Recently, the largest genome wide association study with 53 000 cases of IBS across multiple cohorts was completed. In this study, the strongest risk factors for IBS included long-term or recurring antibiotic exposure in childhood, somatic pain conditions (back pain, limb pain, headaches), psychiatric conditions (anxiety, depression, excessive worrying) and fatigue.
The genes included CADM2, BAG6, PHF2/FAM120AOS, NCAM1, CKAP2/TPTE2P3, and DOCK9. Four of the six loci are highly implicated in anxiety/mood disorders and there was a strong genome-wide genetic correlation of IBS with anxiety, neuroticism, depression, insomnia, and schizophrenia.
Moreover, the high genetic correlations persisted after considering individuals with phenotypic overlap, suggesting common etiological pathways between IBS and anxiety/mood disorders.
Implication of the central nervous system was further suggested by the finding that the six identified loci regulate gene expression in many genes primarily expressed in the brain. As already mentioned under ENS above, the genes NCAM1 and CADM2 were two genes which regulate neural circuit formation and influence changes in white matter microstructure in IBS and mood disorders. Specifically, they regulate synaptic cell adhesion molecules, which are present in dorsal root ganglia sensory neurons throughout development, mediate adhesion of sensory axons, and induce neurite outgrowth.
The heritability of IBS was estimated to be around 6%, suggesting that disturbance of the brain-gut axis by environmental factors arising from the exposome such as early adversity, psychosocial stress, learned behaviours, diet, and possibly dysbiosis play a prominent role.
Considering these new genetic findings and the reported frequent comorbidities of IBS with other chronic pain and psychiatric conditions, it is becoming increasingly recognised that IBS is part of a constellation of symptoms that occur on a larger spectrum of altered brain-body interactions. This concept is consistent with the ‘somatic symptom disorder’ concept, previously proposed. The main co-occurring symptoms include hypersensitivity to multiple internal and external sensory stimuli, which could explain the observed association with a variety of seemingly unrelated external and internal factors, previously reported. Other co-occurring symptoms include mood problems, fatigue, and problems with sleep onset and maintenance, as well as memory disturbance.
The neurogenetic basis integrating mood/anxiety and central amplification of sensory inputs (‘central sensitisation’) based on many of these genetic hits have been well established.
There is growing evidence from clinical, preclinical, and genetic studies supporting the existence of shared p factors in IBS and often comorbid gastrointestinal and non-gastrointestinal pain conditions, as well as psychiatric conditions. Despite shared vulnerability genes, different influences from the environment (exposome) in particular during childhood ultimately shape the specific clinical phenotype.
The emerging disease model can explain the failure of reductionistic single mechanism targeted treatment approaches and is consistent with the evidence for the effectiveness of personalised multidisciplinary approaches involving behavioural, dietary, and pharmacological interventions.
Mayer, E.A., Ryu, H.J. & Bhatt, R.R. The neurobiology of irritable bowel syndrome.Mol Psychiatry 2023:28;1451–1465. https://doi.org/10.1038/s41380-023-01972-w