Fixing Functional GI Disorders Using Microbes: Easier Said Than Done

When we use the term ‘disorder’ to describe illness, it begs the questions what is ‘order’ and what happened to it? In attempting an answer, we have to consider the features of the disorder. Functional gastrointestinal disorders (FGIDs) are complex, multi-system phenotypes with an array of presentations and comorbidities (1). These include dysmotility, visceral hyperalgesia, autonomic nervous system dysfunctions, familiarity, psychosocial triggers, and postinfectious events. The inference is that the orderly state is not terribly resilient or stable. Yet, such a conclusion would be doing a disservice to evolution given that most humans do not suffer from gastrointestinal disorders. To understand these conditions, investigations have focused on physiological and psychological factors or the so-called bidirectional communication pathways that render the term “gut-brain axis” (2). This axis initially only referred to the connection between the nervous system and gut function, but it has been expanded to include native gut microbiota. This concept was supported by rodent studies showing a role for the vagus nerve in transferring microbial signals that influence brain responses (3, 4). This has stemmed from appreciating the preponderance of microbes in the gut which in turn led to hypothesizing that microbial metabolites hold the key to resilience or disruption. This is essentially a reductionist approach that ignores the other microbes in the body, including ones linked through the vagus nerve (5). It suggests that the microbial products have a significant influence on the brain, but do we have sufficient data to prove that? An excellent recent review suggests not in humans (6; see Table 2 showing only mouse data). To date, there have been no measures published on neurotransmitter levels in the blood and brain of humans post-fecal microbiota transplant (FMT) or probiotic treatment. Some tools exist as demonstrated by the use of diffusion magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and positron electron tomography to measure functional effects of serotoninergic receptor (5-HT2AR) stimulation by a naturally occurring psychedelic prodrug, psilocybin (7). A number of microbes have been hypothesized as potentially being able to affect human brain chemistry from the gut and related FGIDs. Strains of bacteria potentially useable as probiotics are known to produce neurochemicals including gamma-aminobutyric acid (GABA), serotonin and acetylcholine (8). One recent study has shown the existence of GABA-producing pathways in Bacteroides, Parabacteroides and Escherichia species present in the gut (9) which makes it more difficult to prove that the ingestion of a probiotic lactobacilli was directly responsible for higher levels of this inhibitory neurotransmitter. Interestingly, this paper reported use of fMRI to show that lower levels of GABA-