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The Cost and Science of Disease with Dr Johan Van Den Bogaerde

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The Cost and Science of Disease with Dr Johan Van Den Bogaerde

Science studies continue to unravel the mysteries of our health and disease causing agents - or do they? In the pursuit of knowledge, are the narratives of those 'interpreting' scientific data influencing our health care decisions?

In this episode Dr Johan Van Den Bogaerde and Andrew embark on a robust and thought-provoking discussion challenging conventional perspectives on illness vs. disease, targets vs. markers and why we need to change the way we look at health care, end of life care and aging. They also dive into the complexity of the microbiome and why the blood-brain-barrier should be called a highway, not a barrier.

Covered in this episode

[00:47] Welcoming back Dr Johan Van Den Bogaerde
[01:24] Differentiating between illness and disease
[04:05] Treating acute trauma vs chronic illness
[08:23] Aged care and the deconditioning of our bodies
[19:08] The dangers of poorly designed studies and anti-scientific bias
[34:38] Targets vs markers
[38:00] VOMIT syndrome and over use of medical imaging
[40:40] The microbiome and the gut-brain highway
[47:01] Building the microbiome
[52:30] “Wow” studies


Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us on the line again today is Dr Johan Van Den Bogaerde. He completed his undergraduate training in South Africa with postgraduate training in the United Kingdom at Cambridge, St. Marks, and Hammersmith Hospitals. He's been seconded to several professorial and senior lecturer positions, and he currently maintains links with his local university on the Sunshine Coast in Queensland. Johan has very broad interests, including the study of the microbiome, oesophageal pathology, motility disturbances, inflammatory bowel disease, and functional bowel disease. I welcome you warmly back to FX Medicine. Johan, how are you?

Johan: Very well. Thank you, Andrew, nice to hear from you again.

Andrew: Johan, thank you so much for taking time out of your busy schedule. I know that you have a day always, you start early. Today we going to be talking...we're going to be covering several broad areas I guess in the umbrella of mental health or neurobiology. But we need to start off with a few fundamentals and a few definitions if you like. So firstly, what's disease and what's illness? What’s the difference?

Johan: I think this is an absolutely crucial aspect of understanding where we are as a society, and how we as a society interact with medicine. And medicine has become almost an industry. Disease is defined as a condition, for instance, someone with pneumonia, someone with a heart attack. We've got certain ways of treating this, we make the patients better and they continue with their treatments. Illness is the effects of the disease on patients' lives and how patients deal with this. And it's got much more to do with how we care for patients, how we look after patients, and how we monitor and manage their disability. We can measure disease, and we can do studies about disease. But we are much more limited and, in fact, probably as doctors, less interested in how the patients cope with their disabilities, and particularly how their families cope with their disabilities. And I think, this dovetails into the different spectrum of how disease has changed, and how we as a population has changed. If you think back even just 100 years ago, the main problems facing society were those of hunger, those of infectious diseases, and poor sanitation and housing. Although there's still a lot to be done this has changed substantially. And certainly, in the Western world, we've largely beaten infected diseases. We've become very, very good at managing acute diseases. And I think the absolute zenith of managing acute diseases is how we've learned to manage acute trauma.

Now, I was thinking about this a couple of nights ago, when I read an article about, it's being done in the United States, in the big teaching hospital there, where they have looked at taking in people with gunshot wounds and knife wounds that are basically dead when they arrive, and they then infuse ice-cold saline into their veins, and they put them into a state of suspended animation and then can operate for two to three hours. Now, at this stage, they've actually cooled down the brain completely. And it has been done for some time in surgical procedures that we cool patients down, but this is a completely different level of cooling down. We cool down patients to 15 degrees then and that gives the surgeon time to do dramatic things, operate in the brain and get, you know, operate, you know, punctures in the heart.

Andrew: That's 15 degrees Celsius?

Johan: Fifteen degrees, yes. And they bring them...they infuse urgently and quickly, ice-cold saline into the patient.

Andrew: Wow.

Microbiome Diversity and Faecal Transplants with Dr Johan Van Den Bogaerde - LISTEN NOW

Johan: And that keeps them going. And a very good friend of mine called Peter van Gelder, who's a wonderful surgeon went to work as a volunteer in Kandahar, and he works in the American Medical base there. And if they could bring in anyone with a pulse, and these are deeply traumatised patients that have been blown up with explosive devices and are very, very traumatised, losing multiple limbs and completely bled out. But Peter told me if they get anyone in with even the thread of a pulse, they can pull these patients through 98% of the time.

Andrew: This is the golden hour, yes?

