This Podcast Will Kill You - Ep 28 H. pylori: Don't try this at home

Episode Date: May 28, 2019

This week's episode comes with a warning: don't attempt this at home. While self-experimentation has led to many a scientific breakthrough, we're definitely not advocating it. But it happened to work out for the best for Barry Marshall and Robin Warren, even earning them a Nobel prize. That’s right folks, today we’re talking about none other than Helicobacter pylori, the curvy little bacterium identified only a few decades ago to be a causative agent of peptic ulcer disease, a major risk factor in the development of gastric cancer, and a fierce warrior who can survive the harshest of environments: your stomach. See omnystudio.com/listener for privacy information.

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I didn't tell anyone, not even my wife or Robin, until afterwards. I asked my boss in gastroenterology, Ian Hisslop, to do an endoscopy for me one day. As he put the scope down me, he was saying, Barry, I'm not. going to ask why I'm doing this. And from around the tubing, I gritted out, just take the biopsy. So he took some biopsies from me, and they were all clear, no bacteria. Then I infected myself with bacteria that I'd cultured from a patient who did not actually have ulcers, just indigestion and gastritis. I was able to eradicate his infection with some antibiotics, so already I knew that I could, if necessary, take a treatment which worked on this bug. I had some safety features

built in, I thought. I drank the bacteria, and at first I was okay. But instead of being perfectly well and having a silent infection, after about five days, I started having vomiting attacks. Typically, at dawn, I would wake up, run to the toilet, and vomit. And it was a clear liquid, as if you had drunk a pint of water and regurgitated it straight back. Not only that, there was no acid in it. I remembered from my medical student days that if you have a meal where you drink so much beer that it's coming back up straight away, it doesn't have any acid in it. I knew there was something unusual about vomiting and not having acid. And this is just one experiment on yourself, and you say, am I imagining this?

Until I had another biopsy, I couldn't know for certain that I had the bacteria. Finally, after 10 days, I had the biopsy, had another endoscopy, and the bacteria were everywhere. In the lining of my stomach, there were absolute millions of the white, cells that we call pus cells, polymorphs. There was no acid being produced by my stomach. I was very uncomfortable with that endoscopy, gagging and throwing up. But I'd proven that the bacteria could infect a healthy person and cause gastritis. I'd proven Robin's disease. That's a really good one. I love that one. The words from the man himself, Barry Marshall. So that was from an interview conducted by Dr. Norman Swan in 2008 for the Australian Academy of Science.

Sorry, I didn't read it in an Australian accent. I'm not sorry. I think that everyone will forgive you. I think they'll be thankful for it. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're talking about helicobacter pylori.

Wonderful little bacteria. Just such a gem. Okay. So before we get into all of the nitty-gritty of the horrible things that it can do to you, let's get into the nitty-gritty of what we're drinking. What is our quarantini? Well, of course, it's Barry's Beaker.

Barry, because Barry Marshall, one of the co-discoverers of this link between H. Pylori and ulcers and gastritis, et cetera, et cetera, who we just heard from in our firsthand account. Yeah. And so imagine as you're sipping this quarantini that you are Barry Marshall taking that sip of the inoculate of H. Pylori to give yourself gastritis. So yum.

In the name of science. All in the name of science. That's what we cheers to today. Yes. So what are we cheersing with? What's in this drink? Oh, yeah. Okay.

So it has got coffee because coffee. definitely exacerbates. Ulcers. Ulcers. It's got, well, alcohol in the form of rye whiskey. It's got chocolate liqueur and hazelnut syrup. Yes. Yum.

Soup's delish. And so we'll post the recipe for that quarantini and for our non-alcoholic placebo rita on all of our social media pages. TPWKY on Twitter. And this podcast will kill you on Facebook and Instagram. And we'll also post it on our. website, this podcast will kill you.com, where if you haven't already, you can also find our merch. Yep.

Whoop, whoop. All right. So should we just jump right into the podcast today? Yeah, I'm really excited about this one. We too. We're always excited, though. I know. It's good.

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Helicobacter pylori is a gram-negative bacterium, and the truth is that over 80% of people who are infected are acolyt. symptomatic. So that's probably at least one of us. Yeah, statistically speaking. It's highly likely. So that's interesting. I never thought about getting tested. Have you ever had any ulcer symptoms or gastritis? No. Well, I'm having some right now, but that's unrelated. Another burrito for breakfast? Well, you know. Okay, so H. Pylori is shaped a little bit like a helix, which is where it gets the Helicobacter from, but it's not a spirochete, like a spiraled bacteria. It's actually just a curved

rod. And importantly, it has flagella on it, which it uses to move. And it's a very highly motile bacteria. And that'll become even more important as we talk about the pathophysiology of this disease. So the transmission is actually not entirely clear, which I think is so interesting. Yeah, that is really interesting. Yeah, we don't really know how people get infected. The thing is, it's estimated that up to 50% of the world's population is infected with H. Is it vertically transmitted then, like mother to offspring? Great question.

