J Neurogastroenterol Motil.  2018 Jan;24(1):96-106. 10.5056/jnm17021.

Gene Expression Profiling and Assessment of Vitamin D and Serotonin Pathway Variations in Patients With Irritable Bowel Syndrome

• Dussik CM
• Hockley M
• Grozić A
• Kaneko I
• Zhang L
• Sabir MS
• Park J
• Wang J
• Nickerson
• Yale SH
• Rall CJ
• Foxx-Orenstein AE
• Borror CM
• Sandrin TR
• Jurutka PW

• KMID: 2417277
• DOI: http://doi.org/10.5056/jnm17021

Abstract

BACKGROUND/AIMS
Irritable bowel syndrome (IBS) is a multifaceted disorder that afflicts millions of individuals worldwide. IBS is currently diagnosed based on the presence/duration of symptoms and systematic exclusion of other conditions. A more direct manner to identify IBS is needed to reduce healthcare costs and the time required for accurate diagnosis. The overarching objective of this work is to identify gene expression-based biological signatures and biomarkers of IBS.
METHODS
Gene transcripts from 24 tissue biopsy samples were hybridized to microarrays for gene expression profiling. A combination of multiple statistical analyses was utilized to narrow the raw microarray data to the top 200 differentially expressed genes between IBS versus control subjects. In addition, quantitative polymerase chain reaction was employed for validation of the DNA microarray data. Gene ontology/pathway enrichment analysis was performed to investigate gene expression patterns in biochemical pathways. Finally, since vitamin D has been shown to modulate serotonin production in some models, the relationship between serum vitamin D and IBS was investigated via 25-hydroxyvitamin D (25[OH]D) chemiluminescence immunoassay.
RESULTS
A total of 858 genetic features were identified with differential expression levels between IBS and asymptomatic populations. Gene ontology enrichment analysis revealed the serotonergic pathway as most prevalent among the differentially expressed genes. Further analysis via real-time polymerase chain reaction suggested that IBS patient-derived RNA exhibited lower levels of tryptophan hydroxylase-1 expression, the enzyme that catalyzes the rate-limiting step in serotonin biosynthesis. Finally, mean values for 25(OH)D were lower in IBS patients relative to non-IBS controls.
CONCLUSIONS
Values for serum 25(OH)D concentrations exhibited a trend towards lower vitamin D levels within the IBS cohort. In addition, the expression of select IBS genetic biomarkers, including tryptophan hydroxylase 1, was modulated by vitamin D. Strikingly, the direction of gene regulation elicited by vitamin D in colonic cells is "opposite" to the gene expression profile observed in IBS patients, suggesting that vitamin D may help "reverse" the pathological direction of biomarker gene expression in IBS. Thus, our results intimate that IBS pathogenesis and pathophysiology may involve dysregulated serotonin production and/or vitamin D insufficiency.

Keyword

25-Hydroxyvitamin D; Biomarkers; DNA Microarray; Serotonin; Tryptophan hydroxylase

MeSH Terms

Biomarkers
Biopsy
Cohort Studies
Colon
Diagnosis
Gene Expression Profiling*
Gene Expression*
Gene Ontology
Health Care Costs
Humans
Immunoassay
Irritable Bowel Syndrome*
Luminescence
Oligonucleotide Array Sequence Analysis
Polymerase Chain Reaction
Real-Time Polymerase Chain Reaction
RNA
Serotonin*
Transcriptome
Tryptophan
Tryptophan Hydroxylase
Vitamin D*
Vitamins*
Biomarkers
RNA
Serotonin
Tryptophan
Tryptophan Hydroxylase
Vitamin D
Vitamins