Johan: Well, just the second you get them. Even the hours, if they're just coming with even the faintest heartbeat, barely alive, they can get pulled through. So acute medicine, treating patients that are in dire straits, getting surgically involved, that sort of acute interventional stuff we as a medical society have become incredibly good at. What we're not good at is chronic disease. We're not good at frailty, for instance. Frailty has become a separate entity really. So, frailty refers to patients who are unwell and deconditioned, living in care, where they don't have a single disease, they’ve just got a constellation of comorbidities if you would that makes them ill and unwell and eventually makes them do badly. We also know that if these patients come to hospital and suffer from something like delirium, which is an acute neurological, you can say confusion, which indicates always that there's some disease going on and it's affecting a fragile brain, that these patients have got a very high mortality. There was a Dutch study showing in patients above the age of 80 that had delirium in the hospital setting, their mortality over the next year was in excess of 80%. So there's this very important interaction with chronic disease, and then how the neurobiology interacts and how patients eventually die. And before they die, are they decompensated...

Andrew: Yeah.

Johan: ...into a state of frailty and then become incredibly vulnerable to disease. But also the interaction between society and these patients, and the interaction between the family of the patients who then become carers, and the level of support they should get, which in every society in the world, is really very insufficient. So though we're making gigantic strides and we conquered many diseases, we haven't really conquered the way that deconditioned older patients who are neurologically compromised, how they enter the last phase of their life.

Andrew: Yeah.

Johan: And I think that's where the focus of our society and our caring should be, because that's where there are enormous holes appear in our sort of medical services.

Andrew: Indeed, it's been rather widely spread in the news about, I mean, disgusting care in, not just one but several nursing homes around Australia. And it's become such an issue that now the government is looking at this issue Australia-wide. What they've found, though, is that, you know, parents are largely overmedicated so that they're basically zombies. Whereas I remember years and years ago, some very advanced nursing homes who wouldn't have one pet, let allow people to have pets, and even if that resulted in, you know, a cat eating somebody else's bird and then having an all-in fight, that was life. That was living.

Johan: Indeed. I’m very pro, and I believe, for instance, and there's been good data on that. If patients go to the hospital, one of the most dangerous things for any elderly person is to end up in hospital. What happens to any elderly person in hospital is that they firstly, get put into pyjamas.

Andrew: Yes.

Johan: And secondly, they get put into bed. Now, if you...we have, our muscles and nerves are very different to many animals. And this is a very interesting point. If a bear hibernates, which they do for six months, a bear goes and has lots of fat stores, it goes into a cave, and it lies completely still more or less for six months. Then the bear gets up and it wanders out. It has no muscle atrophy. Its muscles stay strong and fit. And the bear doesn't lose any protein mass, more or less. If you did that to a human, the human would lose all their muscle mass.

Andrew: Yeah. Yeah.

Johan: Humans have evolved in a very interesting way. We have evolved that if we don't use our muscles, the muscles immediately become virtually atrophic, so they become unusable. That's evolutionarily very, very helpful to a species that's always having feast or famine. 

Andrew: Yeah.

Johan: So if you as a human species are on the dry season on the savannah where we probably started off, and there's no food, the wildebeests are dying, then that makes sense to have tiny muscles that need very little food to sustain them. When you get food again, the muscles can grow very big and strong again.

So our bodies are designed that if we don't use our muscles, they immediately just fade away. They vanish virtually. If you take an elderly person who is in any case deconditioned and you put them on a bed for a week without any movement, that person will lose 50% of their quadriceps muscle. Now, the quadriceps muscle is the muscle that makes your leg work. That's the big muscle on the top of your leg. So, even a young fit person will lose about 50% of quadriceps muscles if they don't use them at all for a week. So we are taking deconditioned patients, we're putting them in a completely different situation where they don't recognise anything. They've got cognitive impairment, they go into delirium, they lose a lot of their muscles, and that's the beginning of the end for many of these fragile neurological patients, or any elderly patient.

Andrew: Yeah.

Johan: I worked in a hospital where there was an old fashioned matron, who would not allow patients to wear pyjamas during the day. So...

Andrew: Loving it.

Johan: ...all the patients had to wear normal clothes. They had to sit in chairs. 

Andrew: Yep.

Johan: They weren't allowed to be in their beds, and they got out of hospital a lot quicker because they were empowered. Hospital was a place where you could get intravenous medication, you could get physiotherapy and care. It wasn't a place to just lie in bed and let your muscles just fade away and let all your mobility go away and develop bedsores and embolisms.

Andrew: Yes.

Johan: So we've got to absolutely change the way we look at care, and we got to totally changed the way we look at getting old. I always say to my older patients that the older you get, the more you have to exercise. When you're young, you’ve got so much reserve you don't really have to exercise that much. But when you get old, there is this very unpleasant entity called age-related sarcopenia, which simply means as you get older you lose your muscles. And as you get older you decondition. And your...the essence of conditioning is core muscle strength, as we well know. Now, when I examine older people and not even terribly old people, people in their 50s or 60s, one of the manoeuvres I do is actually let them try and lift their legs and I can look at the abdominal musculature. You'd be surprised how few people can actually lift their legs and hold their legs straightened out in the air against any gravity for longer than about five seconds. It's actually unbelievable and that's quite a good measure of your core muscle strength.