I haven't seen any data that suggests that it's directly vertically transmitted. Most of the data that I've seen suggests that it's either fecal-oral or just through saliva. Okay. So it could be that mothers pass it to their offspring indirectly, but not directly through what we would normally consider vertical transmission. Okay. Okay. Interesting. But yeah, it's very interesting that it's unclear how this bacteria that is so widespread is actually transmitted. And so is it because it could be transmitted in many different ways? It's likely not just one? I mean, potentially, yeah. I really don't know. That's not what I was expecting.

I know. It's not what I was expecting either. Cool. It's, yeah, there's not a lot of evidence that it necessarily persists in the environment, but the fact that it's so widespread suggests that maybe it actually does somehow. And the other thing is that it's really easy to infect children, but the people who tend to be most infected are actually adults and not necessarily children. So that's pretty weird too. So children clear the infection?

maybe, but then do they get re-infected, or is it just that they actually don't get infected as children? Like, if you screen a bunch of children, most of them are not going to be infected. If you screen a bunch of adults, a lot of them will be infected. But children are just as susceptible as adults. And usually if you have something that's transmitted fecal oral, you might think that children would get it more frequently than adults because they're more likely to put poop in their mouths and things. Yeah. Anyways, we don't know exactly how it's transmitted. But we do know the kinds of symptoms that it causes.

So acutely, an acute infection shortly after you're infected, you can get symptoms of acute gastritis, which basically is just inflammation and irritation of the gastrointestinal tract. So maybe some abdominal pain, maybe some nausea, like good old Barry tended to experience, sounds like. But often you don't get any of these symptoms. What usually happens is that the helicobacter develops into a chronic infection. It basically just lives, makes a home in your stomach mucosa. And this is impressive because your stomach is a pretty inhospitable environment, right? The pH is like two. It's between 1.5 and 3.5, which is really, really acidic. And on top of that, it's constantly moving. Your stomach fills. up with food and then it has to empty out. And to keep all of the stuff that you eat from going back up and out your esophagus, it's always undergoing peristolsus, which are these rhythmic

contractions that it does in order to push the food out into your duodenum, which is the first part of your small intestine. So it's not a static environment. It's a super dynamic environment. So how can this measly little bacterium survive in such difficult conditions? Do you want to know? I do want to know. Why I'm here. It has two main mechanisms by which it's able to survive. First of all, it has those flagella.

So flagella are basically protein structures coming off of bacteria that they can use to swim. So once the helicobacter pylori makes it into your stomach, it can resist being flushed out of your stomach with the rest of your food because it can swim against the current. that's a very powerful flagella I know right they have like four so you could say flagella okay those are some powerful flagella

yeah they're really powerful and then they can use them not just to swim against the current of peristolsus but to swim down into the mucus that lines your stomach so for a little bit of basic stomach anatomy because your stomach is such a harsh acidic environment your stomach cells produce a ton of mucus, and that mucus lines your stomach cells in order to protect your own cells from getting eaten away and eroded by that acid.

So the mucus forms this like protective lining. The helicobacter can use those flagellas to kind of burrow their way into that mucus layer. Oh. Yeah, it's pretty cool. And a lot of times they actually live in that mucous layer. But if they wanted to, they could swim down through that mucous layer and actually attach directly to the epithelial cells. They have these special proteins called adhesens that adhere to the epithelial cells. And that way, it's another mechanism by which they can make sure they don't get flushed out.

Okay. So they're very good at, A, swimming against the current, down into your mucus and potentially attaching to your epithel. cell. So that's the first way that they're able to survive. The second way is that they actually can neutralize their own microenvironment. Oh, cool. Right. Sort of like their own little pod of bubble, like a little, the bacteria in the bubble. Right. Exactly. So if the pH directly surrounding the bacteria is too low or too acidic, they produce uriase, which is an enzyme that breaks down urea, which is a normal waste product that's found throughout your body, that when it's broken down, breaks down into carbon dioxide and ammonia. And ammonia is a base. This base neutralizes

the acid immediately surrounding helicobacter bacteria so that they can live happily ever after in a slightly less acidic environment. Isn't that cool? That's really cool. So they're good swimmers. they can stick to your cells and they change their own microenvironment to be more hospitable for their growth and survival. Huh. Okay, so the thing about H. Pylori infection is that there are two different interrelated long-term issues associated with chronic H. Pylori infection. Because again, this is a bacteria that essentially makes its home in your stomach and lives

there for a very, very long time. All right. These two different issues, they're related, but they're also kind of opposite, which I think is really interesting, and it seems like it's not entirely understood yet. But the issue that you end up with depends on where in your stomach these bacteria colonize. Okay. Okay. So if H. Pylori colonizes in what's called the antrum of your stomach, which is closer to the output end of your stomach, then what it tends to do by mechanisms we don't fully understand is it causes hyper-secretion

of acid. So it actually increases your acid output. And if your stomach is making too much acid, that acid overflows out of your stomach and into your duodenum. This causes chronic irritation of your duodenum that leads to what we call gastric metapagia. Gastric means your stomach, and metapagia means your cells are changing in shape and type. So it means that your intestinal cells start to look more like your stomach cells. Ooh, that's really weird. It's really weird and it's not good. This leads to duodinal ulcers.

