Brain-Gut FeelingWritten By: N A Koloski; M Jones; J Kalantar; M Weltman; J Zaguirre; N J Talley
The Brain-Gut Pathway in Functional Gastrointestinal Disorders Is Bidirectional
A 12-Year Prospective Population-Based Study
The ‘little brain’ in the GI tract’s enteric nervous system is intimately linked to the central nervous system, and this linkage may be key in the pathogenesis of Functional Gastrointestinal Disorders.
Here we report a novel, comprehensive, prospective longitudinal population-based study assessing the relationship between psychological factors and FGIDs. The primary aim of the study was to determine whether it is the brain that drives the onset of functional gut symptoms, or whether in FGIDs perhaps the gut drives the brain as manifest by psychological distress, particularly anxiety or depression. We found support for both the brain–gut and gut–brain hypothesis in FGIDs. For example, among subjects who did not report having a FGID at baseline, we observed that those who had higher levels of anxiety at baseline (but not depression) were significantly more likely to develop a FGID 12 years later. However, baseline anxiety and depression were not significantly correlated with any specific GI symptom at follow-up. We also found support for the alternative gut–brain hypothesis in FGIDs. That is, we observed among subjects who did not have clinically elevated levels of psychological distress at baseline, a FGID diagnosis at baseline was significantly associated with higher levels of subsequent anxiety and depression at follow-up. For specific GI symptoms, we observed that abdominal pain, postprandial fullness, early satiety and bloating, but not bowel symptoms, were significantly correlated with follow-up anxiety and depression, although the associations were all modest.
As part of the study we examined the incidence of any FGID and IBS and FD over a 12-year period. We found that 34% of subjects developed a new onset FGID over 12 years; a total of 9% developed new onset IBS. This onset rate for IBS was lower than reported by others, including Ford et al in a 10-year population-based follow-up study who found 15% developed new onset IBS; however, their study population was older and they used the less stringent Manning criteria for IBS. The incidence of FD was 4%, which is similar to previously published figures. We also showed that the number of people who did not meet criteria for a FGID at follow-up was similar to the new onset of these conditions, indicating that the prevalence of FGIDs is remarkably stable over time. This confirms previous longitudinal studies of up to 12 years, showing that the prevalence of IBS and FD is relatively stable over time in a population, although fluctuations in both the presence and severity of symptoms are common.
These data provide some of the first direct evidence to indicate that the brain–gut pathway is bidirectional; that is, both brain–gut and gut–brain dysfunction may be occurring in FGIDs. While numerous studies have found an association between psychological distress and FGIDs, supporting a potential brain to gut mechanism, the majority of these studies were cross sectional and did not allow for true causal associations to be assessed. Of the few prospective studies that have been conducted, only IBS has been assessed. Gwee et al evaluated 75 patients admitted to hospital for gastroenteritis. Of the 22 patients who subsequently developed IBS symptoms, they reported higher scores for anxiety, depression, somatic distress and neuroticism at their hospital admission compared with those who returned to normal bowel function. These findings remained significant even after controlling for the confounding effects of having an acute illness. However, the inclusion of hospital patients with post-infectious IBS makes it difficult to generalise these findings to all people with IBS. Koloski et alprospectively evaluated 361 patients with unexplained abdominal pain and 120 controls with a questionnaire every 4 months over a 12-month period. Psychological distress was higher in controls who reported having GI symptoms compared with those who did not at the 4-month, 8-month and 12-month follow-ups, reaching significance at the 8-month and 12-month follow-ups. However, the short follow-up time, failure to include subjects meeting the threshold for IBS, and smallish sample sizes make it difficult to generalise the findings to FGIDs.
The gut–brain finding in FGIDs in this study is novel but deserves further replication. One possible explanation is low-grade intestinal inflammation with mast cell infiltration and activation sets off the release of cytokines and chemokines into the circulation that alter central nervous system functioning, inducing anxiety. Thus TNFα levels have been shown to correlate with anxiety in IBS, but more data are needed.
We also aimed to explore whether the brain–gut mechanism is the same in two specific FGIDs, although here the sample sizes were smaller. In IBS, we found clear-cut support for the brain–gut hypothesis; that is, that psychological distress drives IBS symptoms. For example, among subjects who did not report having IBS at baseline, we observed that those who had higher levels of anxiety and depression at baseline were significantly more likely to develop IBS 12 years later. The sample size was too small to explore IBS subgroups. Gwee et alalso showed that psychological distress predates post-infectious IBS. However, their sample was limited to hospital patients with IBS who had severe gastroenteritis at baseline.
We found similar results for FD. Among subjects who did not report having FD at baseline, we observed that those who had higher levels of depression at baseline were significantly more likely to develop FD 12 years later. However, this was not the case for anxiety. These findings are in line with an earlier prospective study by Koloskiet al. They found that psychological distress was significantly higher in controls who reported having GI symptoms, including abdominal pain, compared with those who did not at the 8-month and 12-month follow-ups. However, this study was limited by the failure to include people meeting Rome criteria for FD and a short follow-up time. Our study extends these results by applying a longer 12-year follow-up and including people who met Rome II criteria for FD, although the diagnosis was not endoscopically confirmed. In contrast, there was no evidence for the alternative gut–brain hypothesis in IBS or FD. Thus it appears that higher levels of psychological distress may be a precursor to the subsequent development of IBS and FD symptoms, but not vice versa.
For FGIDs as a whole group, we observed that the brain–gut and gut–brain mechanisms appear to be in operation. It is possible that the gut–brain direction may be dominant in other individual FGIDS and this is driving the association; however, this needs further investigation.
This study was methodologically superior compared with previous longitudinal work. We prospectively followed up a community sample of healthy controls and cases to see if psychological factors measured at baseline predicted the subsequent development of FGIDS, including IBS and FD, over a 12-year period, and vice versa. The original sample was randomly selected from the Australian electoral roll, which by law requires that people aged 18 years and over be registered. Therefore, the results should be generalisable and unbiased. The original sample responded to the first questionnaire with a 72% response rate. We then achieved a 60% response rate to our follow-up questionnaire 12 years later. We did not find any major systematic differences between responders and non-responders, although responders to the 12-year follow-up were more likely to have a FGID diagnosis at baseline. We also used well validated measures of psychological symptoms, including the DSSI which provides published cutoffs for clinically elevated levels of distress. However, we do not know whether these findings would also apply to other psychological factors, particularly somatisation. FGIDS were diagnosed according to modified but well accepted Rome II criteria using a validated questionnaire assessing functional GI symptoms. Moreover, we excluded subjects who had self-reported organic diagnoses that may have been able to explain FGID symptoms, helping ensure that the FGIDs were not misclassified. We also found very low overlap rates (of 1%) between IBS and FD at baseline and follow-up in this particular cohort.
There are several implications resulting from this study. First, FGIDs in the community are chronic and while there is a waxing and waning of symptoms they do not usually disappear on their own, making them an important target for treatment. Second, in the FGIDs, including IBS and FD, the hypothesis that early identification and treatment of psychological distress in patients presenting with abdominal pain like symptoms will help prevent the subsequent development of persistent FGIDs now needs testing. In addition, adequate management and treatment of FGIDs may also help to prevent subsequent development of anxiety and depression.
In conclusion, it appears that central nervous dysfunction in the FGIDs may be bidirectional. In IBS and FD it also appears that the brain–gut pathway is dominant.