Andrew: Right.

Johan: So that the deconditioning of body and of brain and the way they go together, and not even to mention the deconditioning of the gut, which is my special interest, is extraordinary. If you have people living in care situations with very limited diet and very limited contact with other people, their gut bacteria degenerates into a very poor quality very, you know, they...it causes the extinction of most of the species in their gut. 

Andrew: Yeah.

Johan: And that as we know now, and we can maybe speak about the gut-brain access following on from this. So they decondition their gut bacteria as well. So deconditioning is a universal illness which, you actually need to fight against. And you've got to fight against it with all your relatives, with all your friends, every elderly person you know, every elderly patient, they've got to exercise more. They're got to have a more varied diet than young people. They should have more physical contact, they should hug people, hold people, mix with people. They should be... It's, the isolation doesn't only change your mental and your cognitive state, but also it changes the bacteria in your gut.

Andrew: Absolutely.

Johan: So the way we as a society treat old people is almost equivalent to torture. You put people in a situation where they've got very little social contact, where nobody touches or hugs them anymore, and if anything serious happens to them they get put in a hospital which is incredibly unhealthy. They are over medicated. So they've given pain medication and opioid medication and opioid patches, which are extremely invasive as far as the brain is concerned. And, you know, are sedated, if they're in any way difficult, these patients are sedated. They're given hypertensive treatment to bring their blood pressure normally too low, so they fall over when they get up. Overmedication, giving a patient a tablet is easy and giving a patient pain tablets particularly, and tablets that calm them down…

Andrew: Yeah.

Johan: …that’s an easy but a devastating approach,

Andrew: It's so easy to when you think about staffing levels in hospital, in nursing homes I'm picking on here. When you look at staffing levels it's far easier to use medication to maintain the status quo, if you like, rather than engage in a lot of one-on-one conversation, some of which, as you say, you know, are difficult patients as they get old, and they might have issues that they haven't expressed, or they might even be quite delirious. And that takes a lot of manpower. 

Johan: Yes.

Andrew: So, unfortunately, the financial, you know, the economics says, "We don't want to pay for that. We'd prefer a tablet."

Johan: Absolutely. So I mean, that's, you know, the essence of what's going on here. But we can, if let's do a little bit of a thing that I feel quite serious about, that we can move over if you wish, and to the gut-brain access, if that's okay or we can carry on with this.

Andrew: Well, just one last point I wanted to make on that. Patients, if you like, or residents, people living in retirement homes. I was so warmed when I saw a recent YouTube video of the staff of someplace had organised a water slide. You know, when you put the plastic down on the grass and you run the hose over it? And they had a very big blow-up ring and they held the patients by, they secured them if you like with almost like seat belts, if you like and they held their hand so they were all safe and secure. And then they ran them down this water slide, and the joy on the patients. 

Johan: Joy, exactly.

Andrew: And what I noticed was the lineup at the back of the video, the other residents going "Let me go." People want fun, if they could only get it.

Johan: Yes. So we need to look after the patient's circadian rhythms, so they must be able to have sunlight in every day.

Andrew: Ah, yes. Yes.

Johan: We must look after conditioning. I think conditioning is the essence of healthy ageing. Conditioning is every elderly person should walk I think at least an hour a day. You don't have to do it fast, you don't have to go far, but you must be mobile and you have to keep walking. I think sitting is the new smoking…

Andrew: Absolutely.

Johan: …as lots of doctors saying that this is really bad for you. So if you can stand, but sitting is dreadful, lying down in bed should be only done at night. And I think every elderly person should have a dog.

Andrew: Oh, yes.

Johan: That's what I think.

Andrew: Absolutely. Just on that point of walking. I recently read an article, and it was saying that the faster you walk in earlier life speaks volumes as to how you'll do in later life with regards to dementia. Now having...

Johan: I think with so many... I think this is a very important point, but I'm going to now introduce us, if you would, to the concept of surrogate markers.

Andrew: Yes. Okay.

Johan: And that’s a very... So what you talking about is a study which says that if you walk briskly as a younger person, it's pretty...

Andrew: It's correlated.

Johan: ...it's correlated or predicates that you're not going to get dementia, that there's less dementia as you get older. Now, I think, so I think that's very, very bad science, and I'll tell you why.

Andrew: Okay, yeah.