Okay. Okay. So you've got acid spilling out of your stomach into your duodenum, causing irritation and cell changes that lead to ulceration, which are basically holes that form in the layers of your small intestine. Okay. So I have a question. So you said that if the bacteria are in the output end of your stomach, then stomach acid

production increases, but doesn't that make the environment more inhospitable? So is it your body's reaction? It's not that bacteria that are producing the acid. It's your body being like, wait, there's your neutral. too much? That's a really great question. It's not entirely clear. It's suggested that maybe they damage certain cells that would decrease acid production, so then they end up overproducing acid because those like inhibitory cells are damaged. It's totally unclear. And it's about to get even weirder because that's not the weirdest part. Okay, good. Great. Yeah. Okay. So that's how you end up

getting duodinal ulcers if you have an H. Pylori infection. That's not the only thing you can end up with. If H. Pylori colonizes higher up in what's called the body of your stomach, closer to the input end of your stomach. That's like the big section, the big fleshy lump part? Yes. Okay. Not so tubular? Not so tubular, exactly. If it infects there, it actually decreases acid production. Okay. Now I'm confused.

I know, right? So H. Pylori, if it infects higher up in the body of your stomach, it actually tends to lead to acid hyposecretion, less acid secretion, which increases inflammation because the cells are invading in that portion of your stomach and they're directly causing inflammation. So it's not the acid itself that's causing an ulcer like it is in the duodenum. It's the bacteria itself causing. ulcers in the stomach from the inflammation. Interesting. Okay. And on top of that, your stomach cells undergo what's called intestinal metapagia. So now your stomach cells look less like stomach cells, more like intestine cells. They can't handle the acid that is there. So that further leads to gastric ulcers and gastric ulcers can lead to gastric cancer.

Okay. Hold on a second. So let me just get this straight. Depending on where these bacteria colonize in your stomach, it can either make your stomach look more like your intestine or your small intestine look more like your stomach. Yes. That's bizarre. I love it. So bizarre. It is fascinating. And it's completely different mechanisms, right?

Like in one, you're ending up with hyperscretion of acid, in one you're ending up with hyposecretion of acid. In both, you end up with ulcers, and in one you end up with cancer. And that's with the gastric. The gastric. Yeah. Okay. So can we just do terminology really quickly? Absolutely.

Because I read so many different words in front of ulcer. So there's peptic, there's duodenal, there's gastric, and is peptic just an umbrella term for stomach ulcer? I believe so. Yeah. Peptic ulcer disease is just you've got an ulcer somewhere around your. stomach. A duodenal ulcer is an ulcer in your duodenum, so that's the first part of your small intestine. Those ulcers have a very, very, very, very low risk of ever developing cancer. They basically,

you basically never get cancer in your small intestine for whatever reason. It's very rare. They can erode all the way through and then cause massive bleeding, but you don't tend to get cancer in your small intestine. Gastric ulcers are an ulcer in your stomach, and those do have a pretty high rate of converting into gastric cancer. Okay. Okay. I think I've finally got that location and the umbrella terms down. It's a lot of words.

Yeah. So that's how they cause disease. We know very little comparatively about H. Pylori, less than I expected, quite honestly. Well, it's a pretty recent discovery. It's true. It's true. Okay. So if you are infected and you are showing symptoms, like what are the symptoms or signs that you

experience if you have peptic ulcers or gastritis or whatever else? Like, is there a difference between the ulcers and the symptoms? Yeah, it's a great question. So you can't tell the difference between something like gastric cancer and just peptic ulcer disease based on symptoms alone because the symptoms are actually very similar, if not exactly the same. Oh, my God. Great. So you could be like, is this an ulcer or cancer? WebMD might be right.

Don't trust WebMD on this. Let me tell you. But the symptoms include things like a burning stomach pain. So people of peptic ulster disease might often say they have acid reflux. Okay. Right? So you might have like a burning in your sort of substernal region. You might have a feeling of fullness or a lot of bloating in your stomach. you might have nausea or vomiting, especially if you're vomiting something like blood that's suggestive of something like peptic ulcer disease. Your face looks a little horrified. Just the concept. Yeah, vomiting blood, nope. Yeah. And then the other things that we get really concerned about if you have these type of

signs are things like unexplained weight loss because maybe you're not eating as much because you have pain when you eat. so unexplained weight loss or appetite changes and then dark stools because what can actually happen is that those ulcers can cause bleeding and if you're not vomiting up the blood it'll travel through your gastrointestinal tract and by the time it comes out in the stool it doesn't look like blood anymore it just looks like very very dark stools so if you've ever had a doctor ask you are your stool's dark that's what they're asking about is there secret blood is did you eat beats no yeah that's a little different the episode of portlandia where there

it's beats with jeff goldblum yeah is it beats okay anyways yeah anyway yeah so those are the symptoms and you can't necessarily distinguish especially those more severe symptoms of peptic ulcer disease from gastric cancer just based on symptoms so we do what what's called an endoscopy, which is where they put a camera down into your stomach and they take a look at the ulcer. If they find an ulcer, then they can biopsy it and then figure out what's going on. Okay. Is that usually the first step is an endoscopy if you have symptoms, or do they do the breath test or what? So the uriase breath test is a test to check for H. Pylori infection. And yes, you can absolutely do that. So if you go to a doctor with

symptoms of peptic ulcer disease, it's very likely that they'll do a uriase breath test. The other thing you can do is treat the H. Pylori. So it is treatable. It's a little difficult to treat. There's three different medications that you give. First is a proton pump inhibitor, which decreases acid production. Second is two different antibiotics. And you take these for quite a long time. I think it's at least a few weeks of antibiotic treatment to clear that H. Pylori infection. And if your symptoms go away, then it was all from the H. Pylori. And if they don't, then they'll probably do follow-up treatment. So yeah, that's that's H. Pylori infection. How interesting. Yeah. Wow. It's a fun little bug, I think. It's definitely got a lot of tricks up its sleeve.

