Psychology and Neuroscience of Affective Disorders PDF - King's College London

Module: Psychology and Neuroscience of Affective Disorders Week 3: Biological alterations of affective disorders Topic 1: The role of the gut microbiota in affective disorders (Part 3 of 4) Lecture transcript Viktoriya Nikolova, PhD student Department: Centre for Affective Disorders, Academic Psy...

Module: Psychology and Neuroscience of Affective Disorders Week 3: Biological alterations of affective disorders Topic 1: The role of the gut microbiota in affective disorders (Part 3 of 4) Lecture transcript Viktoriya Nikolova, PhD student Department: Centre for Affective Disorders, Academic Psychiatry Slide 4 In this part, we're going to examine the various components of the gut-brain axis, that is the ways through which the guts and the brain communicate and influence each other. Slide 5 So how can we study the gut-brain axis? This picture shows some of the main experimental ways through which we can investigate the role of the gut-brain axis in health and disease. Generally speaking, there's two broader strategies, by adding something and by removing something. So on the top left, you can see germ-free studies. What is that? So this is germ- free animal models, which means these are genetically modified animals that have been raised in the control and sterile condition to not have any gut microbiota. Another strategy is through antibiotic studies. What happens when individuals are given antibiotics is that they essentially wipe the microbiota. And while this may be useful for certain infections or conditions, it is generally harmful to the microbiota. So when we give antibiotics, we can see what effects this causes to other biological mechanisms or behaviour. Similarly, we can produce a similar effect by inducing a bacterial infection, and also measuring its downstream © King’s College London 2022 1 effects on biology and behaviour. We can also add supplements, so things like probiotics, and then observe what impact that has on the microbiota and the gut-brain axis. And finally, we can also do faecal microbiota transplant studies. So this is where we transplant microbiota from one individual to another, and then we observe the changes that this brings on to host biology. Slide 6 Quite a large number of animal studies have been conducted to date to look at the gut-brain axis and its functions, so I've just summarised on this slide a few of them. So studies from germ-free mice, mice given antibiotics, or mice with induced bacterial infection, show that these animals exhibit increased stress response and anxiety and depression-like behaviours. They also exhibit deficits in social behaviour. And in fact, this study in molecular psychiatry from 2013, found that the microbiota is essential for the development of appropriate social behaviour in mice. And finally, these studies have also seen that these animals exhibit cognitive deficits, so in memory and learning. And some of these studies have combined more than one of the experimental strategies that I showed in the previous slide. For example, they have also added a treatment of probiotics. And what they found was that these negative effects of these infections or antibiotics and so on, were either reversed by treatment with probiotics or prevented by pre-treatment with probiotics. Slide 7 Multiple potential direct and indirect pathways exist through which the gut microbiota modulates the brain and behaviour consequently. So let's take, for example, here the HPA axis, which is shown on the left of this graph. Activation of the HPA axis is what produces the stress hormone cortisol, and the production of cortisol is over-activated in affective disorders. Cortisol itself can then affect immune cells, both locally in the gut and systemically. Cortisol can also alter gut permeability and barrier function, so the leaking gut condition I mentioned earlier, as well as changing the gut microbiota composition itself. And this entire cascade of events can also be triggered in the opposite direction, starting from gut microbiota composition. Neurotransmitter production is also directly dependent on bacteria. And particularly serotonin, because the majority of it, about 95% of our body's serotonin is produced and located in the gut. Some of it as you see on this picture will go via the vagus nerve to the brain. Tryptophan is an essential amino acid for the production of serotonin, and probiotics, for example, have been found to increase the levels of tryptophan. Another important impact of the gut microbiota and also of probiotic agents is that they can alter the levels of circulating inflammatory cytokines, and this can have a marked effect on brain function. This is done directly by certain bacteria, but more often it's through their ability to produce short chain fatty acids as the ones I mentioned earlier in part 2. And to define them a bit further, short chain fatty acids are bacterial metabolites of dietary fibre, which produce important anti-inflammatory cytokines and promote a healthy state in other ways as well. There are also direct neuronal connections via the vagus nerve and the enteric nervous system, that are strongly implicated in relaying the influence of the gut microbiota to the brain and vice versa. © King’s College London 2022 2 Slide 8 So some of these mechanisms were evidenced in the earlier animal studies I mentioned as well. So for example, in these studies, increased levels of tryptophan were found, increased levels also of brain derived neurotrophic factor, which is necessary for neuronal growth. And the pre-treatment of probiotics, or the treatment with probiotics after infection was found to decrease HPA axis activation, and reduce pro-inflammatory cytokines. Slide 9 And to summarise, here is another nice figure demonstrating what happens in a healthy and an inflamed state of the gut-brain axis, and so what happens in psychiatric disorders versus a healthy state. So in an unhealthy microbiota, what we have is an increase of inflammatory bacterial species, which then leads to intestinal barrier leaks. So the intestinal barrier is compromised, which can then lead to increased inflammation, circulating inflammatory cytokines, and also stress hormones. Whereas in a healthy microbiota, we would see homeostasis, and a tight and healthy gut lining. © King’s College London 2022 3