Johan: I read an article the other day and every one of us reads articles in the popular press daily which say the following, and this article, in particular, said that it was shown that if you brush your teeth three times a day, it reduces cardiovascular disease by 10%. Okay, now, that's if you simply listen to that, I didn't read the paper myself, I just read the commentary on the paper. If you look at that, that would, that implies a cause and effect relationship between cardiovascular disease and brushing your teeth, which may well be so. We know that gum disease is important. And we know that they've even identified certain organisms, particularly the organism called phylomonous gingivalis, which may be associated with developing dementia. And we know that organisms and infections as a whole and your inflammatory burden does affect different diseases and can possibly affect cardiac disease. Indeed, there are some people that think cardiac disease has an infective base. So there could be something genuine in there. But my feeling is probably that the person who is brushing his or her teeth three times a day is also exercising a lot more…

Andrew: Yeah.

Johan: …is also eating a lot more fresh food, is also of an utterly different socio-economic class is probably someone who doesn't smoke either. And that's...so these spurious associations...

Andrew: The confounders, yeah, the variables.

Johan: ...these confounding variables are absolutes, make people not believe in science because they are not true. A very good example of this is the recent careful analysis which was done about the effects of eating red and processed meats. Now, for the last 20 years, we've been hearing that red meat and processed meat causes everything from cancer to obesity to high cholesterol. That's now being debunked. These and it's you know, the guidance now says, "Yes, you can eat red meat three times a week." What these studies do, and what these poorly designed associative studies do, is make people lose confidence in science. And that's the evilness of our age, that people have lost confidence in science. And this anti-scientific bias can be laid at the foot of scientists, of medical researchers who produce conflicting information, who produce bad papers, who are responsible for bad science. If you look at bad science, and they're so many different examples of this, you find that many of the scientific papers, even the best ones are not reproducible.

I read a recent article, which was devastating. They looked at the reproducibility of the hundred, or they identified 100 very important articles, very important studies, mostly in the field of oncology. And they looked at, I think 30 or 40 of the top oncology articles which have changed the way we treat cancer patients. And the majority of these papers were not reproducible. So that makes us very concerned. So even the best science, the best of our science is often not reproducible, and there's many different reasons for that. But if people who read and know and study science and certain fields such as oncology recognise that if there's a weakness in the way our scientific method is working, then it's obvious that people who aren't scientists who keep reading about the different opinions, who keep reading things that were the gospel 10 years ago are now debunked as complete rubbish, of course people are going to lose confidence in science. Of course people are going to make their own intuitive decisions, ideas which really are a little bit not clever. 

Andrew: Yeah.

Johan: But you can understand the anti-science bias which is taking over the world, and it's because of scientific laziness, and poor studies, and bad interpretation of data, and these crazy surrogate markers. Which, you know, it's very easy to make a paper and look for an association. And then, you know, you find an association and then you correlate the association. You know, red meat is bad for you. Maybe it isn't. Antioxidants, for instance, there was a very extensive literature about antioxidants...

Andrew: I hate that term.

Johan: Yes, absolutely. So most people that you speak to will say, "Well, antioxidants, it's really good, it prevents cancer" When the actual big study was done, there was no difference. The incident of the...

Andrew: Why would you want to stop oxidation if oxidation is how we get mitochondrial energy from? I think the term was wrong.

Johan: Yeah, absolutely. But you know, there was this very powerful feeling for at least a decade that antioxidants prevent cancer. And there was some very persuasive circumstantial evidence for it. When the evidence was examined in a proper study that showed that, in fact, there was no difference between the cancer incidence in people who took lots of antioxidants and those took very few antioxidants. And in fact, there was a slight increase in cancer in the patients in the antioxidant group which was not statistically significant.

So, I mean, if, you know, and this, you know, it's crazy, but no wonder people lose faith in what 'so-called' experts say. No wonder the experts have been discredited because quite often the experts talk absolute rubbish. Their studies are poor, and they use the wrong endpoints and these surrogate endpoints which don't correlate to the truth. So I can understand that people become anti-science, I can understand that people laugh at experts, but that's a real danger. And I think there are some things which are important and some things that we actually do know, quite a lot of things we don't know. But, you know, that's my little sort of you know… 

Andrew: Look, you're absolutely right. It's really interesting to me when you see a study by a major group, even a guideline producing group, and yet you'll get experts who are advising them. And I'm going to take vitamin D because I know of this story, Professor Michael Holick said, "Why are you continuing to use these minuscule amounts when you've got obese people that sequester vitamin D in the fat and it won't work? Why are you continue to do it?" Reinhold Veith, da da da, they all chimed in. Did they listen? No. What happened to the study? Negative. Therefore, the message goes out; "Vitamin D doesn't work." 

Johan: Absolutely.