It's got a lot of tricks and we, there's so many that we don't know yet, which I think is so fun and interesting. Yeah. So, Aaron, how do we get here? Where'd this thing come from? Oh, I can't wait to tell you. Good. a little break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's Working Hands hand cream is such a relief.

It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments.

It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is, outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit o'keefs company.com slash this podcast and code this podcast at checkout. Texting privacy policy and terms and terms posted at textingterms. Texting enrolls you for

occurring automated text marketing messages. Message and data rates may apply or place stop, opt out. Visit ISSA online for details. Excuse me. What do you do for a living? Weight tables. You like it? Not really. Do you work out? Every day. Best part of my day. Would you like to get paid to work out? Are you kidding me? How? With ISSA, you could be become a certified personal trainer in as little as six weeks. Once you're certified, you can start your own business. Work at a gym or just do it as a side hustle. Some trainers are making as much as $100 an hour.

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It's not. It's old? It's really old. We've always had ulcers. Actually, kind of. So humans in H. Pylori have been together for thousands of years. So since before humans left East Africa over 50,000 to 70,000 years ago. Holy cow.

Yeah. So which explains why there's such a huge proportion of the population that's infected, it's really just been with us. So researchers can actually see the traces of different waves of human migration in the genetic diversity of these H. pylori strains. Stop it. Yes. I love it when we get to talk about human migration because of disease. I know. It's really cool. So basically, as a general rule with this, the most genetically diverse H. Pylori strains are associated with the oldest migrations and the source population in East

Africa when humans migrated out. And then the genetic diversity decreases with each migration and then distance and so on. So, yeah, isn't that cool? Yeah, I love it. All right. So we've got this evolutionary evidence of early human and H. Pylori associated. and we've also got ancient writings about ulcers and gastritis. So gastric symptoms have been recorded for millennia, dating back, of course, to Hippocrates. Where would we be without Hippocrates? Nowhere. Not on an episode of this podcast will kill you. Nope.

So yeah, so Hippocrates described epigastric burning, like indigestion, and air swallowing, both of which are symptoms of gastritis, I think. Is air swallowing just burping? Air swallowing is what was written. Weird. Maybe it's just burping? I don't know. And around the same time as Hippocrates, there is an inscription carved on a pillar at the temple of Asclepius at Epidaris that might be describing how to perform surgery on a gastric ulcer.

Ooh. Quote. A man with an ulcer in his stomach. He incubated and saw a vision. The god seemed to order his followers to see. seize and hold him that he might incise his stomach. So he fled, but they caught and tied him to the door-knocker. Then Asclepius opened his stomach, cut out the ulcer, sewed him up again, and loosed his bonds. He went away whole, but the chamber was covered with his blood.

What earth? One star. That's just inscribed on a pillar at a temple? Yeah, I don't. It's a story of we're going to do surgery on this guy against his will. I don't know, but we should add that to our like TPWKY. Take a picture of this and also our personal vacation list. Oh, yes, 100%. Yeah.

So we also, in addition to this pillar, we also have a mummy dating from a little bit after this around 167 BCE from the Western Han Dynasty that appears to have a peptic ulcer. We don't know if it was caused by H. Pylori, but yeah, definitely seems possible in a mummy. Wow. Isn't that cool? That's so cool that mummies are preserved so well that you could see something like that in the tissue. I know. So about a thousand years after that, we get a bit more specific when even Sina, Avicenna, wrote about how some of these painful or uncomfortable symptoms appear after you eat. he even went as far to suggest that the pain, heartburn, and thirst felt by some people were all caused by gastric ulcer. Okay. Then in the late 1500s, so about 500 years after Avicenna described this, the first gastric ulcer was definitely described by the Italian physician Marcelo Donati.

During this time, anatomical descriptions from dissections of human cadavers were getting super popular. and so people were starting to take a note of the inflammation and ulceration of the mucosa in their cadavers. I didn't see anything about numbers through the ages in regards to the prevalence of gastric ulcers. I think that would be a really hard thing to estimate, and especially since it's been with humans for, since humans have been humans, basically. Yeah.

Yeah, it was probably pretty prevalent at least. And also we can guess that it was pretty prevalent based on how many descriptions there were of it and how much people started to pay attention to it as cadaver dissection was a lot more popular. And then came to 1600s. Microscopy was developed and popularized by a couple of big names, but probably the biggest name is Anthony von Leuwenhoek. The impact of his technology and also how far it has come today really should get an episode of its own. Wouldn't that be fun? Yeah, for sure. I love the history of microscopy. But the important thing is that microscopes allowed people to see this whole new world,

which had been invisible to them up to this point. Essentially, this led to the field of microbiology and molecular biology because people could finally start understanding how the pieces that made up living organisms fit together. Bacteria were described and started being blamed, rightfully so, in some cases, for many diseases, and people started sticking everything they could find under these new lenses, and stomach tissue or stomach contents was no exception. And because bacteria live on basically every surface ever, of course stomach contents look to be chalkful of bacteria.

