 Gut-Brain access is a term which is used for bi-directional gut-brain interactions. And this gut when we talk about, we know that it has its own network of neurons known as Entric Nervous System. In fact, it is so extensive that sometimes it is known as Second Brain. Now this connection between the brain and Entric Nervous System of the neurons, it is not limited only to the neuron interactions. Rather, there are many players which are playing a huge role in that and one of those players is the gut microbiome. Gut microbiome is kind of an ecosystem of various microorganisms which are present in the gut and which are basically living in sync with the cells of our own body and the number of these microorganisms which are present in the gut is estimated to be actually 10 times of the total number of cells which are present in the body. So, they have a huge role in this gut-brain interaction. So, what is happening is basically our gastrointestinal tract has a network of neuron known as Entric Nervous System and this nervous system is solely responsible for the gastric motility, gastric secretion, regulation of gastric blood flow means even if its connections are removed with that of the higher centers still it will be able to work on its own. However, the role of the higher centers is to influence the activity which is happening in the Entric Nervous System in case of environmental stresses. So, this brain can override the reflexes which are happening just by the network of neurons in the Entric Nervous System. So, that is one aspect. Secondly, this gut microbiome actually is responsible for the formation of lot of substances which interact with this Entric Nervous System and also with the brain neurons. So, from the brain basically we are more interested in the autonomic nervous system neurons that is the sympathetic and parasympathetic neurons which influence this Entric Nervous System plus the sensory information which is going from Entric Nervous System to the higher centers influence this outflow from the brain also the molecules which are produced by this gut microbiome affect this sensory information which is going to the higher centers not only that it also affects the outflow from the brain. So, this bi-directional exchange of information between the brain and gut is known as gut brain axis and you see here how brain is influencing gut microbiome as well that is because in certain conditions like suppose severe stress chronic stress is there then it affects the permeability of the epithelial layers of the gastrointestinal tract and hence affects how gut microbiome will be affecting the functional aspects. So, with this little introduction let us go into the specifics of this gut brain axis. Now these interactions between the brain Entric Nervous System and gut microbiome are basically of three types which we call as types of signaling and these are neural signaling, entroendocrine signaling and immune signaling. Neural signaling is basically the connections between the neurons then entroendocrine our gastrointestinal tract has cells known as entroendocrine cells which produce certain substances which have an effect on the brain and then there is immune signaling that is how the gut is affecting the functioning of the immune cells which are present within the gut and with that it is affecting the neural signaling as well. So, with this let us go into details of each of these signalings and we will try to understand them with some examples. So, here this diagram is showing the layers of the gastrointestinal tract and the various connections. So, this is the mucosal layer where we have the epithelial layer and the lamina propria. In the lamina propria we are seeing various immune cells that is the gut associated lymphoid tissue then here there is submucosa and in submucosa we have mesonus plexus which is important for the regulation of gastrointestinal secretion and blood flow and then there is the circular and longitudinal muscle layer and in between these two layers we have the myentric plexus and myentric plexus is responsible for the regulation of the GI motility. So, if you see the connections the mesonus plexus yes it is supplying the epithelial cells and it is important for gastrointestinal secretion then myentric plexus here I have just shown a basic connection where we have one neuron which is making contact with the epithelial cells and the secretions from epithelial cells actually stimulate this neuron and this neuron in turn makes connections in a retrograde manner and in andrograde manner. So, for example when there is a stretch of the gastrointestinal tract what happens that there is a release of serotonin by the epithelial cells and this serotonin then stimulates this afferent neuron which in turn makes contact with neurons both in retrograde manner and andrograde manner and the retrograde neuron releases neurotransmitters like acetylcholine and substance P which are responsible for the contraction of the muscular layer and the andrograde neuron releases a nitric oxide and VIP that is vasoactive intestinal polypeptide which is responsible for the relaxation of the muscles ahead of the bolus which is causing the stretch or the chym which is causing the stretch. So, this simple arrangement is responsible for peristalsis but you see I have also shown how there are afferents which are going to the higher centers and there are efferents which are coming from the higher centers basically the sympathetic and parasympathetic efferents. So, this neuronal connections in the enteric nervous system that is the mind trick and misnus flexes as I told before is itself can regulate the functions of the enteric nervous system. However, it is overridden by the autonomic nervous system and this autonomic nervous system where the center of the autonomic nervous system is the hypothalamus and hypothalamus receives a lot of information from various other areas. So, there will be effect of further higher centers on the output of this autonomic nervous