Andrew: And now there's only very few studies where they used reasonable doses, and there's still a lot of conjecture on whether vitamin D works once you've got a disease, I understand that. But when even guideline groups won't listen to experts in the field, where are we?

Johan: Well, I'll give you that if we always... It's always fun talking to you, Andrew, because it's more of a conversation than, you know, and we can...we go where our minds go, which is great. I really enjoy it. 

Andrew: Yeah.

Johan: But I'll give you another example. So, a recent study, because I'm a gastroenterologist and I do some on-call work, quite a lot actually, we get called for patients who bleed. And quite often we get calls for patients who bleed rectally. And there's a big issue about when you look inside the colon of a patient who's bleeding rectally? 

Andrew: Right.

Johan: And some people think you should look very quickly. And there's some people who actually put tubes down patients noses, wash them out of saline and look within a couple of hours. And then there are other people who say let's rather wait for 24 hours and then, I believe you can wait for much longer than that, two or three days, depending on the clinical situation. So this was addressed in a very sort of substantial guideline. And they looked at the two approaches, the one really going quickly and do the colonoscope within the first 24 hours, and the other one, take a bit of time, look after the patient, and do the colonoscopy after 24 hours. And to do something, particularly colonoscopy within 24 hours within, sometimes less than 12 hours is very difficult because you got to prep the patient. Things happen at night, you got to get your theatre stuff together, that's quite a procedure. To wait the next day or day after, is much more achievable in the hospital setting, and it's much easier for the nurses and obviously for the people doing the procedure. It was clear that there was no difference in mortality between the two groups. So there was no strong indication for going in quickly and doing a colonoscopy, and indeed, in my opinion, it's actually quite dangerous because you go into a poorly prepared colon. The most common cause of bleeding in these patients is diverticular disease, and in fact, it's quite easy to perforate an unprepared bleeding patient with diverticular disease.

Andrew: Right.

Johan: So I've got quite a strong opinion on that. The editorial at the end of this paper, the editorialist who is a very senior person then said, "Well, the data showed that it doesn't really make a difference, but I'm still going to continue doing the immediate colonoscopy." So I mean, that...so even the experts discount the evidence...

Andrew: Yeah.

Johan: ...which was quite good evidence. So if we...if an expert editorialist says, "Well, the data says this, but I'm actually not going to do it anyway," then what chance do any normal people have?

Andrew: Yeah.

Johan: You know, people who aren't experts in a very specific field.

So, you know, we have to really take people along with us, tell them, "Listen, guys, this is really good stuff. This is the truth. This is genuine data. This is not some rubbish. We have to believe this data and we should...this isn't a guideline that we should follow. And it can make a difference." The problem also, of course, that when you deal with chronic illnesses, which is what most of our society is suffering from now, you don't make overnight differences. A patient with an appendix which is infected gets better within 24 hours if you take out the appendix that's infected. Patients with multiple sclerosis, you know, that's a long-term disease. 

Andrew: Yeah.

Johan: Patients with cardiac disease, that's a long-term disease.

So, you know, we, there's a completely...there are no miracle instant cures for long-term diseases. There's no instant cure, for instance, for Alzheimer's disease, there's no instant cure for diabetes. There's no instant cure for vasculopathy which is, which is, I think, one of the most important diseases that we deal with now, your vascular system.

Andrew: Diffuse vasculopathy, yeah.

Johan: Yes, vasculopathy, which affects...that causes strokes, cardiac disease, but you're not going to suddenly eat celery and reverse your vasculopathy. It's never going to happen.

Andrew: What? Who suggested that one?

Johan: Well, it's just an idiotic example.

Andrew: Can I ask a question about what the difference is between a marker and a target?

Johan: I think that sounds like a very easy question to answer.

Andrew: Is it?

Johan: But I think it's actually quite a difficult question. A target, let's say you're looking at hypertension. So measuring your blood pressure would be a marker of hypertension. Reducing your blood pressure to 120 over 80 would be the targets of hypertensive treatment. So a raised cholesterol, reducing your cholesterol is the target. So, yeah. So there's loads of different markers. Cancer markers, for instance. So if you've got prostate cancer, then your prostate-specific antigen is a marker. It's a very flawed marker and it has very many limitations as a marker, but it's a marker of disease. You take out the prostate, the prostate cancer is gone now, and the prostate-specific antigen goes down. And then you can look at the prostate-specific antigen and if it goes up, then that's a marker of recurrence of the disease. So that's sort of how it works.

Andrew: Yeah.

Johan: But markers are very often not terribly good in medicine. So let's say cancer markers are very unsensitive, and they very unspecific.

Andrew: Yeah.

Johan: And they actually caused quite a lot of anxiety where they shouldn't cause anxiety. So you get, for instance, the CEA marker is a marker of colon cancer. So sometimes, if a GP would do a CEA marker, you'd see "Oh, it's a little bit up," patients will get worried. But in fact, it's just related to someone who smokes a little.

