Author: Ruchi Maniar Edited by: Ruth Sang Jones
On Thursday 10th of May, SIU Katowice invited Prof. Ted Dinan, Professor of Psychiatry and a Principal Investigator in the Alimentary Pharmabiotic Centre at University College Cork. After receiving his PhD in Pharmacology from the University of London, he was a Senior Lecturer in Psychiatry at Trinity College Dublin. He previously held the position as Chair of Clinical Neurosciences and Professor of Psychological Medicine at St. Bartholomew's Hospital, London. Currently, he is a Fellow of the Royal Colleges of Physicians and Psychiatrists and a Fellow of the American College of Physicians. Having published over 450 papers and numerous books on the pharmacology and neurobiology of affective disorders, he is seen as an expert in immune and endocrine aspects of depression and gut microbiota.
The new focus on microbiota has resulted in a paradigm shift in neuroscience and mental health, in terms of depression, anxiety, metabolic syndrome and obesity.
Prof. Dinan began the talk by outlining how diet, menstruation, our circadian rhythms and age all affect the diversity of our intestinal bacteria. We all carry a kilo of microbiota, but the diversity is what affects our future predisposition to neurological diseases later in life.
He described that in the 1970’s, before drug therapy was introduced, peptic ulcer disease was treated by carrying out a full vagotomy, and interestingly, the patients that underwent this operation developed Parkinson’s disease less often than patients who did not have this procedure. There is evidence that the toxin alpha-synuclein, commonly implicated in Parkinson’s, is produced in the gut and transcends up the vagus nerve to the brain, hence patients who have had vagotomy do not carry this predisposition.
Professor Dinan went on to further clarify the route of microbiota into the brain. Many neurotransmitters can be produced by the gut microbes, including tryptophan, a precursor of serotonin, and gamma-aminobutyric acid (GABA), which can be produced by Lactobacillus buchneri. These then travels via the enteric nervous system (ENS) in the gut to enter the nervous system. Likewise, the vagus nerve serves as a bidirectional route between the brain-gut-microbe. Even short chain fatty acids generated by the microbial digestion of fibre can travel to the brain and bind to G-protein coupled receptors; an example is butyrate, which has been found to be an epigenetic modulator. Professor Dinan further illustrated the findings of a study whereby germfree animals, i.e. microbiota deficient, were observed to be more unsociable, exhibited abnormal myelination in some areas of the brain and had atypical neuroplasticity as well as brain progenitor cells.
The remaining talk focused on studies that highlighted the effects of psychobiotics, probiotics, prebiotics and diet. Pro-biotics refers to the live bacteria whilst pre-biotics is the fibrous dietary content that promotes beneficial bacterial growth. Psycho-biotics are probiotics that influence their host mental health.
Psychobiotics- Microbes and Mental health
Prof introduced his his maternal separation model studies for depression, where rat pups where removed from their mother between days two-twelve for three hours each day and then returned back to their mother, thereby reducing their exposure to the mother's microbes. He found that these pups, when they grew to maturity, displayed highly anxious behaviours and increased levels of inflammatory markers and cortisol levels, He also talked of a similar study in humans, where the faecal samples of both depressed and healthy patients was sequenced, and he discovered that indeed, the microbiata are different in diversity and richness, even if controlled for age. Another study investigated the effect of eliminating rat microbiota with a cocktail of antibiotics; the rats were subsequently transplanted with microbiata from humanised depressed or healthy patients. Surprisingly, those that received the depressed transplants displayed anhedonia, C-reactive phase protein elevation (implicated in depression) and a decrease in metabolism of tryptophan.
In other areas of psychobiotics, Professor Dinan mentioned Bifidobacterium infantis 35624, a probiotic that has been found to increase tryptophan and decrease cortisol, with similar results seen with Lactobacillus. R. Both of these as probiotics showed antidepressant activity in the forced swim test, a rodent behavioural test used for the evaluation of antidepressant drugs. In his studies, he showed that Lactobacillus. R decreased expression of GABAa in the prelimbic cortex, the basolateral and the central amgydala, as well as decreased expression of GABAb in locus coeruleus in addition to affecting to the CA1 and CA3 neurones in the hippocampus, thus altering fear response, anxiety and arousal. Moreover, he demonstrated that if animals have had a full vagotomy, Lactobacillus. R. has no affect on the animal compared to an animal that has undergone sham vagotomy and/or takes a placebo.
Microbes and Cognitive Function
When it comes to probiotics, studies have shown Bifidobacterium longum has an impact on anxiety and cognitive function. When presented with a Barnes maze, the animals who were given the probiotic learned the escape route faster than those animals who were not given the probiotic. Performing a similar crossover study in humans, participants were given either a placebo or Bifidobacterium longum for one month and switched to the other for one month. It was discovered that participants felt less stressed in the month that they were given the probiotic, demonstrated by fewer errors performed by these participants on the CANTAB cognitive test and alterations in EEG output.
Interestingly, inulin found in food items such as chicory, Jerusalem artichokes and celery promotes the growth of Bifidobacterium, acting as a natural prebiotic, subsequently promoting good health. Breast milk also contains the same sugars that behave the same way inulin does in adults. Prebiotics such as fructooligosaccharides (FOS) and galactooligosaccharides (GOS) have been shown to promote positive results in the forced swim test and the tail suspension test, where a combination of both FOS and GOS demonstrated a decrease of awakening cortisol levels in animals, especially GOS in humans.
A good diet
Prof. Dinan talked of a direct correlation of unhealthy foods and a low fibre diet with depression, stating that Mediterranean diets have been found to be associated with lower levels of depression, attributable to the high intake of fruit, vegetables and fish. He spoke of a study that backed this up, where patients who had depression were randomly allocated a Mediterranean diet or counselling support, and those that were on the Mediterranean diet exhibited a dramatic drop in their MADRS score for depression.
Additionally, Prof. Dinan mentioned that a common side effect of antipsychotics is weight gain in patients, typically within two-three weeks of starting their therapy. Intersingly, when germfree animals were given olanzipine - the most common antipsychotic drug - they did not show a weight gain, thereby suggesting specific microbiota may be required to put on weight.
To summarise, Professor Dinan presented us with a fascinating talk, coupled with clinical studies and research to supplement our understanding. He showed us that gut microbiota has a proven impact on the brain, and can be used to treat stress-modulated disorders by diet, psychobiotics or even prebiotics.