Some of these microscope lookers became convinced that the bacteria were the cause of gastric inflammation and disease, and a couple of these people had identified bacterial colonies in gastric ulcers and in the surrounding mucosa and went so far as to say that these bacteria were the cause of ulcers. So that was in 1875. Whoa. Yeah.

They were like, oh, there's bacteria here. It seems to be in a lining. It seems to be associated with inflammation. This is what causes the ulcers. So then what happened? Why did it take us another 100 plus years to figure it out? Okay. Well, I'll get to that.

But yeah, it did kind of, the link didn't necessarily. become forgotten, but it definitely was not as popular as some of the other leading hypotheses. Interesting. And so the late 1800s did see some other progress regarding bacteria and peptic ulcers and gastritis. For instance, the pathologist Arnold C. Clebs, who was son of the Clebs for whom Clebsiello was named. Yes.

He spotted a bacillus in the gastric glands, which he noted were inflamed. And so this could be actually the first sighting of H. Pylori infectious gastritis in humans. And then there was an Italian anatomist named Bizoero, who reported his findings of a spiroquite-like organism in the stomach lining of several dogs that he studied, which was probably a helicobacter species. And remember those two guys who I just mentioned that first declared this link between gastric ulcers and bacterial infections? So even though mostly everyone else had dropped that concept, they were still convinced. And so by 1888, a ton of progress had been made in identifying different bacterial species and the diseases they caused just in general. So these guys started picking candidate microbes, such as staphoreas and strep,

to see if they caused ulcers when injected into the stomach of various lab animals. And no surprise, they did. But that was sort of a problem, right? Because if all of these different species could cause gastric ulcers, how do you distinguish between the types of ulcers and between whether this bacteria causes an ulcer or whether they're just general ulcer causing bacteria? Right. After Latoul was able to induce ulcers in his guinea pigs, other people started to get

interested and found that a whole bunch of bacterial species could lead to gastrododinal ulcers. But there was still so much to be figured out. and gastric ulcers were a tricky business because like I said, you can get ulceration with many different diseases and you could induce it with many different bacterial species. So how do you pinpoint exactly which species causes ulcers for sure rather than just these opportunistic infections? Right. Or which does it in real life versus just if you injected in the lab? Exactly. Yeah. And so really what became more popular in terms of why gastroids, and peptic ulcers exist, was that excess acid. That was it. And that could be triggered by the

ingestion of foods or drinks, high in acidity, stress, et cetera. And this explanation resolved a few things that were maybe a bit more difficult to align with the bacteria hypothesis. So often people who experienced ulcers didn't have symptoms all of the time. They had flare-ups and then they would resolve after cutting back on certain foods or taking loss of anti-acids. And so during this time, it was basically conventional wisdom that bacteria couldn't survive in the high acidity environment of the stomach. So if bacteria were found in the lesions, they were probably from ingested food, or the stomach was weakened enough to allow for these opportunistic invaders.

So it was like they were secondary, the ulcers were the primary, rather than interesting. Yeah. And it wasn't so much that people weren't finding H. Pylori and stomach tissue. A campelobacter-like or curved rod bacteria had been reported as part of the gastric flora for decades. But no one had had much luck in investigating them. In the 1950s, someone named E.D. Palmer decided to take a closer look, and he concluded that they were just normal commensals of the mouth. These curved rod bacteria were basically cast aside as unimportant.

which really kind of held back the field probably for a few decades. All right, let's take stock of where and when we are. It's the early 1980s, and the excess acid hypothesis was the prevailing one, despite some reports in the late 70s of epidemic gastritis with hypokorhydria, so low acid. Oh! And findings of gram-negative bacteria in association with acute gastritis. Oh my gosh, I'm getting really excited.

So the bacteria hypothesis is still hanging in there, and one of its proponents is an Australian pathologist named Robin Warren, who was working at the Royal Perth Hospital in Western Australia. Warren had a hunch that the gastric ulcers he had seen in patients over the years had bacterial origins. In 1981, he had written a letter to another doctor asking whether there were any gastroenterologist that wanted to work on uncovering this mystery with him. And this doctor just happened to show this letter to a young physician named Barry Marshall, who had just started his gastroenterology fellowship term, where he would have to come up with a research project to do.

Oh, my gosh. Can you even imagine being like, yeah, it's my first year of fellowship and I need a project. Oh, this sounds great. And then it's H. by Lori. Oh, my gosh. it would be incredible. And I mean, I think it was like, so from all of the different things that I read, their personalities were perfectly suited to one another and to solving this problem.

That's so cute. You have Robin Warren who seemed, from what I read, to be very methodical, very detail-oriented, very sort of like step one, step two, step three. And then on the flip side of that, you have this young, like, sort of energetic, impatient guy, Barry Marshall. And so they balanced each other out really well. And they were both, I think, most importantly, iconoclastic. They wanted to fight for this hypothesis because I think I quote or something, well,

I'm not going to quote actually. Because I think that for Robin Warren, he was most fascinated by the fact that these bacteria were somewhere they shouldn't be. Yeah. And Barry Marshall wanted to. wanted this opportunity to prove everyone else wrong. Of course. So it was just the perfect combination of things.

