 Felly byddoch yn ei pwysig oedd fawr y dyfod i'r Yngrifennu ym 1910 a'r digwydd yn ynddo i ysgrifennu pallennu, yn cyfaint eu du bobl rwy'r crywau a'r rhaid i'r unig, ac mae'n ddalwch o'r pewd i'r rhaid o'r bydd yw'r iawn i'r Llywodraeth i'r ddim yn ei wneud, mae'r ddysgu yng Nghymru yn yw'r awlion, mae'n ei ddegi'r nghymru, ond rblwyddynol y ddweud i'w llawer i'r cyfle yma. Yn Ynw, wedi ei gweithio ond y Cymru, wedi ei gweithio ond ein gwrthiaid o'r ddiwedd. Mae'r ddegi hi'n gweithio o'r ddegi hwnnw. Mae'r rhannu atrolog o ymgyrch. Mae'r rhannu atrolog o'r rhannu o'r rhannu, felly mae'n dysgu i gyd yn gyntaf. Mae hynny'n gwybod i'r rhannu ar ymgyrch ond mae'r rhannu i gyd yn cyd-reifftyr i gyd yn cymryd o'r cyhoeddau cyllidol o ran o'r rhannu ar gyfer ysgol. Ac mae'n ddiwrnod o'r gweithio. Mae'r rhannu i gyd yn cywyd i'r rhannu i gyd. A dyma'r gweithio i gyd yn gweithio, ac yn dweud o bosb ddysgwyr roedd o'r blynyddiadau a barod o'r lleol, ac mae'r cyn Animals M дажеol o ran o'r blynyddiadau ac yn ei braŷn. Mae'r dartyn yfodol y gallwn yn fawr, yn ei ddarllen i ddod, bod'r bactiwyr yw'r oed erthyn i'r cyd-recodyniad o ran yr unan synghwynyddu, yn y cynnes hynny o'r llwyg unan synghylch yn gyd. But what I want to emphasize is that anatomically the nervous system immediately below the epithelium and the dend Test south population that drives the immune system is actually communicating anatomically and certainly as torque is occurring all the time. So, it is not possible to dissociate effects, as I have described, from effects of the immune system on the nervous system ac y nôr systemau yn y sylfaenau. Llywethaf yn y dyfodol, yn y gyfyrdd, ac mae'n cael bod â'r twfyn yn y gwaith llef. Mae'n cael bod yn gweithio'ch gael, byddwn i gael y cyfrifio, mae'n gael y gafel sydd yn y cyfrifio'r unwyr yn cyfrifio'r unwyr yn cyfrifio'r unwyr yn cyfrifio'r unwyr yn cyfrifio'r unwyr yn cyfrifio'r unwyr. Ond y ffrindig o'l astod yr ein gwlad amddraeddion, ac y rhagorau aesbaith ym Mhwnau Nachos yna yn ymlaen i'r parig maen nhw. peidio'r yma ar y gefnod ar psyll yma i gael y rhywun yn olygu fel yma i gael y ffordd yma. Y llun ymlaen yma yw dyma i'r pethau gennych ar y posibl sydd o flynyddiad, ac mae'n'glasoedd sydd o bryd ychydig mewn rhywun yma i'n credu i'r ffordd, ac yn cael cael ei ddweud am y cyfathodau, yn cyfathodau, bydd angen o'r systyth. A oedd amdano'r cyfathodau i'r ddweud o'r bod yn cael ei ddweud o'r hynny'n gwneud, ond oedd mae'n cyfathodau i'r ddweud i'r cyfathodau o'r cynnigol, a'r cyfathodau i diolch yn cael ei ddweud o'r cyfathodau i'r cyfathodau. o'r wneud hynny o fyny'r cymdeithasol hyn o'r dowell eu cyflodyg yma oddi gael dim iddyn nhw'n gliwedol. Fel cyflodau cyd-dŵl, oherwydd y maedhaf ymwyllyeb yn iawn yn ychydig – mae'n angen i'r rôl i'w ffordd ac fyddwn i'w rôl i'r rhain – mae yna dweud o gwnewch yn llawiau athgwrt yn angylchedd, fel y cyflodau cyllid am gyllid yma arfod a lwnnod o'r cyflodau am ddigon i'r gei yma ymddyll yma pheth bod o'i cael ei bod yn ei gynnydd. ac yn y modd o bwysigol yn y ffordd. Mae'n gwneud o gwneud o bwysigol ac yn unig ar y ddweud. Mae'r cychwyn cerddurau rheswedd, yma, gan ymddangos o gwych yn ymddangos i'w gweithio'r bwysigol, ac yn ymddangos i'r ffwrdd yn ymddangos i'w gweithio'r bwysigol, a'r ffyrdd yma ynglyn â'r bwysigol, efallai yn ymddangos i'w gweithio'r bwysigol, But the feeding simply in a germ-free animal with no material whatsoever, approximate, acetate, or use it, or the mixture, promotes the generation of inhibitory, immunoregulatory T cells. So simply the products themselves of fermentation may have this effect. Nomiwpisu-do in Japan, wrote this landmark paper in 2004, demonstrating that the stress responses in germ-free were exaggerated. But what he particularly showed, and it has relevance to the comments of the previous speaker, was that the change which could be induced by feeding either bacteria from a normal animal into the germ-free, or a particular bifidobacterium, the mon-association, could in fact change this back to normal, but only if this would be given in early development. So this is clear evidence of the programming that was referred to earlier, a word of caution on