Bugs, trauma and brain architecture: an association awaiting an explanation.
Ever since its characterisation some ten or more years ago, scientists have speculated that specific changes in the colonic microbiome could account for IBS, but until recently there have been few direct insights. All that is known is that IBS is associated with a depletion and instability of the microbiome, though one study showed that while about 40% of patients had a normal microbiome, the remaining 60% formed a cluster with an increased ratio of firmacutes associated taxa compared with bacteriodetes related taxa. Moreover patients whose microbiota more closely resembled normal controls had more depression and anxiety, suggesting that in the remainder, IBS was more instigated by gut disturbances.
This year, Dr Emeran Mayer’s group in Los Angeles have extended the results from that paper with a study that provides the first direct link in humans between changes in the microbiome, identified by RNA sequencing, alterations in brain structure, determined by multimodal brain imaging and early adverse life events. This study is important in that it links major theories of IBS together – the sensitive brain/gut, the microbiome and traumatic life events.
The authors studied 29 patients with IBS and 33 patients healthy controls. Investigation of their microbiome by RNA sequencing identified two major subsets. In 16 of the 29 patients studied, the microbiome was similar to that seen in a cohort of normal subjects in that it contained a predominance of bacteroidetes spp over firmacutes spp. In the remaining 13 subjects, the reverse was observed, firmacutes were dominant. These distinctions were independent of bowel habit and symptom criteria, though gut transit time, which might be expected to influence the microbial composition of the colon by modifying nutrient delivery, was not measured; neither was visceral sensitivity. Nevertheless, the group with a microbiome unlike normal controls showed a longer history of IBS, higher scores on the emotional sub scale and increased volume in the regions of the brain stem responsible for sensory integration. They also scored more highly for early adverse life events, such as death or separation of parents and childhood abuse.
Their results could be interpreted in several ways. Firstly, specific changes in the microbiome, primed by early life events could affect development of the sensory elements of the brain stem to make the gut sensitive to life events as well as diet. In that regard it may be relevant that the same group also demonstrated increased numbers of clostridia spp, which have been shown to promote the production of the brain/gut transmitter, serotonin, from the amino acid, tryptophan in germ-free mice. Second, it might be the brain architecture that is primed by early adverse life events. This might induce changes in the microbiome though changes in gut function and/or nutrient delivery brought about by the autonomic nervous system. Moreover differences in the sensory processing might render people with IBS more susceptible to changes in the microbiome and traumatic life events. Maybe all are correct.
Although the results from this study cannot be said to indicate a specific microbial signature for IBS, identifying IBS subgroups based on gut microbiota, their related metabolomic profiles and corresponding brain signatures could provide a basis for categorisation and more targeted treatments. For example, trials of probiotics might be more usefully targeted to those patients with IBS who have an abnormal microbiome, while patients with post traumatic IBS might respond optimally to a combination of psychotherapy and probiotics.
An adverse Firmacutes/Bacteroides (F-B) ratio is not restricted to patients with IBS. It is also found in patients with obesity and people with increased fat intake. Perhaps the abnormal microbiome alters the permeability of the gut allowing bacterial invasion and causing low grade inflammation throughout the body.
While associations between the microbiome, brain structure and early adverse life events do not determine cause and effect, they support and extend existing theories and raise hypotheses for future studies. Thus, the importance of this study is more exploratory than definitive. It raises a multitude of questions and will undoubtedly provoke a plethora of specific studies. In particular it would be interesting to know whether adverse F-B ratios are stable in a cohort of IBS patients or whether they change with diet. Also what is the significance of this microbial distortion? Might it be a crucial factor for the the development of a range of otherwise unexplained, low-grade inflammatory illnesses? Recent studies suggest not.
The Sensitive Gut 