The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease

Abstract

Background and Aims Protein profiling in patients with inflammatory bowel diseases (IBD) for diagnostic and therapeutic purposes is underexplored in IBD. This study analysed the association between phenotype, genotype and the plasma proteome in IBD. Methods Ninety-two (92) inflammation-related proteins were quantified in plasma of 1,028 patients with IBD (567 Crohn’s disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci (pQTL) analysis). Intestinal mucosal RNA sequencing and fecal metagenomic data were used for complementary analyses. Results Thirty-two (32) proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins independent of active inflammation. Sixty-nine (69) proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 (FUT2) gene (rs602662) and two independent cis-pQTLs of C-C motif chemokine 25 (CCL25) affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression (e)QTL-variant (rs3745387) of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of fecal butyrate-producing bacteria. Conclusions This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD and identifies disease-associated pathways that may help to improve disease management in the future.

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

“…In the present study, a higher adherence to a pattern high in sugar and refined carbohydrates was associated with lower levels of plasma FGF-19, a result that was robust throughout all stratified analyses for IBD type, disease activity and protein intake and remained significant after adjusting for surgical history, a known risk factor for impaired FGF-19 signalling [22]. FGF-19 is a protein produced mainly in the ileum upon activation of the Farnesoid X Receptor (FXR), which inhibits hepatic bile acid synthesis [26].…”

“…Interestingly, coffee contains chlorogenic acid (CGA), a compound to which this IL-12-lowering effect has previously been attributed to, since this is consistent with data from experimental studies showing the inhibition of IL-12 secretion upon stimulation of adenosine 2A receptors (of which CGA is a common ligand) [47]. Of note, cigarette smoke exposure is often associated with decreased plasma IL-12B levels, also in patients with IBD [22]. In IBD, the IL12B gene, encoding for the p40 subunit of IL-12, is a known IBD susceptibility locus [48].…”

“…FGF-19 is a protein produced mainly in the ileum upon activation of the Farnesoid X Receptor (FXR), which inhibits hepatic bile acid synthesis [26]. Lower FGF-19 levels have been observed in IBD, especially in CD patients with ileal disease involvement or surgical history [22]. Previous studies have demonstrated that intestinal inflammation, together with impaired intestinal barrier integrity and malabsorption of bile acids, is associated with the decreased release of FGF-19 into the circulation [27][28][29].…”

“…Subsequently, the analysis was performed stratified by CD (n = 264) and UC (n = 190) while adjusting for disease-specific clinical scores, medication use and surgical history (Supplementary Methods). Finally, we stratified according to disease activity, i.e., separating patients with quiescent (n = 239) and active disease (n = 200) [22] and according to protein consumption deviating from recommended intake [8], i.e., separating patients with sufficient (n = 256) and insufficient (n = 193) protein intake in grams per kg of bodyweight. Protein intake below the recommended daily allowance (0.8 g/kg in remission and 1.2 g/kg for active disease) was deemed as insufficient intake [14,23].…”

Harnessing the Biology of Canine Intestinal Organoids to Heighten Understanding of Inflammatory Bowel Disease Pathogenesis and Accelerate Drug Discovery: A One Health Approach

“…Although IBD was initially thought to be due to specific pathogen exposure, current studies propose that perturbations in commensal enteric bacteria play a role in the development of IBD ( Packey and Sartor., 2008 ). Commensal GI microbiota may contribute to the development of IBD by carrying atypical virulence factors or constituting abnormal compositions of the microbiota resulting in an altered metabolome ( Bourgonje et al, 2021 ). On the other hand, it has been speculated that if the host has defective intestinal barrier function resulting in increased immune response against commensals.…”