Identification of a Pain-Specific Gene Expression Profile for Pediatric Recurrent Abdominal Pain

Abstract

Objectives: Functional Abdominal Pain (FAP) and Irritable Bowel Syndrome (IBS) are common recurrent abdominal pain diagnoses with the hallmark, lack of inflammation. To identify a biological signature for IBS/FAP in the colon, this study used genetic profiling to uncover gene expression changes associated with IBS/FAP and abdominal pain.Methods: Patients (8 to 17 years) newly diagnosed with IBS or FAP were enrolled in the study. At diagnostic colonoscopy, three rectal biopsies were collected, and gene expression analysis was performed using a Qiagen PCR Array. Relative fold difference in gene expression for 84 pain-associated genes was calculated using the 2-ΔΔ Cq method compared with pain-free controls. Factors affecting pain burden (Pain Burden Interview; PBI) were analyzed, including age, sex, rectal inflammation, and gene expression. Data were analyzed using multiple stepwise linear regression and 2-tailed t tests (P ≤ 0.05).Results: Of the 22 total patients in the study, 19 were diagnosed with either IBS-Constipation (frequency of 5.26%), IBS-Diarrhea (47.37%), IBS-Mixed (10.53%), or FAP (36.84%). IBS/FAP patients reported significantly higher pain burden at the time of diagnosis compared to pain-free controls (p < 0.001), as well as significantly higher abdominal pain (p = 0.01). Of the 84 genes, expression of GRIN1 (p = 0.02), MAPK3 (p = 0.04), P2X4 (p = 0.04), and PTGES3 (p = 0.02) were all significantly associated with PBI score.Discussion: Abdominal pain associated with IBS/FAP in pediatric patients may be linked to the expression of GRIN1, MAPK3, P2X4, and PTGES3, pointing to potential novel therapeutic targets for management of recurring abdominal pain.

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction

“…The gut microbiome is a complex environment comprised of diverse bacteria that produce beneficial metabolites (e.g. short chain fatty acids, SCFA) critical to colon structure and function ( Willits et al, 2021 ). Although there is not a strictly defined “eubiotic” or healthy microbiome composition among humans (and mice), typical microbiomes are enriched in the bacteria phyla Firmicutes and Bacteroidetes .…”

“…Gut dysbiosis has been implicated in the pathogenesis of multiple diseases like inflammatory bowel diseases (IBD), autoimmune disorders (i.e. arthritis), diabetes, etc, while germ-free mice are protected in these models ( Willits et al, 2021 ). Restoration of the “healthy” microbiome often corresponds to improvement in other health conditions.…”

“…LPS can directly stimulate sensory neurons via Toll-like Receptor 4 (TL4) ( Opal, 2010 ) inducing depolarization, initiating cell signaling, and driving gene expression changes critical for increased neuronal activity ( Ochoa-Cortes et al, 2010 ). In addition to the direct effects of bacteria, short chain fatty acids (SCFAs) produced by microbes are used by gut wall epithelial cells as fuel for cellular metabolism ( Willits et al, 2021 ). When there are shifts in microbial colonization, this can change SCFA abundance and negatively affect host cells through a variety of mechanisms.…”

Effect of PTGES3 on the Prognosis and Immune Regulation in Lung Adenocarcinoma

“…Prostaglandin, produced in a COX2-dependent manner, could act on the epithelium to regulate intravasation and immune cell function in malignant cells [ 16 , 17 ]. Previous studies have revealed that PTGES3 participates in the regulation of various diseases, including pediatric recurrent abdominal pain, oscillatory shear stress, dyspepsia, and cancers [ 18 – 20 ]. In recent years, there has been an increasing interest in the tumorigenic role of PTGES3 in multiple cancer types, including colorectal cancer, prostate cancer, and acute lymphoblastic leukemia [ 8 , 22 ].…”

A pilot case-control study on the fecal microbiota of pediatric functional abdominal pain-not otherwise specified and the role of early life stress

“…To date, diagnosis is strictly based on symptoms and exclusion of other medical conditions, with reliable biomarkers still lacking. In general, FAPDs are referred to as disorders of the gut-brain-microbiota interaction, though etiology and pathophysiology are not yet fully understood [2][3][4] . Genetic, psychosocial, and physiological factors might contribute to the disruption and/or impairment of the gut-brain-microbiota interaction.…”