The inflammatory bowel diseases Crohn’s disease and ulcerative colitis typically start in the second or third decade of life, and lead to life-long recurring inflammation of the intestinal tract which cause severe symptoms and life-long suffering. The prevalence of these diseases has massively increased in ‘Western countries’ over the last 4 decades with now ~5 in 1,000 individuals affected. Over the last decade, the prevalence is also fast rising globally, especially in China. The reason for this increase remains entirely unclear, and is ascribed to unbeknownst ‘environmental factors’. Such factors are thought to trigger disease in an individual, especially if such individual carries genetic risk factors of disease. A major breakthrough has been the discovery of the coordinates across the genome that confer susceptibility, and the identification of individual risk genes.
The inflammation that ensues from such environment – gene interaction appears directed against the intestinal microbiota, which is the entirety of microbial life that is present in our intestines. The microbiota consists of hundreds of different bacterial species with great inter-individual variability, and overall constitutes 1-10-fold more bacterial cells than host cells. While these bacteria fulfil a very important function in health, they become the target of a pathological immune response in inflammatory bowel disease. To gain insight into the processes that lead to Crohn’s disease and ulcerative colitis, we develop methods to uncover how the pathological immune response contributes to disease, which arises from a complex gene-environment interaction. We thereby hope to unravel the fundamental basis of these diseases, a prerequisite for preventing and curing them.In this project, we have investigated how risk genes and environment collude to drive a pathological immune response. We developed methods to survey what the immunoglobulin response, which is markedly elevated in both Crohn’s disease and ulcerative colitis, is directed against. We observed that endoplasmic reticulum stress within the intestinal epithelium orchestrates a protective IgA immune response directed against select parts of the intestinal microbiome. Deficient ATG16L1-dependent autophagy in the intestinal epithelium triggered an elevated mucosal IgA response, which was similarly observed in humans homozygous for the Crohn’s disease-associated ATG16L1 risk variant.
We further identified hyperactivation of the endoplasmic reticulum sensor IRE1α as the driver of the Crohn’s disease-like inflammation that ensues when the intestinal epithelium is deficient in ATG16L1 and XBP1. This IRE1α hyperactivation occurs specifically in specialised Paneth cells, which secrete antimicrobial peptides and locate at the bottom of small intestinal crypts. This presents a hugely attractive target for small molecule drugs for the treatment of ileal Crohn’s disease.
Finally, by studying an open reading frame (C13orf31) of which a coding variant is linked to Crohn’s disease and leprosy, we surprisingly discovered an unprecedented enzyme of central purine metabolism, which is evolutionarily conserved from bacteria to man. This enzyme, which we named FAMIN, combines within a single catalytic pocket activities of an adenosine deaminase, a purine nucleoside phosphorylase and a methylthioadenosine phosphorylase, with that of an adenosine phosphorylase. The latter had been considered outrightly absent from eukaryotic metabolism, whereas the former had been thought to be the sole domain of namesake enzymes ADA, PNP and MTAP in any form of life. These enzymes where considered the sole sources of purine nucleobases adenine, guanine and hypoxanthine. FAMIN enables a so-called purine nucleotide cycle at the centre of a cell’s energy metabolism. Hence our goal of gaining insight into disease mechanism has surprisingly revealed a fundamentally novel enzymatic activity that is conserved from bacteria to man and is at the centre of a cell’s energy metabolism. This has wide ramifications for human health and disease, far extending beyond inflammatory bowel disease.