I love it. Yeah. Okay. Marshall decides to join this project. And neither of them had strict backgrounds in microbiology. So they decided to, you know, say, who cares? We're going to try to do this anyway. We're going to isolate and culture this campbellobacter-like bacterium that Warren had found in so many of his patients.

I also wonder a bit about whether not having that microbiology or gastroenterology specific background probably helped them a bit too, sort of not having those preconceived notions or the dogma that are so pounded into you during particularly research training. Yeah, you haven't already been sort of indoctrinated or ingrained on any one specific belief. So you have this option to just explore all these different. possibilities. Yeah. Thinking outside the box is much easier when you don't know the shape of the box that you're in. Totally. Yeah. In any case, they started their microbe hunt, not necessarily starting out saying that these bacteria caused ulcers, but more, hey, look what we found. It's a new bacterial species that can survive in the gut, and maybe it has some links to gastritis and inflammation. But saying you're going to isolate and culture an undescribed bacterium is quite different than actually

doing it, as they both learned. Culturing something new can be a bit of a tricky game. You have to figure out the or know the right culture formula to use and the right settings for optimal growth. And when something is as extreme as something that can live in your stomach's acidic environment, it's a difficult place to start. Yeah. So after months of trying to culture isolates from gastritis patients and not getting anything, they may have started to lose a little hope. But then a fortunate accident occurred, as these things do, seem to happen. It turns out that the lab tech who was responsible for culturing the isolates and checking on those cultures was throwing away the plates or broth after two days.

Oh. This was happening at a hospital. Hospital is busy place. It tends to be chaotic. There's a lot of other epidemics and things going through the lab, so there really wasn't room for dozens of stomach bacteria culture plates to just hang around. But on a particularly busy weekend, Easter weekend, in fact, the tech didn't have enough time to look at the plates after the usual two days,

so he left them over the weekend until Tuesday, five days after the biopsy. and when he went back to check on the cultures, boom, colonies were present. They were just slow. They were just slow. Little babes? They're like, give me some time. Yeah. I'm growing here.

So these bacteria had probably been in all or at least the vast majority of those samples, but they just needed a little bit longer to incubate. So now that Marshall and Warren could culture these bacteria, they could do so many things. They could find out what antibiotics could be used against it, try to develop an animal model of infection, try to find out what these bacteria were related to, and most importantly, try to find out what these bacteria did in the stomach.

So they decided to test 100 patients to see if the bacterium was present and to look for patterns of infection or any sort of disease state, and they found that all patients with duodenal ulcers had the bacterium. Not conclusive, but definitely suggestive. Marshall and Warren then started to develop a hypothesis. These bacteria caused gastritis, and then gastritis leads to ulcers. People could have recurrent ulcers because their immune system would be stronger at various points or whatever,

but the bacteria would always be there, so it never went away completely. And this also explained why earlier trials of physicians treating their gastritis patients with antibiotics saw a reduction in acid and symptoms. They tried to publish some of their findings in The Lancet in a letter and as an abstract at an annual meeting of the Gastroenterological Society of Australia, but faced difficulty and rejection. Yeah. The Lancet couldn't get reviewers to agree on whether their findings were important or whether

their conclusions were true. And the Gastroenterological Society of Australia just flatly completely. rejected their abstract. They were like, we received 67 submissions and we could only accept 56 this year. We're sorry we couldn't get yours. Those are the numbers. Why did they have to point out how many there were? And why 56? It just seems unnecessarily harsh. Can you not just put up a couple extra boards to tack your poster on? I mean, goodness. I know, right? Seems rude. So the Bacteria hypothesis seemed to fit with so much of what was known about ulcers, but this concept met with a ton of resistance among doctors, many of whom would dismiss the bacteria as being

opportunistic, only able to establish after the stomach was already weakened. And they would argue that if this bacterium actually caused disease, the link would have been made a long time ago. That's so silly. Yeah. I mean, after all, it had been observed in the stomach for ages, so it should have been known by now. things weren't always civil and there was a lot of rude or dismissive comments made behind Marshall and Warren's backs and many did not take them seriously as not having official microbiology or gastroenterology credentials. Then the ulcer drug business, which was one of the biggest in the 1980s, wasn't exactly

in support of this notion. Something I never thought of before reading this article. People with gastritis or ulcers were spending a little bit of money every day on the drugs, and they were often long-term, if not lifetime, customers. So if you could cure those conditions with the course of antibiotics, boom, the industry would be devastated. Yeah. So they spent a bunch of money doing research trying to prove that ulcers were not caused by bacteria.