system. For example, we see the changes in various reflexes which are occurring in the autonomic nervous system. One of these very important is defecation reflex where we see in case of environmental stresses defecation reflex may be inhibited by output from the autonomic nervous system and this environmental stresses is perceived by what? It is perceived by the higher centers which in turn are stimulating the autonomic nervous system. So, this is just one aspect of gut brain access that is neuronal signaling. Coming to the involvement of entroendocrine cells or what we call is neuropeptide signaling. So, there is a huge role of gut microbiome in this type of signaling. One of them is where gut microbiome is responsible for conversion of dietary fibers, the undigested material in the food to short chain fatty acids and this short chain fatty acids is responsible for a lot of effects. One of this is that it decreases inflammation in the GIT, the short chain fatty acid butyrate. It works on gut associated immune system and is responsible for decreasing inflammation in GIT. Next very important pathway which have been found in gut brain access is conversion of tryptophan to serotonin. Actually, the serotonin 95% of the serotonin is produced in GIT and that is why it has been found that change in the gut microbiome what is known as dysbiosis decreases the serotonin in our body and is responsible for many diseases like depression. So, how this happens is the short chain fatty acids act on the endocrine cells by means of receptors. So, there are receptors here known as free fatty acid receptors and these endocrine cells are responsible for this pathway conversion of tryptophan to serotonin. So, short chain fatty acids when they act on these receptors they stimulate the conversion of tryptophan to serotonin and then the release of serotonin within the GIT and most of it enters into the blood as well. So, remember that GIT is responsible for 95% of serotonin production in our body and this serotonin within GIT is very important for regulation of GI secretion, motility as I told you that a stretch is responsible for the secretion of serotonin which acts on the afference and stimulates the anterogrid and retrograde neurons. Then third one is that these short chain fatty acids act on certain cells on helium actually the L cells on helium and cause release of GLP-1. So, you see how this gut microbiome is also responsible for glucose homeostasis because this GLP-1 enters into the blood and is responsible for the secretion of insulin which causes decrease in the blood glucose level. Then there is release of other neuropeptides as well that is the neuropeptide Y which is responsible for stimulating food intake and there is peptide YY which decreases the appetite. So, depending on the products these neuropeptides are released by the enteroendocrine cells of the gastrointestinal tract and who is doing all this thing it is basically the gut microbiome which is converting the dietary fibers into short chain fatty acids. Then there is another aspect which we all are aware of that is the conversion of primary bile acids into secondary bile acids. These are also done by gut microbiome and these secondary bile acids they also have certain functions where first they act on again L cells of the helium and cause release of GLP-1 which again is responsible for improving the regulation of glucose metabolism. Not only that it actually acts on helium causing the production of fibroblast growth factor. Fibroblast growth factor specifically it is fibroblast growth factor 19 which enters into the circulation and can cross the blood-brain barrier as well. So, it crosses blood-brain barrier and activates the nuclei in hypothalamus causing suppression of hypothalamic pituitary axis. So, when this axis is suppressed what is happening are cortisol secretion in response to stress decreases. So, you see how our brain activity and in turn the hormones which are being released by the brain which in turn will affect the entire body that is just being affected by what is the action of the gut microbiome causing the formation of secondary bile acids. And there is huge literature on this gut microbiome that how it changes in various condition especially with what we eat. So, yes we can say that what we eat is definitely affecting our brain. So, this was about the neuropeptide signaling and the major role of gut microbiome in neuropeptide signaling the action of the short chain fatty acids the release of the various peptides by the endocrine cells and how it can also cross the suppression of hypothalamic pituitary axis. Let's go back to our initial diagram to understand immune signaling. So, you see here in this diagram this layers I told you mucosalair, submucosalair and the muscularis layer but you see here that this epithelial cells as it is in contact with the lumen of the intestine but there is a layer of mucous which is separating it from the lumen and there is a thick mucosalair. So, this part is a thick mucosalair and there is a loose mucosalair and then there is presence of this gut microbiome. So, epithelial cells are not in direct contact with the gut microbiome. So, you see our immune cells are little bit kept separated from the components of the lumen only when it is able to breach these barriers then they stimulate the immune cells and this barrier is basically obviously this mucous layer and there are tight junctions which are present in between these epithelial cells and it has been found that there are various aspects which can affect this barrier. One of this is chronic stress. In chronic stress because of the release of cortisol by our HPA axis there is decrease in this mucous production. So, this layer actually thins out in case of chronic stress and these microbiome which is present in the contact with this mucous layer now can come in contact with these immune cells. Not only that actually there is a two-way relationship where these microbes which are producing the short