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



Participants (n = 2885) were a random population sample from Newcastle and Hunter New England, Australia who responded to a validated survey in 2012 and agreed to be contacted for future research. Of these, n = 1900 completed the 1-year follow-up survey (response rate = 67.6%).


The original and 1 year follow-up survey contained the follow measures

  • Modified Rome III Questionnaire.[23] This is a self-report instrument that measures functional gastrointestinal symptoms experienced over the prior 3 months. Previous testing has shown this instrument to be reliable and valid. This measure was used to diagnose IBS and FD.

  • Hospital Anxiety and Depression Scale was used to assess psychological distress.[24] The questionnaire contains 14 items that assess anxiety (seven items) and depression (seven items). Each item is rated on a four-point scale ranging from 0 to 3, such that each sub-scale has a maximum score of 21. Higher scores on the Hospital Anxiety and Depression Scale indicate depression or anxiety in a patient. A score of >11 of 21 on the Hospital Anxiety and Depression Scale domains was used to indicate elevated levels of anxiety and depression, respectively.[24]

  • SF-12 was used to assess health-related quality-of-life.[25] This is a 12-item generic quality-of-life measure assessing mental and physical functioning over the past 4 weeks. Examples of questions assessing mental functioning included 'Have you felt calm and peaceful?' and 'Have you felt down hearted and blue?' Physical functioning was addressed with questions such as 'During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)?

We also recorded demographics age, gender and educational level attained (<high school, high school, >high school).

Rome III Definitions2

Irritable Bowel Syndrome. Symptoms of recurrent abdominal pain or discomfort and a change in bowel habit, with symptoms experienced on at least 2–3 days in the last 3 months. Two or more of the following must occur at least sometimes (>25% of the time):

  • Pain is relieved by a bowel movement

  • Onset of pain is related to a change in frequency of stool

  • Onset of pain is related to a change in the appearance of stool.

Constipation predominant IBS was defined by the presence of hard but not loose stools.

Diarrhea predominant IBS was defined by the presence of loose but not hard stools.

Functional Dyspepsia. The presence of one or more of the following symptoms at least 1 day a week in the last 3 months.

  • Post-prandial fullness

  • Early satiation

  • Epigastric pain

  • Epigastric burning

Epigastric pain syndrome (EPS) was defined by the presence of epigastric pain and/or burning. Post-prandial distress syndrome (PDS) was defined by the presence of post-prandial fullness and/or early satiation.

Procedures. The study was approved by the Hunter New England Human Ethics Committee. Participants who had indicated in the original survey that they did not object to being contacted for future research were sent the 1-year follow-up survey. Participants in the follow-up study were sent a participant information sheet outlining the study, the survey and a reply paid envelope. We used the Dillman Total Design Method[26] for the follow-up of nonresponders. The follow-up protocol included a reminder/thank you letter sent to all participants at week 1, a replacement survey sent out to nonresponders at week 4 and a reminder/thank you letter sent at week 5 to those nonresponders identified at week 4. Additional measures to maximise response rates included a personalised covering letter personally signed by the chief investigator, an easy to understand attractive coloured questionnaire booklet, and postage stamps on envelopes. Participants did not receive any remuneration for their participation.

Statistical Analyses

The sample is described with respect to baseline prevalence of IBS and FD including 95% confidence intervals and with respect to disappearance and onset of IBS and FD between baseline and follow-up ( Table 1 ).

The formal statistical analysis sought to understand the bidirectional relationship between change in gut symptoms (IBS and FD) and changes in mood and quality-of-life (QoL). This was approached in two ways. The first evaluated brain–gut and gut–brain longitudinal predictions. In individuals who were stratified as free of IBS or meeting IBS criteria at baseline anxiety and depression scores were separately used to predict IBS status at 1-year follow-up using unconditional logistic regression. Since both anxiety and depression scales are reported on arbitrary numeric scales where a single point change is not considered clinically significant, interpretation of the odds ratios for baseline anxiety and depression predicting follow-up IBS status was facilitated by dividing the raw scores by their standard deviation. This results in a one point change corresponding to a one standard deviation change which is large in relative terms. While there is no independent definition of 'large' or 'small', clinical trials are often powered for the equivalent of 0.5 or even 0.3 standard deviations. Another point of calibration is that in terms of degree of discrimination between groups, a standard deviation of 1.0 would correspond to an area under the receiver–operator characteristic curve of 0.77, which represents discrimination clearly above clinical 'noise'. This was repeated for FD and represents a brain-to-gut relationship. These results are reported in Table 2 . Subsequently, in individuals stratified as normal or elevated on anxiety at baseline, IBS and FD status were separately used to predict anxiety score using linear regression. Due to non-Normal distribution of residuals formal statistical inference has been based on the nonparametric bootstrap using 2000 replications. This was repeated for depression. A score of >11 of 21 on the Hospital Anxiety and Depression Scale domains was used to indicate elevated levels of anxiety and depression respectively. These results are reported in Table 3 and represent a gut–brain relationship. The second approach classified individuals into four categories representing their change in FD status (Table S1) and change in IBS status (Table S2) and described the corresponding change in anxiety, depression and QoL.

An analysis to determine the order of the natural history of FGIDs (IBS or FD) and mood disorders (anxiety or depression) was also undertaken in the subset of individuals for whom in the order of appearance during the course of the study could be ascertained. Individuals who qualified for an FGID or a mood disorder (but not both or neither) and who subsequently developed the other condition were considered. Individuals who qualified for a mood disorder at baseline and an FGID at follow-up were considered brain-to-gut, while those who qualified for an FGID at baseline and a mood disorder at follow-up were considered a gut-to-brain direction.