Shocking. Right. Even though their research was sound, Marshall and Warren had to demonstrate the cause and effect of the bacteria and ulcer, that the bacteria caused gastritis and ulcers, not that the ulcers paved the way for the bacteria, but they couldn't get the bacteria to infect any animal models. So, like you heard in our first-hand account at the beginning of the episode,

Barry Marshall took it upon himself to take a swig of the bacterial culture from a 66-year-old non-ulcered dyspeptic man after first establishing Marshall himself had no gastric ulceration or inflammation. Within less than two weeks, all of those symptoms appeared, and the final confirmation came in the form of an endoscope. The infection seemed to more or less resolve on its own for Marshall, but the putrid breath that's characteristic of this disease remained. So his wife was like, if you don't take antibiotics to get rid of this,

you have to leave the house. So he took antibiotics and got rid of it. But it worked. It worked. And so Marshall's, we have an N of two, actually, or at least of two that I could find. So Marshall's self-inoculation was followed up by another Australian guy named Morris, who did the same. My only Australians. They're all just like Steve Irwin. They're like, I'm just going to go for it. And progress has been made.

But this guy, poor guy, was not as fortunate as Marshall because it took him five years for his gastritis to resolve, even with treatment. So don't try this at home. No, do not. Eventually, people started coming around to the idea, especially in Australia, and doctors started to use antibiotics to treat patients they would have otherwise done surgery on to remove part of the stomach or the intestine. Yeah. Of course, they saw positive results, but other places were a lot slower to try out the treatment, and that's not surprising.

Like, I can't really fault them for that. Giving antibiotics willy-nilly is not a good idea, even if you have strong suspicions they might work. And so the study had to be repeated there all over with the drugs available. And ideally using a double-blind trial where both those administering the drugs and those getting the drugs didn't know whether they were giving slash being given treatment or placebo. And the results were clear. Gastritis and ulcers could be healed by antibiotics. It became the guideline for treatment in many places. And I can imagine it must have felt really good to have that sort of vindication, even if it came with a several-year delay.

Barry Marshall wasn't done yet, though. He helped to develop the breath test for H. Pylori, which was, yeah, and that was really wonderful because that meant that people didn't necessarily have to have endoscopies, which were uncomfortable and cost a lot of money, particularly if you're in the U.S. And you have to pay for most everything. Right. Plus, you can do it a lot easier. You don't need specialized equipment.

You don't need specialists. You can just, you just breathe. Yeah, it's really cool concept. I kind of love it. In the two decades or so, after their early 1980s letters in the Lancet, the world had definitely been changed by their discovery. Long-term suffers of gastritis and ulcers could find relief, and the risk of developing stomach cancer could even be reduced a bit. So for their efforts, Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine in 2005. exactly 100 years after Robert Koch was given the Nobel for his discovery of the tuberculosis bacterium.

Wow. And I read that Robin Warren's wife, Wynn, predicted them getting the prize all the way back in like 1984 after their first Lancet pub was accepted. Really? Yeah. They went out to dinner and she was like, this is going to get you the Nobel Prize. That's adorable on so many levels. Yeah. Isn't that? I really love it. Okay.

All right. So with that, I'll hand it off to you. Erin, tell me about the epi of helicobacter pylori today. Oh, I can't wait too. Today, it's estimated that right around half of the world's population is infected with H. pylori. That's a lot of people. It's a lot of people.

So I found a recent paper that I will definitely post a link to you. because it has some nice maps. It's a meta-analysis trying to really look at prevalence across different countries. And in developing countries, the rate seems to be about 50%. In developed countries, about 34%. And overall global prevalence, at least according to this study, was about 45%. So maybe it's going down a little bit from the numbers that we see cited most often. Okay. But obviously, not every person infected with H. Pylori is going to get gastric cancer or even Peptic ulcer disease. And there's a lot of research that's being done into the mechanisms of how H. Pylori causes disease. And one of the big thoughts is that it's virulence of the strain of H. Pylori.

Okay. So there's a lot, like you said, there's a lot of diversity across H. Pylori. There's a lot of different strains. And some of them are more virulent than others. Some produce more inflammation, and it tends to be that those that produce more inflammation are associated with higher risks of cancer. And it also could just be individual genetics. So if you are a person who's genetically predisposed to cancer and you happen to get an age pylori infection, then your risk of cancer might be additionally increased. Okay. But that's, those are small studies in their infancy. We don't really know who is going to get cancer if they have an H. Pylori infection and who isn't at this point.

Right. So, yeah. I found some, a really interesting in one little paper that I'll link to where they talked about hookworms. Oh. They talked about helmets and people are saying maybe infection with helmets, which we know can modulate the immune system, can reduce gastric inflammation and reduce the risk of cancer.

So if you're co-infected with H. Pylori and helmets, maybe your risk is less of getting gastric cancer. Hold on. But that's, first of all, that's bizarre. Second of all, doesn't, didn't we learn that having chronic infection with helmets creates an inflammatory state, which is often leads to an increased risk of cancer, generally speaking? Totally does, yeah. So I don't understand. It's not, there is not evidence that this is true in humans. It does seem to work in animal models. Okay. Who knows?

It decreases your risk of gastric cancer but increases your risk of colorectal cancer. I don't know. I mean, you lose if you do, you lose if you don't. Right? We'd never win. Yeah. The bacteria always win. That is, that's going to be on the gravestone of humanity.

Yeah. So in terms of gastric cancer, I thought people might be interested in some gastric cancer stats, since that's kind of the most serious outcome of H. Pylori infection. I'm definitely, yeah. Depending on what source you read, gastric cancer is either the second or third leading cause of cancer death. Really? Yes.

