The Brain-Gut Pathway in Functional GI Disorders
Objective Psychological factors are known to be associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD). No prospective studies have evaluated whether it is the brain (eg, via anxiety) that drives gut symptoms, or whether gut dysfunction precipitates the central nervous system features such as anxiety. In a 12-year longitudinal, prospective, population-based study, we aimed to determine the directionality of the brain–gut mechanism in FGIDs.
Design Participants (n=1775) were a random population sample from Australia who responded to a survey on FGIDs in 1997 and agreed to be contacted for future research; 1002 completed the 12-year follow-up survey (response rate =60%), with 217, 82 and 45 people meeting Rome II for new onset FGIDs, IBS and FD, respectively. Anxiety and depression were measured using the Delusions Symptom States Inventory at baseline and follow-up.
Results Among people free of a FGID at baseline, higher levels of anxiety (OR 1.11; 95% CI 1.03 to 1.19, p=0.006) but not depression at baseline was a significant independent predictor of developing new onset FGIDs 12 years later. Among people who did not have elevated levels of anxiety and depression at baseline, those with a FGID at baseline had significantly higher levels of anxiety and depression at follow-up (mean difference coefficient 0.76, p<0.001 and 0.30, p=0.01 for anxiety and depression, respectively). In IBS higher levels of anxiety and depression at baseline were predictive of IBS at follow-up, while only depression was predictive of FD at follow-up.
Conclusions The central nervous system and gut interact bidirectionally in FGIDs.
The functional gastrointestinal disorders (FGIDs) manifest as a characteristic combination of chronic or recurrent symptoms arising from the gastrointestinal (GI) tract. FGIDs are extremely common, affecting at least one-third of the population. Half of all patients with gastrointestinal complaints seen in primary care have FGIDs, and up to half of all referrals to specialist gastroenterologists are for FGIDs. FGIDs generally persist lifelong and significantly impair quality of life.
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 FGIDs. Multiple pathophysiological disturbances have been identified in subsets with these disorders, including disordered motility, visceral hypersensitivity, abnormal gas handling, disturbed intestinal flora and low-grade intestinal inflammation (particularly mast cell and T-lymphocyte infiltration). A cytokine response has been documented in irritable bowel syndrome (IBS) and functional dyspepsia (FD), and tumour necrosis factor α (TNFα) levels have correlated with anxiety; cytokines have been postulated to drive psychological distress in the FGIDs. However, a unifying theory that explains all of the FGIDs has remained elusive, although there is emerging agreement that gut dysfunction (perhaps driven by low-grade inflammation secondary to increased permeability) is likely to be key in a subset of people.
Another promising unifying theory to explain FGIDs is primary central nervous system dysfunction, which clinically manifests as psychological distress and may drive GI distress. A plethora of literature supports a role for psychological factors, including anxiety, depression and somatisation in FGIDs. A number of studies have shown elevated psychological distress (anxiety, depression and somatisation) in outpatients and volunteers with FGIDs, and among non-consulters from the community with FGIDs. A causal link is supported by symptom improvement following psychological interventions such as cognitive behavioural therapy versus usual care or placebo. Randomised controlled trials have confirmed that antidepressants, both tricyclics and serotonin reuptake inhibitors, are superior to placebo in IBS, although their role in FD remains uncertain and their exact mechanism of action is unknown. Pathophysiological studies and longitudinal studies have shown an association of FGIDs with stress, although the majority of these studies only assessed IBS and FD, have been retrospective and have not been methodologically rigorous enough to ascertain if there is a causal connection. Acute infectious gastroenteritis can precipitate IBS and FD presumably in people genetically predisposed to these conditions, and in those who develop post-infectious IBS, the risk appears to be increased if there is pre-existing psychological distress.
Thus, there is evidence that a brain to gut pathway may account for GI symptoms in some FGIDs, but other evidence points to the gut being the primary driver of symptoms (via gut to brain connections perhaps through cytokines). However, it is not known which of the various FGIDs, if any, is dominant. In this study, we aimed to determine whether it is likely that a brain–gut or a gut–brain pathway operates in the FGIDs. We also aimed to explore if the brain–gut or gut–brain pathways are the same for all FGIDs by looking at these pathways in IBS and FD separately. We hypothesised that anxiety and depression drive the new onset of all FGIDS, including IBS and FD.
