Evidence That Independent Gut-to-Brain and Brain-to-Gut Pathways Operate in the Irritable Bowel Syndrome and Functional Dyspepsia

A 1-Year Population-Based Prospective Study

N. A. Koloski; M. Jones; N. J. Talley


Aliment Pharmacol Ther. 2016;44(6):592-600. 

In This Article


The irritable bowel syndrome (IBS) and functional dyspepsia (FD) are two of the most prevalent functional gastrointestinal disorders (FGIDs).[1] While by definition FGIDs are characterised by GI symptoms that are not explained by known structural or organic abnormalities,[2] there has been a recent shift in the conceptualisation of these disorders as potentially disorders of the brain–gut axis.[3,4]

The brain–gut axis refers to the biochemical signalling taking place between the gastrointestinal tract and the central nervous system, and this linkage may be a key in the pathogenesis of the FGIDs.[4] Brain-to-gut pathways are considered to be primarily involved in these conditions based on several sources of evidence, including epidemiological studies showing that psychological factors are independent risk factors for meeting criteria for a FGID,[5–8] psychological treatment studies that show symptom improvement with psychological therapy is superior to wait listing[9,10] and evidence from pathophysiological and animal studies.[11–13] However, more recent evidence is emerging that dominant gut-to-brain pathways may also operate in a major subset of these disorders.[3,14–18]

Some of the first direct evidence in humans that the brain–gut relationship in FGIDs may be bidirectional has come from epidemiological studies. Koloski et al. prospectively followed up 1002 cases and controls randomly selected from the Australian electoral roll with a postal survey 12 years after they first participated in the study.[3] FGIDs were defined using the Rome II criteria and psychological distress was assessed using the Delusions Symptom State Inventory at baseline and follow-up. They showed that among people free of a FGID at baseline, higher levels of anxiety but not depression at baseline was a significant independent predictor of developing new onset FGIDs 12 years later. Among those who did not have elevated levels of anxiety and depression at baseline, individuals with a FGID at baseline had significantly higher levels of anxiety and depression at follow-up. Further validation of these findings, however, is yet to be published in full.

Animal studies in mice further support gut-to-brain signalling through the microbiome that can modulate anxiety.[19] In patients with IBS, significantly higher baseline cytokine levels have been observed compared with healthy controls including tumour necrosis factor alpha, IL-1beta and IL-6.[15] Furthermore, lipopolysaccharide-induced tumour necrosis factor alpha production significantly correlated with anxiety in IBS (r value of 0.59);[15] higher circulating tumour necrosis factor alpha levels have also been reported in FD.[16] These data suggest low grade gut inflammation in IBS and FD (e.g. via mast cell or eosinophil infiltration) with cytokine release may at least in a subset directly induce the observed psychological comorbidity so deeply characteristic of the syndromes.[20–22]

While studies provide support for a bidirectional brain–gut relationship in FGIDs, the concept of a distinct gut-to-brain syndrome, potentially implying the need for a different treatment algorithm compared to those with brain-to-gut dysfunction, remains controversial. Furthermore, no studies have confirmed these findings using a shorter time frame or with the most recent Rome III criteria, or with alternative measures of psychosocial distress. Therefore, we aimed to extend the findings from previous research applying a shorter time frame. We conducted a 1-year prospective follow-up study of Rome III defined FGIDs including IBS and FD using a valid psychological questionnaire designed specifically for people with physical problems. We hypothesised there is a specific gut-to-brain syndrome, where GI symptoms precede the onset of psychological distress in about half of all those who eventually suffer with an FGID.