Wow. I know. I didn't realize that it was so high either. So the first is lung cancer. Okay. That's the number one cancer diagnosis and the leading cause of cancer. cancer death. And then the most recent stats that I saw actually had colorectal cancer causing more deaths than gastric cancer, at least in this last year. Okay. And this is, this is globally?

This is globally, yeah, worldwide. And what numbers are we talking about? Great question. According to WHO, there were 1.03 million new cases of gastric cancer diagnosed in 2018. One million new cases. One million new cases in one year. In one year. And that's estimated. Right. And 783,000 deaths.

Oh, my goodness. I know. It's really high. For comparison, lung cancer, which is number one, 2.09 million cases, 1.76 million deaths. Okay, so similar. That's very interesting of the new cases and the death ratio is very similar with those. Yeah, we are despite so much not good at treating most cancers. Yeah. It seems like we have a long way to go. Yeah, the death rates for cancers like gastric cancer and lung cancer really have not decreased over recent decades. It's very, very interesting, actually. It's alarming.

Yeah. But the overall rates of diagnosis of gastric cancer do seem to be decreasing. And it's thought that this is due to a number of different things, but treatment of H. Pylori is really high on the list of things that we think have helped to decrease the incidence of gastric cancer. So that's pretty exciting. That's really cool. Well, thanks again to Marshall and Warren. March. By the way, can I put in a quick plug for the Nobel Museum in Stockholm?

Yes. Tell us all about it. You just visited. I was just there. And it was, first of all, Stockholm is amazing. And the museums are incredible and everything about it is a wonderful place. And I love it. Number one, Abba Museum.

Number two, Nobel Museum. Is that right? Yeah, probably in that order. And yeah, so they have some cool little exhibits on these two on Marshall and Warren, and they have the tube from which Marshall drank the inoculate to infect himself. Oh my gosh. I get so excited by things like that. Oh, it was thrilling. I just stood there and I was like, I don't care if I'm blocking people. I need to see this. So I took a picture.

Yeah, I'll definitely post it on. on social media. Excellent. Oh, I can't wait. Yeah. Oh, I love those kind of museums. They're so fun. They are so fun.

Okay, sorry. I totally interrupted you. So tell me, so what's going on with research or more preventative things for gastric cancer and peptic ulcers in general? Yeah. So there's a vaccine. What? That's awesome.

It's awesome. It's super exciting. It's undergone at least phase three clinical trials, which is usually sort of the last phase before things get licensed in China. It's an oral vaccine, but I know that I found earlier studies on injectable vaccines as well. But I think in this case, an oral vaccine makes so much sense because it's, first of all, it's a GI bacteria. So giving something orally means that the vaccine is producing immunity in the cells that are actually going to be exposed to the bacteria. So it's a great idea. But oral vaccines are also a lot easy.

or two administer. You don't have to have specialized medical personnel. So I love that it's an oral vaccine. And the efficacy that they found so far is about 70% effective in preventing infection with H. Pi-Lory, which is super exciting. Yeah. So I'll post a link both to the, there's the phase three trial paper and then there's also a really cheeky paper. I want to read you the title of it. So cute. It's called At Last. vaccine-induced protection against helicobacter pylori. At last. At last.

So I'll post both of those on our website as well so that you can read more about it. But yeah, there is a vaccine, which is very exciting. I'm not sure how much longer it will take to get to market in China, where you have higher prevalence of H. Pylori than you do in the States and how long it might take to get it in the States. But it's pretty huge and very exciting. Yeah, I want that vaccine. Just in case.

Well, I feel like, do you feel every time you get a vaccine a bit more like a superhuman, like a superhero? We've talked about this. Yeah. Yeah. I could totally see that. Yeah. Yeah.

I also think this is so exciting because we are learning more and more about the associations with infectious disease and cancer. Yes. And other chronic diseases. Yes. And being able to produce a vaccine that literally prevents cancer or, Are you kidding me? That's amazing. It's incredible. And I think that the number of unexplored links keeps growing. And those that are being explored also keeps growing. And I think that's just

going to be one of the big futures of medicine is finding these links between infectious disease and chronic disease. Absolutely. I agree. We're biased because we love infectious disease, but yeah. But no, it's huge. And also really important if we can lessen some of the burden of disease around the world. Absolutely. Yeah. Oh. So yeah, that's H. Pylori. Wow. I really liked this one. Me too. It was really fun to do. I had a great time researching it and talking about it. It was fun and learning about it. Yeah. Okay. All right. So should we do sources? Let's do it. Okay. So I have a bunch of different articles that I read and we'll post, I'll post all of these. But two, I want to shout out. So one was called a century of helicobacter pylori. And that was by Kid and Modlin.

And also, I leaned very heavily on this incredibly thorough and long interview of Barry Marshall, which is what our first-hand account was extracted from. So we'll definitely post all of those and the other articles as well. Excellent. Yeah, you can find all of those on our website. This podcast will kill you.com under the episodes tab. You can find all of our sources from this episode and every episode. And...

What about you? You have any sources? None. I mean, I shouted out the one, and I'll post links to all of them. Okay. Yeah, cool. Thank you to Bloodmobile for providing the music for this and all of our episodes. And thank you, all of you, listeners.

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