Hippocrates said ‘all disease begins in the gut.‘ This quote was used in the title of a paper by Lyon (2018), which asks: ‘what is the evidence that gut microbes can affect the brain, and could we really treat brain disorders by changing the composition of the gut microbiota?‘
The question is attracting increasing global interest from researchers, with Cork, Ireland, becoming a growing centre of excellence. Dr Niall Hyland is a pharmacologist and senior physiology lecturer at APC Microbiome Ireland, a world leading Science Foundation Ireland Research Centre based at University College Cork. Hyland recently beat a field of almost 200 international applicants to secure a €100 000 global grant from Nature Research and Yakult to determine how gut bacteria affect medications for depression and anxiety.
‘Microbiota' refers to the trillions of microbes, comprising of 700–1000 different bacterial species reside in the gut, whereas ‘microbiome' refers to the collective genomes of these microbes.
The rise of extended-release drug formulations, particularly in neuropharmacology, may increase the number of psychoactive drugs reaching the bacterially-dense large intestine, exposing them to microbiota-mediated degradation (Walsh et al, 2018). Further, Kelly et al (2015) have cited clinical evidence that ‘broadly suggests that the gut microbiota can modulate brain development, function and behaviour by immune, endocrine and neural pathways of the brain-gutmicrobiota axis.'
Dr Hyland told the Journal of Prescribing Practice: ‘individuals respond to medications in different ways, and it appears that each person's microbiome may play a significant role in how drugs are absorbed and metabolised by the body. Recent research has shown that a person's microbiome affects their response to chemotherapy and other medications such as for Parkinson's disease (PD)’.
In relation to PD, Hyland's colleague Professor Cora O'Neill, director of the Cork Neuroscience Centre, explains that ‘the enzymes that degrade L-dopa occur in microbiomes from human stool samples and that L-dopa degradation occurs with considerable variation in people with and without PD … that L-dopa degradation can be predicted predominantly by microbial tdc gene expression and Enterococcus faecalis abundance in stool samples… [and] that higher amounts of tryptophan decarboxylase gene in stool from PD patients correlate with increasing L-dopa dosage and disease duration’ (O'Neill, 2019).
Hyland will investigate how the microbiome affects the ability of individuals to respond to antidepressants and antipsychotics: ‘if depression has a knock-on effect on the microbiome and can generate gut-related disorders like irritable bowel syndrome, how might depression affect the ability to process antidepressant and antipsychotic drugs?’
Hyland's team will also analyse the gut bacterial communities and enzymatic activities in patients with depression before treatment with medication and then analyse drug responses: ‘we plan to use the pharmacokinetic results to build a computer model to predict how patients might respond to specific drugs based on the composition of their microbiomes. We hope it will enhance treatment efficacy and increase patient compliance’.
How relevant might this research be to pharmacists on a day-to-day basis? ‘As far as prescribing practice is concerned,’ says Hyland, ‘in the future we might be able to predict from an individual's microbiome whether they will either respond to a drug or not, whether they may develop side effects, or whether a particular drug prescribed for one indication might alter the metabolism of another drug, prescribed for a concurrent condition, via its effects on the microbiome’.
Hyland explains that from studies beginning to appear in the literature, and from some of their own unpublished work, both pre- and pro-biotics can affect the expression of enzymes in the liver that are responsible for drug metabolism: ‘It may be,’ adds Hyland, ‘that in the future prescribers and pharmacists may have to probe into a patient's use of pre- and pro-biotics, which could affect the way a prescribed drug works’.
Dr Hyland suggests that this expanding field will become an area of increasing importance in drug-discovery, pharmacokinetic profiling, and modelling for new drugs: ‘It will also be an important consideration for those involved in the probiotic market space to be aware of’. And in this respect, it was interesting to note that Gondalia et al (2019) ‘explore links between bipolar disorder, inflammation and gut microbiome with a focus on dietary, pro- and pre-biotic interventions as potential adjuvant therapies for use in the management of mood disorders such as bipolar disorder’.