Andrew: Yeah.

Johan: The PSA can be up a little bit and that may be related to a little bit of prostatitis, and not prostate cancer. So when there's been a, a very good friend of mine who's the Director of Oncology here, said that he doesn't really use cancer markers because they just cause anxiety and they don't contribute to meaningful decisions, you know. So I think there's got to be a lot of judgment involved in this.

Andrew: Is that sometimes though, not using them in screening, but once you have defined disease, well then you can use them to track treatment.

Johan: Yeah, that can mean different things. Like, if you got a patient with colon cancer where the CEA maker is very high, you take out the colon cancer and you monitor CEA marker. When it starts climbing up, you think that something's going on here, and you gotta look for a secondary. That is a sensible approach and the way we should use markers. But the way we shouldn't use markers is a patient comes in, "I'm a bit worried doctor, I've lost a bit of weight." "Okay, we'll do all your, cancer markers." You need about 20 of them around. You do 20 cancer markers, "Oh, no, one of the cancer markers is slightly up, this is a worry." 

And then you embark on a, on a series and there's a wonderful syndrome, which is called the vomit syndrome, V-O-M-I-T. It's almost one of my favourite syndromes. And the acronym means Victim Of Medical Imaging Technology. Have you heard of that yet, Andrew?

Andrew: No. I haven't heard of that, but I know that we're over imaging.

Johan: So if you do, because our imaging is now so sensitive, if you do CT scans, for instance, you often find little lesions in the pancreas, and then patients gets, "Oh, you got a little lesion in your pancreas." Very often it's not important at all and, you know, it's actually, evaluated pancreas is extremely dangerous because it's, you know, to get at the pancreas, and there's been some catastrophic decisions. I've a very good colleague of mine is a wonderful man said to a patient, "Look I'm sorry you've got pancreas cancer because of the CT scan." And the patient said, "Thanks doc. How long do I have?" And he said “Well, maybe a year,” and there wasn't any therapy suggested. It was a, you know, it's a very poor survival. 

Andrew: Poor prognoisis.

Johan: We know that in the last 20 years the survival of pancreas cancer has actually gone down.

Andrew: Yep.

Johan: So, you know, we think we making wonderful progress. No, we're not. Pancreas cancer is dreadful cancer and the survival really is lower than 5%. There was a little look as if it could be improving but that's only because they included the neuroendocrine tumours, which is a much more benign group of pancreas lesions into the data set. So it was a, once again, a spurious dataset. And the real survival for the classic adenocarcinoma of the pancreas hasn't improved at all. So anyway, so this colleague of mine said to the patient, you know, so the patient said, "What should I do?" He said, "Well, have fun for a year." So the patient went and spent all his money and had a fabulous time with his wife. And they toured the world and came back in a year's time and the guy was hale and hearty. So that was the incorrect diagnosis. So the problem being then that he'd spent all his money and that the lesion had disappeared. My suspicion is that he actually had, didn't have pancreas cancer, he had something called autoimmune pancreatitis, which is a rare variant and we do sometimes see that. It's like there's lots of stuff, our technology isn't always wonderful.

Andrew: No. Let's move on a little bit to the gut-brain barrier. And I think, in fact, what about this concept of the microbiome? We know that diversity is great. We know that we need good bugs. But we don't have the availability, at least not at the moment, to ensure that we can change a microbiota. 

Johan: Yes.

Andrew: We don't even know what a good one is.

Johan: Yes. So just a very brief introduction to the microbiome. And I'm going to repeat your sentence because it's such an important sentence. And there's a little mistake in your sentence.

Andrew: Yeah. There usually is.

Johan: I'm going to point out the little misconception there because that's very, very helpful.

Andrew: Yeah.

Johan: So we have up to 10,000 species of organisms in our guts, 39 trillion as opposed to 30 trillion cells, many, many more DNA and gene products from your gut than your own body makes, massively important. And you spoke about the gut-brain barrier. 

Andrew: Ah.

Johan: It’s not a barrier, it's a highway.

Andrew: Right. Okay. Yeah.Okay.

Johan: So there definitely, there is a...

Andrew: The blood-brain barrier. Yes.

Johan: ...there is a blood-brain barrier, and we can discuss that a little bit. So that sort of protects your brain from things, because the brain is a site that sort of protected from stuff that happens because it's so important. And there is a barrier between your gut and the stream of food and bacteria, your gut lining, and you do get things like leaky gut, particularly with inflammatory bowel disease. But we should rather think about the microbiome and the gut and the brain as being a giant two-way highway with fabulous fibre optic cables of the highest order connecting them. We mustn't think of them... They are one unit really, don't you think? So the gut has billions of neurons. The gut makes substances which, neuropeptides and substances that interact with the brain. We all know about serotonin. The gut makes most of your body's serotonin. We know that, that's the guts is probably responsible for causing 
Parkinsonism. We know that the microbiome affects profoundly depression, anxiety, brain function. That's extraordinary how important the gut is and how important these organisms are. 