programming because in human and in clinical situations this is a controversial area and it is not clear that programming in this respect is the same in the human. Many of us have now shown that if you treat a normal animal with a probiotic, and this is very species and strain dependent, that you can actually do exactly the same as pseudo-show and attenuate the HPA axis response. It's felt that the stress response and the exaggerated long-term stress response that occurs, for example in the human, is the underlying feature in many situations relating to depression, somewhat in anxiety, but certainly in post traumatic stress disorder. There is very little evidence as yet in the human that you may well ask, so what do we bother at a time when we treat mice and show that anxiety is in fact improved. So the translation is crucial. This paper in 2021 showed that in this case, Calveticus and Elongil, when fed to normal women, in fact resulted after a month in promising improvements in three tests of mood and it also reduced the treatment for our urinary cortisol. This is the only evidence so far in the human that the mouse data that I showed is in fact translatable. So we've been able, especially my colleague, has been able to use a particular system to look at the enteric nerves and to try and see whether or not the bacteria which are clearly affecting the nervous system are in fact affecting the enteric nervous system and this is an important component of the pathway that my bacteria could then influence basically the brain. It is shown that when it comes to it, we're down to a particular ion channel which is expressed in a whole variety of different cells and that when we feed a particular lab, lab to Berserw's Romosis, that we can actually show not only this effect on the local nervous system but also a systemic effect on mast cells and T cells and that this channel may underlie the mode of action. So we're down to a specific ion channel in the pathway. Masmain and Caspar have shown that the bacteria or these fragilis exopolysaccharide actually by itself can recapitulate all of the immunological events which the feeding of the parent organism can produce. And we've shown that this particular polysaccharide A is able in the same way to reproduce exactly what we can show in the nervous system and this suggests that it is a component or carbohydrate component of this bacterium anyway and possibly others that are commensal or probiotic that actually have the desired effect. We fed this particular organism, and it's an act of psilosamagnosis, entomys, and these are two examples of behaviour in these animals and in fact you can see after 28 days that there's a difference and these are in fact anxiolytic or anti-anxiety-like behaviours. We looked at a whole series of neurochemical changes which are gamma receptor related and these are related to the tranquilising effects of benzodiazepines. So by feeding this particular organism for 28 days we changed the behaviour, we changed the gamma receptors in the brain and we found that if we cut the vagus nerve all of these effects were in fact removed. So we're now tracing the effects of the luminal bacteria all the way to the brain by the amputeur, by the immune system, by the main vagal tract. Now this is not the... We can also recall from the vagus nerve, we can show that there is an increased activity in the vagus nerve and we are able now to screen the bacteria for this particular activity which we are hoping will in fact be transasible to the human. Now this is not the only way in which these bacteria can actually influence behaviour and this came out by Steve Collins and Jamech Burcik also at our university. It took advantage of the fact that the NIH with mice are not anxious at least in these studies and the bounty mice are relatively anxious and they showed that they could do fecal transplants of one to the other and that within two to three weeks the behaviour of the transplanted recipient received or then adopted the behavioural pattern of the donor which is really quite an extraordinary observation and supports this question of the fact that the bacteria in the intestine have a lot to do with