chain fatty acids they maintain this tight junctions. So, when there is decrease in these micro-organisms of the gut then these tight junctions loosen. So, again our immune cells can come in contact with the toxic elements which are present in the GIT. So, you see the neuronal signal and the hormonal signal from the body that is the cortisol can change the permeability of this gut barrier and also the microbes can directly affect the permeability of the gut barrier. So, once this permeability is affected say suppose in case of chronic stress what will happen? How it will affect the body? Let us see that. So, this gut microbiome like all other microbes have some pathogen associated molecular patterns which are recognized by the cells of our body and one of these pamps is lipopolysaccharides and there is a huge research going on in this lipopolysaccharides and how it affects the neuronal signaling within the GIT. Others are also there depending on the microbes that they will have different different pamps. So, there can be the flagella of the bacterium and there can be other pamps as well and once this gut mucosal barrier is broken what will happen? The immune cells which are there they will be stimulated and there will be activation of different immune cells they which include the B cells, the neutrophils, the macrophages actually the macrophages and the various antigen presenting cells which include the B cells, genetic cells all will be stimulated and this will lead to a pro-inflammatory condition because these cells are going to release certain cytokines which include IL-alpha, interleukin-beta, TNF-alpha which can cause various effects. So, you see how the release of the cortisole in case of a stress is further leading to a pro-inflammatory condition within the body because of the release of various cytokines by the immune cells which are present within the gut. Now these cytokines have various effects they act on the vagal afference within the GIT as well so they will affect the GIT functions right because they are affecting the afference in GIT then when they enter into blood they can cross the blood-brain barrier and once they cross the blood-brain barrier they can directly modulate the brain function and within the brain what they do? They activate a pathway known as Kinyurinin pathway. Okay now this pathway is basically in which tryptophan is not converted to serotonin in fact it is converted to another metabolite that is the Kinyurinin so again what is happening within the brain there is a decrease in tryptophan there is decrease in serotonin leading to depression. So, you see how a stimulus of chronic stress acts via GIT ultimately leading to depression so it has been found that in depression there is chronic low-grade inflammation in the body then second thing is that these cytokines also act on microglia and when they act on microglia on brain there is further release of the cytokines so there is exaggeration of the condition. So, these are just two examples actually lot of research is going on where many findings that how brain function is regulated by the gut activity are coming into domains for example one is Clostridium bacteria it produces a metabolite which inhibits enzyme dopamine beta hydroxylase so dopamine is not converted to epinephrine dopamine beta hydroxylase is responsible for conversion of dopamine into epinephrine so what happens there is increase in level of dopamine and this increased dopamine levels may be responsible for increased psychotic episodes in case of schizophrenia so like this lot of research is going on in this gut brain axis modulation and especially by the gut microbiome in fact there are various methods of manipulating this gut microbiota when we are already aware of that the use of antibiotics when broad spectrum antibiotics are used there is dysbiosis that is the colony of microbiome which is present in the gut is disturbed so there is decrease in the commensal bacteria and there is increased chances of infection by other bacteria so how there because of the presence of commensal bacteria gut immunity is present it is not allowing other bacteria to infect our body then there is a probiotics probiotics for basically maintaining the commensal bacteria within the gut then obviously as I told you before how diet and lifestyle can affect the immune system for example if there is somebody who is living with chronic stress then how the gut activity and the brain activity will be affected and obviously the diet is also responsible for changing in the commensal bacteria then because of this knowledge a treatment has also come up where there is implantation of fecal microbiota so from a healthy donor fecal microbiome may be transplanted into another person who is suffering from certain diseases and one of this is inflammatory bowel disease where fecal microbiome transplantation is done by using enema so I hope you understood little bit about the gut brain axis that how the neuronal signals that is from the higher centers affect autonomic nervous system which can affect the enteric nervous system then sensory information from the gut can affect again the output of the autonomic nervous system from the higher centers that was neuronal signaling then there was a neuropeptide signaling or the enteroendocrine signaling where the metabolic products which are produced by the gut microbiome affect the secretion of various neuropeptides by the enteroendocrine cells and then how these neuropeptides affect the various functions of the body including the regulation of food intake in fact even blood brain barrier the tightness of the blood brain barrier also changes then finally there was immune signaling where we saw that how there is the barrier the gut barrier which is there and when it changes there can be a state of low-grade pro-inflammatory condition thanks for watching the video if you liked it do press the like button share the video with others and don't forget to subscribe to the channel physiology open thank you