And just to speak a little bit about serotonin, there was a study that came out about three months ago in "Nature" which is, you know, the ultimate publishing journal. And to be published in "Nature" is something I've never achieved with, nor will I ever. I'm just not scientifically good enough to ever publish in "Nature." You've got to be a genuine scientist and you got to really know your stuff to get published in “Nature." But there was an extraordinary paper in "Nature" which I think rewrites just about everything I knew about the gut and the brain, which showed that organisms in the gut interact and change serotonin levels in the gut and in the body, that the serotonin that our body produces makes these gut organisms grow much better, so it makes them healthier and more varied.

But extraordinarily, they looked at the genetics of these organisms and they looked at the genetics of our own cellular serotonin receptors. And they found a very strong homology, a similarity in the genes making these receptors. So if you just try and internalise that knowledge, which is like seeing Halley's Comet flash by, doing that, I mean, it's such an extraordinary thing. So you've had an organism which splits off evolutionarily from humans 3 billion years ago. And this organism has developed a receptor for a human brain chemical called serotonin, which is similar to the human serotonin. If this organism is fed serotonin, it grows well and it becomes happy and it interacts with the host organism, the human. If we give that human Prozac, which affects the serotonin receptor, this organism doesn't do well at all. So the Prozac that we are giving the serotonin type that binds the serotonin receptor in human cells, binds to the serotonin receptor in bacterial cells. So the bacterial cells have co-evolved a receptor which is found in human cells. I mean, how cool is that?

Andrew: Yeah. Didn't they also find this same sort of thing with Bacteroides fragilis?

Johan: Yes, a similar sort of, exactly the same sort of study. Yes. Extraordinarily that we have evolved over millions of years with our own organisms. But what's more fascinating is that, let's say an evolution of an organism or a parasite, let's say, we've evolved with skin parasites, with, you know, parasites like lice. And it's only in the last two generations that we've actually managed to control lice, and it's still a big problem. As you know, if you've got a child age school living on and, you know, they come home with lice.

Andrew: Yep.

Johan: So, the louse population and the human population has sort of evolved together.

Andrew: Quite fine, yeah.

Johan: With a gut's bacterial population, let alone the fungus and all the other stuff that grows in the gut, remember that this is a population that starts from new with every human. So when you get born, you have no gut bacteria. You start developing gut bacteria the minute you get born, the minute your mother kisses you for the first time. She starts transferring her gut bacteria to you the minute you pass through your mother's vagina.

Andrew: Yeah.

Johan: That's why there's lots of data saying that vaginal birth is better than caesarean. I don't think that is the truth, because I think very quickly in a normal family that the gut bacteria develop whether, you know, maybe take goes a bit quicker with natural childbirth than with and with caesarean, but it does eventually end up as a good microbiome depending on your family situation. But every child, every baby, is germ-free. There was some data saying that you get bacteria in the placenta, but that's been disproved. They've done...they had a very super-sensitive test in the placenta that was shown that the bacteria in the placenta are probably contaminants, that the placenta is a sterile thing, obviously, I mean, I would imagine it would be sterile. The baby obviously has to be sterile because you don't want an infected baby in a closed space. The amniotic fluid has to be sterile because, you know, you can imagine what happens if a bacterium gets into the amniotic fluid, that will kill the baby very quickly because it's a very rich field for bacteria to grow in. So you get born as a germ-free animal. And then within a very short space of time, you get you all these highly evolved organisms enter your gut, and they enter your gut, depending on where you are. So a child born in a village in Afghanistan would have a different gut biome to a child born in New York, and living in an apartment. I would much prefer the Afghanistan child's microbiome to the New York apartment gut microbiome, but you see, I think that's the essence of what we can do to our microbiome. We can change it, though. And whenever you take antibiotics, your microbiome changes, whenever your diet changes, your microbiome changes. So this is an unbelievably dynamic set of organisms. So it's millions of genes, trillions of organisms, which are robust, but sensitive at the same time.

Andrew: Yeah.

Johan: If they enter the oxygenated air, because they're anaerobic, they die. If you try and culture them, it doesn't work because they don't like being cultured in a lab. They only like growing in your gut, where they grow very well. If you take an antibiotic, they die. Not all of them, but it changes their population dynamics. If you take a faecal transplant, you take someone else's microbiome, you can change it. So, but the microbiome affects things acutely, definitely. So it can make you acutely unwell if it isn't healthy, such as in Clostridium. If you get a Clostridium difficile overgrowth, it’s a toxin, you get after antibiotic treatment, makes you very, very ill, that's an acute disease, you can change that you can cure that with antibiotics, or much better get a faecal transplant. 

