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

Disclosures

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

In This Article

Discussion

This study provides strong direct evidence that the gut and brain interact bidirectionally in both IBS and FD. While brain-to-gut pathways were evident in IBS and FD as expected, the data from this study also suggest that many people with IBS and FD have their disorder begin in the gut, and the gut likely drives psychological alterations in a major group of cases with FGIDs. This study independently confirms previous population-based research[3,18] but applied a shorter timescale (1 year rather than up to 12 years), applied recent FGID diagnostic criteria[2] and tested alternative validated measures of psychological distress in a population setting.

The brain–gut axis is becoming increasingly recognised as critically important in the pathophysiology of IBS and FD, with regional central nervous system alterations in IBS and FD documented with functional MRI or PET scanning studies.[27,28]

We confirm previous cross-sectional and longitudinal findings[3,18] that brain-to-gut pathways operate in a subset of people with IBS and FD. We found among those people free of IBS and FD at baseline, higher levels of anxiety and depression were significant predictors of developing IBS and FD, but not among those who already had IBS or FD. This is in line with our earlier 12-year prospective study, where we found higher levels of anxiety and depression at baseline were predictive of developing IBS at the 12-year follow-up among people free of IBS at baseline, although only higher levels of depression but not anxiety at baseline were predictive of developing FD at the 12-year follow-up among people free of FD at baseline.[3] Our results also confirm a UK GP database study of 5 years of data, where two-thirds of patients with an FGID had a psychological diagnosis first.[18]

We also examined whether a change in psychological distress and quality-of-life was associated with developing FGIDs at follow-up. While we found higher change scores in anxiety and depression as well as mental and physical functioning among people who developed, lost or continued to have IBS and FD over the 1-year time frame compared with those who remained IBS or FD free, only worse mental functioning was significantly associated with developing FD at follow-up compared with people who did not have FD at baseline or follow-up. In terms of IBS, only poorer physical functioning was significantly associated with developing IBS at follow-up compared with people who continued to have IBS at baseline and follow-up. Our data are consistent with one trial showing improving physical activity reduced IBS symptoms.[29]

These data highlight the importance of the brain–gut axis in people with IBS and FD. Anxiety and depression may affect the gut in several ways including increasing sympathetic and decreasing parasympathetic tone in the autonomic nervous system, up regulating the hypothalamic–pituitary–adrenal (HPA) axis including corticotrophin-releasing factor (CRF) and cortisol,[30] as well as through promoting abnormally increased vigilance for gastrointestinal symptoms via the efferent neuro-endocrine loop.[31,32] Understanding more about these mechanisms will likely assist in the development of more effective diagnostic and treatment strategies for people with a clear cut brain–gut disorder.

While the brain–gut axis is thought to account for a significant proportion of people with IBS and FD, our findings suggest that there is also a subset of people with IBS and FD that have a gut-to-brain disorder.[18] In this study, there were 90 individuals who had either an FGID or mood disorder at baseline and who developed the other at follow-up, of whom 1/3 followed the brain–gut pathway and 2/3 the gut–brain pathway. The exact proportions in each pathway, however, do need to be interpreted with caution as we could only ascertain order in a relatively small proportion of the sample. In any case, the evidence suggests that between one-third and two-thirds with an FGID may have a primary gut driven syndrome with the brain secondarily involved. A large UK GP database study recorded both FGID and a mood diagnoses at several time points over the course of 5 years; in the UK GP database around two-thirds had a psychological diagnosis first, vs. one-third having a FGID diagnosis first.[18]

The fact that in this study, we did not observe significantly higher levels of psychological distress at follow-up among those people with IBS and FD who already had elevated anxiety or depression at baseline is further supportive evidence of a true gut-to-brain pathway.

A new model of a microbe-gene-inflammation interaction, where infection can lead to excessive tumour necrosis factor alpha and other cytokine production in vulnerable individuals is beginning to emerge and may in part explain this gut–brain interaction.[33] The activation of the immune system has frequently been observed in patients with IBS compared with controls.[34] Tumour necrosis factor alpha levels have been shown to correlate with anxiety in IBS, but more data are needed.[16] Animal studies of gut bacteria have also shown the bacteria can influence changes in behaviour.[35–38] Alterations of the gut microbiome have been shown in IBS although an exact signature is lacking.[39] One study found that in patients with post infectious IBS the intestinal microbiota differed from other IBS patients and healthy controls and the microbial composition was significantly associated with the Hospital Anxiety and Depression Scale score.[40] Other hypothesised pathways of gut–brain communication include direct secretion of neuroactive chemicals in the gut by bacteria such as fatty acids, GABA and 5-HT precursors and stimulation of secretion of 5-HT from enteroendocrine cells.[41] The efficacy of the non-absorbable antibiotic rifaximin in IBS in about a third of cases is consistent[42] with the hypothesis the gut microbiome modulates the syndrome in a subset but not all patients.[43] A review of pre-clinical studies in patients with Traveller's diarrhoea showed that rifaximin may affect the intestinal mucosa by inhibiting bacterial attachment and internalisation, thereby reducing inflammation.[44] Further research is needed into gut–brain pathways and how these may be translated into the development of more effective management strategies for people with a gut–brain disorder. We speculate although phenotypically identical, those whose FGID symptoms that arise primarily from gut pathways will not respond well to psychological therapy, but will respond to gut directed therapies that reverse key abnormalities such as an abnormal microbiome or possibly T-cell dysregulation.[45] This may help explain the heterogeneity of response in IBS and FD to pharmacological interventions.[46]

This study confirms long-term findings that the brain and gut interact bidirectionally in FGIDs using a much shorter time frame of 1 year. While we did not assess for potential confounders such as changes in medication, life stressors or other nongastrointestinal related conditions, the data from a short-time frame are less likely to be influenced by such confounders. However, these results do need to be interpreted with caution as FGIDs are not all stable over time and fluctuations occurred during this 1-year time period although this did not interfere with observing statistically significant findings of moderate effect size. Aside from the short-time frame, these data also confirm bidirectional brain-gut pathways in FGIDs defined using the more recent Rome III criteria suggesting that these results are not specific to how IBS and FD are diagnosed. In addition, we also confirmed these findings using a different measure of psychological distress. In contrast to our earlier study, we used the Hospital Anxiety and Depression Scale. The scale was developed as a screening instrument for use in hospital out-patient departments, but has subsequently been validated for use with the general population.[47,48] The Hospital Anxiety and Depression Scale unlike many other psychological measures does not contain questions that could be attributed to physical illness, such as headache or dizziness which are often extra-intestinal symptoms reported by people with IBS and FD. We achieved an acceptable response rate and did not detect any major selection biases.

In conclusion, this study provides further strong evidence that the gut and brain interact bidirectionally in IBS and FD and extends past work to a shorter timescale. The data also confirm that there is a subset with FD and IBS that have their disorder begin in the gut and the gut may primarily drive psychological alterations in some with FGIDs.

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