Quantitative and integrative analysis with historical perspective of inflammatory bowel disease research: Understanding etiology and pathogenesis as a result of an interactome or "network effect"

Abstract

Inflammatory bowel diseases (IBD) present a complex etiology associated with multiple factors interacting at different functional levels (i.e., risk genes, molecules, immune cells, biological processes and environment). The wide diversity of factors and associated variables studied over the last 3 decades in the context of IBD has challenged our ability to integrate the empirical information available in humans. Thus, our goal was to quantitatively analyze how representativeness of components of different functional levels and their interactions have changed over the last 30 years of IBD research in humans. A bibliographic search in Pubmed was performed aimed at extracting experimental studies on IBD in humans published between July 1990 and June 2020. This resulted in 25971 valid abstracts. A search for 1380 specific variables in these abstracts was conducted automatically using customized code in Matlab. The selection of these variables was based on recent reviews and, genetic and molecular catalogues. Publications showed a 5-fold annual rate increase from 1990 to the present. Representativeness of molecular and cellular components remained relatively constant over time, while genes showed a peak increase in publications between 1990 and 2005, with an increasing diversity of genes studied. Microbiota-sensing related variables showed a constant increase in publications. Specifically, components such as IL-1, IL-6, IL-10, NOD2, IFNγ, NF-κB, ATG16L1, TNF, T helper, Treg, macrophages and monocytes emerged as the most frequently studied elements. These components appear as integrative nodes in the network of variables involved in the manifestation of IBD. Our quantitative analysis with historical perspective supports the need to comprehend IBD as the resultant of an interactome or ‘network effect’. It also highlights the importance of elucidating the dynamic relations between nodes to comprise etiology and pathophysiology.