But the microbiome-associated other diseases, in particular, the neurological diseases or chronic diseases, and it looks like there's an association between your microbiome and autism, and there's some very strong data about that. And it looks like there's an association between your microbiome and the development of Parkinsonism. Definitely, with the development of depression, your microbiome could be extremely important. With the development of chronic liver disease, and hepatitis and alcoholic hepatitis, your microbiome is involved. So your microbiome is involved in lots of chronic diseases. So changing the microbiome, yes, we can change it. What is the optimal microbiome? We don't know but you probably find the best microbiome somewhere in Tanzania or Afghanistan. So living that sort of lifestyle, maybe without the political instability would be nice.

Andrew: I don't whether I'd like fricassee to antelope intestine though.

Johan: No, of course not. But you know what I mean. So we can change the microbiome, we can change it for the worst, and we can change it for the better. We know what's bad for the microbiome. We know what's good for the microbiome. So we can change things, we can perturb it. But the effects of a good microbiome are in decades measured, not in months, or weeks or days, but decades. We know that the microbiome is, for instance, involved in colon cancer, but you certainly aren't going to have a colon cancer and start eating, you know, good healthy village food and get a fantastic microbiome, and cure your colon cancer.

Andrew: So this is the thing between the marker and the target, correct?

Johan: Absolutely. Yeah. So that's sort of how we have to look at.

Andrew: So, I mean, there's so many subjects, in here but just quickly, I mean.

Johan: I'm going to leave you with one thought which is an incredible and just indulge me in this, please, Andrew.

Andrew: Yeah.

Johan: So there was a recent paper looking at studies, which sounded amazing. Okay, so you get studies, for instance, that say, if you treat hypertension, well, the patients do better. Yes, yawn, that's obvious. Okay. But then you get these wow studies that are exciting and that get published all over the place like brushing your teeth three times a day protects you against cardiovascular disease, you know, the wild study. Or, you know, there's bacteria growing in your gut that go into the breast and reconstitute the bacteria in babies. "Wow, how does it work?" Anyway, they looked at the wow studies, they showed that most of the wow studies are not reproducible. And they showed these wow studies to completely normal non-scientific people. And they found, and they just said, "Would common sense dictate that they believed these studies or not?" And they saw that common-sense evaluation of the wow studies was as good as any scientific evaluation of the wow studies in debunking these studies.

Andrew: Right.

Johan: So the rule there, and it’s a genuine rule. And it's been shown that if you see a study where you think, "Wow, this is unusual, or good heavens. I don't understand how this works and it doesn't really make sense. But it sounds exciting," that study is probably wrong. And the best way of assessing that study is to get 100 ordinary people to look at the study and think about and say, "Well, I don’t believe that." So using the sort of common sense approach and just listening to what you've told me about the study and having done a little bit of reading about it, and recognising that I say, "Wow," and that you say, "Wow," and that another 98 people will say, "Wow, that sounds really cool,"...

Andrew: It's probably not right.

Johan: ...it's probably not true. Does that make sense?

Andrew: Yes, it does I mean, we certainly have to reproduce it, that's for sure. And it's certainly got to be reproduced by other groups. That's the whole point about proving science, if you like.

Johan: You see, so the placental microbiome work, which was a similar sort of thing where they looked at the placenta, found bacterial DNA, let's say in the placentas in the lab, that was contamination. 

Andrew: Yeah.

Johan: Because the PCR technique, which is an amplification technique, is so sensitive, that you can have one bacterium or a bacterium could float in from anywhere and it will be, produce a signal.

Andrew: Yeah.

Johan: I think a lot of these studies are PCR-based, which means polymer chain reaction…

Andrew: Yep.

Johan: …which is an amplification cascade, which allows us to assess DNA that's 50,000 years old. It's a super-sensitive technique. And I think it's too sensitive and it leads to contamination, and this sort of wow thing turns out to be not true.

Andrew: Yeah. Let's carry on next time when we delve into the gut-brain highway.

Johan: Highway.

Andrew: And we'll talk about how we can actually help people with neurological disorders.

Johan: Absolutely, I'd love to do that. Thank you, Andrew.

Andrew: Johan, I love chatting with you always. Thank you so much for joining us on FX Medicine today. And I will say one thing, I admire you. I have admired you from the first time I heard your voice.

Johan: Thank you.

Andrew: And I look forward to welcoming you back to FX Medicine. Thanks, Johan.

Johan: Thanks, Andrew. Thanks for calling.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.

Other Podcasts with Johan include:


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