behaviour at least so far in these ailments. This is the other version from Emmawn Myr that was shown as one of our slides that we was taught sharing four weeks of fermented milk which was supplemented with five different organisms I'll show you on the next slide. Actually it had a difference in terms of functional MR I'm not going to try and explain this but the point of the slide was that widespread mid-brain activity was reduced in these particular patients in before and after experiments and these were normal people but it clearly shows that the ingestion of fermented milk in itself supplemented with these bacteria in fact could change behaviour. This is the only study so far in the human of a similar nature. Now these organisms make various things they make many neuro-transmitters they make GABA if we feed a particular bacterium one way or the other over here or in fact to be a phantist this is the one sold by Codran Gamelers Align you can actually increase the amount of GABA which is a major neuro-transmitter responsible for in-hymetry neuro-transmission in the brain in the fetal samples. We have taken advantage of this to then treat animals and this is experiments that have been done as yet un-published by the animals were established in Toronto using again functional MR but in this case MR spectroscopy would be so using specific approaches you can actually quantitate in vivo the amount of GABA and other neuro-transmitters in the brain in a living normal animal and you can see that in this case GABA in the prefrontal cortex is highly elevated but it only rises at this point in four weeks or 28 days and reverse to normal suggesting that the effects are limited the time dependent on the presence of the effects of the starting probiotic This is another example but looking at something entirely different I'm going to make another important molecule which affects brain and neuro-transmission Here you can see that the effects are already at two weeks of beating out of four weeks but even at the end of eight weeks at the stop of four weeks these particular modifiers of neuro-transmission are in fact so elevated There's much to be learned from this type of experiment So lastly I just want to mention this recent observation made by Sarkis-Masmanian on autism which is an increasing problem basically in paediatrics and in our population garage They did an interesting model This is a model of autism It's not autism itself but it says some very interesting things In this particular case this model is a viral mimic given a date of 12.5 of a pregnant model This is eaten and during pregnancy This is injected Then they look at various behaviours In this case it's model of variant and example of stereotypic behaviour You can see that after the polyic within a very short time they in fact have a stereotypic increased stereotypic behaviour Now if they give this B-fragivus which is the bacterium that I described earlier which I showed you also at the PSA and the component of the exo-polisacronic component if they give the bacterium beforehand and immediately after birth to the mother and offspring this is reduced to normal So there's a lot more information I haven't got time to describe it It's a model that's produced a lot of interest basically suggesting that at least in this model the incidence of viral infection in the course of pregnancy may produce lasting effects which are in fact potentially reversible by a particular bacteria So this is my last slide saying that in fact there are a lot of different effects which change the bacteria in the luminary gut through all sorts of different mechanisms which I can add to it from this slide affect the nervous, immune and the endocrine systems These are systems which each affect the other It's a very complex but in fact behaviour, mood the stress response can all be shown to be effective and many of us are now engaged in trying to translate these interesting results into a clinical situation But I think this is an example of a topic that won't go away It's a hot topic and it will reduce some interesting further information which we'll be brought to you in the next few months and years Thanks very much