Stomach Ulcers and Dental Cavities

[Metacelsus]

Link post

(This is a linkpost from my blog, De Novo)

Recently I learned about an effort to prevent dental cavities by using genetically modified bacteria to outcompete cavity-causing bacteria. This got me thinking: why has the idea of preventing cavities by targeting bacteria not been more developed already?

The current situation reminds me of the history of stomach ulcers. Before the 1980s, doctors recommended avoiding spicy foods and reducing stress to alleviate stomach ulcers. However, once Robin Warren and Barry Marshall proved ulcers were due to H. pylori infection,^[1] treatment with antibiotics to eliminate the bacteria became the standard of treatment.

Today, dentists recommend avoiding sugary foods and brushing your teeth to prevent cavities. But we know cavities are caused by bacteria (in particular Streptococcus mutans), so why not directly attack cavity-causing bacteria?

Some potential ideas:

• Selectively targeted antibiotics

• Vaccines (previously tried in the 1980s, not very successful because it’s difficult to get antibodies to penetrate biofilms, and also because S. mutans has several different strains with different antigenic profiles)

• Outcompeting S. mutans with different bacteria (the current effort by Aaron Silverbook, which I think is promising)

Basically, what Aaron Silverbook is proposing to do is recreate a strain of S. mutans, termed BSC3-L1, that is deficient in lactic acid production. This was previously developed by a company called Oragenics, but they abandoned the effort (I think due to financial reasons). It seems Aaron’s team is mostly people from software backgrounds, so they would probably appreciate help from any talented microbiologists who happen to be reading this post.

1. ^

   In a famous case of self-experimentation, Marshall drank a culture of H. pylori and subsequently developed gastritis. For this work, Warren and Marshall earned the 2005 Nobel in Physiology/​Medicine.

[localdeity]

For those wondering about the safety of introducing new bacteria that “outcompete” existing bacteria, Aaron Silverbook’s proposal has a safety review FAQ that, indeed, answered a bunch of my questions, starting with an anonymous question in the comments sidebar:

Q: Why is the GMO bacteria guaranteed to outcompete the native bacteria? Does it reproduce more quickly or something?

A: JH1140 secretes Mutacin 1140, a natural bacteriocin which kills native S mutans

Which is a pretty reassuring answer compared to the other alternatives one might imagine, and lends itself to generalization.

[Zolmeister]

While merely anti-bacterial, Nano Silver Fluoride looks promising. (Metallic silver applied to teeth once a year to prevent cavities).

[gilch]

Long-term use of Xylitol seems to have a persistent protective effect by modifying the oral flora. In the short term, it poisons S. mutans, and in the long term, strains that evolve resistance seem to be less virulent.

[Olli Savolainen]

Xylitol seems to be a source of oxalic acid. I don’t know if it metabolized into that form by the body or gut microbiome, or both, but it definitely shows up in urine. It says “Excessive use may cause laxative effects” on the bag of chewing gum, but I think oxalic acid is a much bigger concern with potential for long term damage to kidneys and joints. Highly processed vegetable rich diets might already contain excessive amounts, especially for people with gut problems and fat malabsorption.

If were talking about easy adjustments to fight caries, how about switching to porridge based breakfast (in place of cereals or muesli) and opting for 100% oat bread instead of dry white bread. This in my experience has a big effect on how much and for how long starchy matter adheres to fissures in teeth.

(I feel like I’m betraying Finland by attacking xylitol. I’m making up for that by talking up oats and porridge.)

[gilch]

In humans? I saw no mention of oxalic acid in what I found on Xylitol metabolism. Do you have a reference?

[RobertM]

Maybe https://​​pubmed.ncbi.nlm.nih.gov/​​8345042/​​ (referenced by https://​​karger.com/​​cre/​​article/​​53/​​5/​​491/​​86395/​​Oral-and-Systemic-Effects-of-Xylitol-Consumption)?

[MondSemmel]

(Apologies for this lengthy aside.)

In a famous case of self-experimentation, Marshall drank a culture of H. pylori and subsequently developed gastritis. For this work, Warren and Marshall earned the 2005 Nobel in Physiology/​Medicine.

This is the first time I’ve heard about this. I’ve previously written about my experience with H. pylori, which makes me appreciate this mad science self-experimentation all the more.

Relevant section on the history, from Wikipedia:

H. pylori was first discovered in the stomachs of patients with gastritis and ulcers in 1982 by Drs. Barry Marshall and Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005 Nobel Prize in Physiology or Medicine.^[169]

[...]

Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomachs of people with gastric ulcers.^[174] The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their Petri dishes incubating for five days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by stress or spicy food, as had been assumed before.^[10]

Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of H. pylori with gastritis and, to a lesser extent, ulcers.^[175] To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy 10 days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent. Marshall and Warren went on to demonstrate antibiotics are effective in the treatment of many cases of gastritis. In 1994, the National Institutes of Health stated most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen.^[176]

It’s remarkably audacious to intentionally self-infect oneself with (what I experienced as) a really painful illness, in order to prove one’s hypothesis. Interestingly, the page on Barry Marshall suggests that he thought it would take years to develop symptoms; I’m not sure if that makes his self-experiment more brave or less:

In 1983 they submitted their findings thus far to the Gastroenterological Society of Australia, but the reviewers turned their paper down, rating it in the bottom 10% of those they received that year.^[14]

After failed attempts to infect piglets in 1984, Sam Wang reported that Marshall, after having a baseline endoscopy done, drank a broth containing cultured H. pylori, expecting to develop, perhaps years later, an ulcer.^[15] He was surprised when, only three days later, he developed vague nausea and halitosis, due to the achlorhydria. There was no acid to kill bacteria in the stomach and their waste products manifested as bad breath, noticed by his wife.^[16] On days 5–8, he developed achlorhydric (no acid) vomiting. On day eight, he had a repeat endoscopy, which showed massive inflammation (gastritis), and a biopsy from which H. pylori was cultured, showing it had colonised his stomach. On the fourteenth day after ingestion, a third endoscopy was done, and Marshall began to take antibiotics.^[17] Marshall did not develop antibodies to H. pylori, suggesting that innate immunity can sometimes eradicate acute H. pylori infection. Marshall’s illness and recovery, based on a culture of organisms extracted from a patient, fulfilled Koch’s postulates for H. pylori and gastritis, but not for peptic ulcers. This experiment was published in 1985 in the Medical Journal of Australia^[18] and is among the most cited articles from the journal.^[19]

Again of note: to produce more conclusive data, he waited 11 days after symptom onset before beginning to take antibiotics. (Though their subsequent paper merely described this as “A mild illness developed, which lasted 14 days”.)

Wikipedia apparently has a full Timeline of peptic ulcer disease and Helicobacter pylori. Quotes:

Morris intentionally consumes H. pylori. Like Marshall, he becomes ill, but unlike Marshall, he is not completely cured by antibiotics. The infection will remain with him for three years.^[48]

Yikes.

[1984:] Thomas Borody developed the bismuth-based “Triple Therapy” consisting of bismuth and two antibiotics. This became the first truly successful treatment for H. pylori with an eradication rate greater than 90%.^[44][45][46] [...]

[1990:] Borody’s triple therapy became commercialized in the United States under the product name Helidac.

So the treatment I got (or precursors to it) started becoming commercially available 5-9 years after the discoveries mentioned above. I assume that’s pretty fast when judged by the standards of medicine? And by the time I developed issues, the treatment had been available for 27 years. I’m not sure whether to consider that “yay progress” or “yikes, what if I’d gotten H. pylori as a child, before diagnosis and treatment became available”.