Predicting the development of inflammatory bowel disease (IBD) by high-throughput profiling of the human serum antibody repertoire

Inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, progressive inflammatory diseases of the gastrointestinal (GI) tract, and are characterized by an inappropriate and uncontrolled immune response triggered by the gut microbiome in genetically susceptible individuals. (7,8) IBD affects more than two million Europeans, around 1.5 million Americans and several hundreds of thousands in non-Western populations. (8) The etiology and pathogenesis of IBD is thought to be of multifactorial origin, consisting of a complex interplay between host genetics, the gut microbiota, the host immune system and environmental triggers, e.g. lifestyle and dietary factors. (9,10) A disturbed balance of the gut microbiota is termed “dysbiosis”, which is characterized by altered gut microbial composition, including decreased abundances of multiple commensal bacterial genera (e.g., Faecalibacterium or Roseburia) and increased abundances of (potentially) pathogenic genera (e.g., Enterobacteriaceae or Ruminococcus). (11) Dysbiosis is strongly associated with the development and progression of IBD. It is hypothesized that an aberrant mucosal immune response is underlying the distinct alterations in the composition, taxonomy, and functionality of the gut microbiota in patients with IBD. (12) The intestinal mucosa constitutes an interface between the mucosal immune system and the luminal microenvironment, where a huge traffic of luminal antigens occurs, which are sampled across the intestinal epithelium by the immune system, acting as an important surveillance mechanism. In the context of IBD, intestinal barrier function is compromised, resulting in excessive uptake of luminal antigens (e.g., bacterial translocation) that may lead to an overactivation of the mucosal immune system, thereby triggering and aggravating intestinal inflammation. (13,14) 
Recently, advances in “multi-omics” technologies led to an increased advocacy of a systems-biology approach in order to gain more comprehensive insight into host genetics, the gut microbiome, host metabolism, and biochemistry, from which several factors may underlie the pathogenesis of IBD. For instance, recent breakthroughs have been made by combining metagenomics, metatranscriptomics, metaproteomics, and metabolomics data in patients with IBD. (15) Until recently, no such multi-omics technology existed that is able to capture the characteristics of host adaptive immunity in a fully comprehensive manner. To better understand the putative interactions that occur between host immunity and the gut microbiota, such technology would be of immense value to uncover potential disease features of IBD, relationships with clinical characteristics of patients, and identification of therapeutic targets.
The human gut contains a vast amount of bacterial species that are able to elicit a multitude of both mucosal and systemic immune responses. (16) Yet, it is unclear which bacterial antigens are targeted by human antibodies and how these immune reactions correspond to health and disease conditions. (17) The gut microbiome encodes for a tremendous number of genes that represent an enormous space for potential protein antigens. (18) As such, it is challenging to fully capture the full human antibody binding repertoire as conventional technologies (e.g. ELISAs) do not allow for such big antigen-antibody measurements at once. Recently, a technology referred to as phage-display immunoprecipitation sequencing (PhIP-Seq) has been developed that allows to systematically investigate hundred thousands of antigens in parallel, which has already been applied in the context of autoimmune diseases and viruses. (6,19-22) PhIP-Seq is based on a huge antigen library consisting of synthetic DNA oligonucleotides that are integrated into and displayed on bacteriophages. Subsequently, these bacteriophages are incubated with human serum to initiate antigen-antibody pairing with all serum reactive antibodies present in the sample. Antibody-bound bacteriophages are then extracted by immunoprecipitation and identified by next generation sequencing, generating a comprehensive library of the serum antigen binding profile. (6) Using PhIP-Seq, the presence of immune responses against hundred thousands of antigens can be detected simultaneously. Acquiring this high-resolution information about the functional serum antibody repertoire may lead to the discovery of specific antibody responses against gut microbiota as well antigens related to inflammation, autoimmunity, and allergy.