Abstract and Introduction
Abstract
Objective Psychological factors are known to be associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD). No prospective studies have evaluated whether it is the brain (eg, via anxiety) that drives gut symptoms, or whether gut dysfunction precipitates the central nervous system features such as anxiety. In a 12-year longitudinal, prospective, population-based study, we aimed to determine the directionality of the brain–gut mechanism in FGIDs.
Design Participants (n=1775) were a random population sample from Australia who responded to a survey on FGIDs in 1997 and agreed to be contacted for future research; 1002 completed the 12-year follow-up survey (response rate =60%), with 217, 82 and 45 people meeting Rome II for new onset FGIDs, IBS and FD, respectively. Anxiety and depression were measured using the Delusions Symptom States Inventory at baseline and follow-up.
Results Among people free of a FGID at baseline, higher levels of anxiety (OR 1.11; 95% CI 1.03 to 1.19, p=0.006) but not depression at baseline was a significant independent predictor of developing new onset FGIDs 12 years later. Among people who did not have elevated levels of anxiety and depression at baseline, those with a FGID at baseline had significantly higher levels of anxiety and depression at follow-up (mean difference coefficient 0.76, p<0.001 and 0.30, p=0.01 for anxiety and depression, respectively). In IBS higher levels of anxiety and depression at baseline were predictive of IBS at follow-up, while only depression was predictive of FD at follow-up.
Conclusions The central nervous system and gut interact bidirectionally in FGIDs.
Introduction
The functional gastrointestinal disorders (FGIDs) manifest as a characteristic combination of chronic or recurrent symptoms arising from the gastrointestinal (GI) tract. FGIDs are extremely common, affecting at least one-third of the population. Half of all patients with gastrointestinal complaints seen in primary care have FGIDs, and up to half of all referrals to specialist gastroenterologists are for FGIDs. FGIDs generally persist lifelong and significantly impair quality of life.
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 FGIDs. Multiple pathophysiological disturbances have been identified in subsets with these disorders, including disordered motility, visceral hypersensitivity, abnormal gas handling, disturbed intestinal flora and low-grade intestinal inflammation (particularly mast cell and T-lymphocyte infiltration). A cytokine response has been documented in irritable bowel syndrome (IBS) and functional dyspepsia (FD), and tumour necrosis factor α (TNFα) levels have correlated with anxiety; cytokines have been postulated to drive psychological distress in the FGIDs. However, a unifying theory that explains all of the FGIDs has remained elusive, although there is emerging agreement that gut dysfunction (perhaps driven by low-grade inflammation secondary to increased permeability) is likely to be key in a subset of people.
Another promising unifying theory to explain FGIDs is primary central nervous system dysfunction, which clinically manifests as psychological distress and may drive GI distress. A plethora of literature supports a role for psychological factors, including anxiety, depression and somatisation in FGIDs. A number of studies have shown elevated psychological distress (anxiety, depression and somatisation) in outpatients and volunteers with FGIDs, and among non-consulters from the community with FGIDs. A causal link is supported by symptom improvement following psychological interventions such as cognitive behavioural therapy versus usual care or placebo. Randomised controlled trials have confirmed that antidepressants, both tricyclics and serotonin reuptake inhibitors, are superior to placebo in IBS, although their role in FD remains uncertain and their exact mechanism of action is unknown. Pathophysiological studies and longitudinal studies have shown an association of FGIDs with stress, although the majority of these studies only assessed IBS and FD, have been retrospective and have not been methodologically rigorous enough to ascertain if there is a causal connection. Acute infectious gastroenteritis can precipitate IBS and FD presumably in people genetically predisposed to these conditions, and in those who develop post-infectious IBS, the risk appears to be increased if there is pre-existing psychological distress.
Thus, there is evidence that a brain to gut pathway may account for GI symptoms in some FGIDs, but other evidence points to the gut being the primary driver of symptoms (via gut to brain connections perhaps through cytokines). However, it is not known which of the various FGIDs, if any, is dominant. In this study, we aimed to determine whether it is likely that a brain–gut or a gut–brain pathway operates in the FGIDs. We also aimed to explore if the brain–gut or gut–brain pathways are the same for all FGIDs by looking at these pathways in IBS and FD separately. We hypothesised that anxiety and depression drive the new onset of all FGIDS, including IBS and FD.
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