are poorly understood. In spite of the large catalog of alterations in the microbiota of IBD patients, inflammation itself can alter the microbiota, leaving open the question of which is cause or effect. The composition and function of the gut microbiota are influenced by many factors, including environmental factors, dietary factors, and, as recent studies have shown, host genetic makeup. More than 200 loci have shown potential to influence the microbiota, but replication and larger studies are still required to validate these findings. It would seem reasonable to consider the combination of both host genetic makeup and the inheritance of the microbiota as interdependent heritable forces that could explain the nature of an individual's susceptibility to IBD or indeed the actual cause of IBD. In this review, we will consider the contribution of the host genetics, the microbiome, and the influence of host genetics on the microbiota to the heritability of IBD.
The aetiology and pathogenesis of inflammatory bowel disease (IBD) remains unclear but involves a complex interplay between genetic risk, environmental exposures, the immune system and the gut microbiota. Nearly two decades ago, the first susceptibility gene for Crohn's disease, NOD2, was identified within the IBD 1 locus. Since then, over 230 genetic risk loci have been associated with IBD and yet NOD2 remains the strongest association to date. As an intracellular innate immune sensor of bacteria, investigations into host-microbe interactions, involving both innate and adaptive immune responses, have become of particular interest in understanding the pathogenesis of IBD. Advancements in sequencing technology have lead to the groundbreaking characterization of the gut microbiota and its role in health and disease. While an altered microbiome has been described for IBD, whether it is a cause or an effect of the intestinal inflammation has yet to be determined. Moreover, the bidirectional relationship between the gut microbiota and the mucosal immune system adds to the multifaceted complexity of intestinal homeostasis. A better understanding of how host genetics, including NOD2, influence immune-microbe interactions and alter susceptibility to IBD is necessary in order to develop therapeutic and preventative treatments.
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