Oral microbiome & periodontitis

Why the mouth has effects beyond the mouth

Porphyromonas gingivalis is the main pathogen of periodontitis, the chronic inflammation of the tissues that support the teeth. Inflamed gums are an open wound surface: if you add up all the periodontal pockets in severe periodontitis, bacteria and inflammatory substances continuously enter the bloodstream over a considerable area. Chronic inflammation is an established driver of arterial calcification.

Accordingly, periodontitis is associated with heart attack, stroke and diabetes in many large cohorts; the American Heart Association has published a dedicated statement on this. Association and mechanism fit together — which makes the matter sound convincing and easily pushes it too far.

The Alzheimer’s finding

In 2019, a group in Science Advances examined brains of deceased Alzheimer’s patients for gingipains — enzymes produced practically only by this bacterium. 96 % of the samples were positive for one gingipain, 91 % for the other: 51 of 53 and 49 of 54. In addition, bacterial DNA was found in the cerebral cortex, and the bacterium in the cerebrospinal fluid of 7 of 10 living patients.

Then the authors went further: they infected old mice orally with the bacterium over 6 weeks. It migrated into the brain, and amyloid beta rose significantly — the protein that forms the plaques in Alzheimer’s. Mice infected with a strain lacking these enzymes did not show the rise. Under a gingipain inhibitor, the bacterial load in the brain fell by up to 90 %, the amyloid rise did not occur, and hippocampal neurons were protected.

For an animal model, this is a remarkably complete chain: pathogen found, transmitted, signs of disease produced, pathogen blocked, signs of disease prevented.

The test in humans

The inhibitor became a drug, atuzaginstat, and a phase 2/3 study: GAIN, 643 people with mild to moderate Alzheimer’s disease, started in April 2019, 48 weeks against placebo. In October 2021, the result came: both primary endpoints missed; neither cognition nor everyday functioning differed.

There was a prespecified subgroup: 242 participants with P. gingivalis DNA detected in saliva — that is, the people in whom the drug had anything to act on at all. There, the higher dose significantly slowed cognitive decline by 57 %. If it held up, that would be by far the best Alzheimer’s result ever achieved.

Three things speak against it. First, the lower dose did not reach significance, whereas a real effect would be expected to show a dose-response relationship. Second, in the same subgroup there was no effect on everyday functioning: a test score moved, life did not. Third, it was a subgroup after a missed primary endpoint — the point at which research most often deceives itself.

Why the question remains open

During treatment, dose-dependent elevated liver values occurred: more than three times the upper limit of normal in 7 % on the lower and 15 % on the higher dose, mostly in the first 6 weeks and all reversible. That was enough for the regulatory authority: in January 2022, the FDA imposed a full clinical hold because of liver toxicity, and in August 2022, the company discontinued the program.

Thus the most interesting Alzheimer’s hypothesis outside the amyloid mainstream was tested once, missed its goal, left behind a tempting subgroup signal and was stopped for safety reasons. No proof, no refutation, but an open ending.

Heart and vessels: a nice curve and a surrogate

In 2007, the New England Journal of Medicine published a randomized study with 120 people with severe periodontitis, allocated to usual dental care or intensive treatment. What was measured was flow-mediated dilation — how well an artery widens when blood flow is stimulated.

The result has a catch, and that is precisely what makes it convincing. 24 hours after intensive treatment, vascular function was worse than in the control group and inflammatory markers were elevated — work had been done in an inflamed wound, and that flushes bacteria and inflammatory substances into the circulation in the short term. After 60 and after 180 days, by contrast, it was better, with improved vascular markers and without serious side effects. The curve looks exactly as it would have to look if the connection is real.

Flow-mediated dilation, however, measures vascular function, not a heart attack. It is a surrogate.

Two studies worldwide

In 2022, the Cochrane Collaboration searched for randomized studies testing periodontitis treatment against real cardiovascular events. It found 2: one on primary prevention with 165 people with metabolic syndrome and one on secondary prevention with 303 randomized participants, of whom only 37 had sufficient follow-up data.

The authors’ verdict is unambiguous: very low quality of evidence. With two small studies at high risk of bias and very imprecise results, no reliable conclusions could be drawn; for secondary prevention, there is no reliable evidence.

The reason is not scientific but financial. There is no patent on tartar removal, so there is no company to pay for a ten-year study. What gets studied is not what matters, but what can be sold — which is why more is known about a new peptide than about gums.

What the studies show

Gingipain detection, Science Advances 2019

Brain tissue of deceased Alzheimer’s patients: 96 % positive for one gingipain (51 of 53), 91 % for the other (49 of 54), pathogen in the cerebrospinal fluid of 7 of 10 living patients. In addition, an animal part with oral infection of old mice and a rise in amyloid beta.

GAIN study with atuzaginstat, 2021

Phase 2/3, 643 Alzheimer’s patients, 48 weeks against placebo, both primary endpoints missed. In the prespecified subgroup with the pathogen detected in saliva (242 people), 57 % slower cognitive decline on the higher dose, without an effect on everyday life.

Periodontitis treatment and vascular function, NEJM 2007

120 people with severe periodontitis, randomized to usual or intensive treatment. After 24 hours, flow-mediated dilation was worse than in the control group, after 60 and 180 days better, without serious side effects.

Cochrane review on hard cardiovascular endpoints, 2022

Search for randomized studies on real cardiovascular events. 2 were found: one on primary prevention with 165 people, one on secondary prevention with 303 randomized participants, of whom 37 could be evaluated. Very low quality of evidence.

Where the data stop

It is not established that treating periodontitis prevents or slows Alzheimer’s. The only targeted test in humans missed both primary endpoints, the subgroup signal had no effect on everyday life, and development has ended. Nor is an effect on real cardiovascular events established.

Status, approval and legal

Periodontitis treatment and professional teeth cleaning are standard dental care and routinely available. Atuzaginstat was never approved, has been under a full FDA clinical hold since January 2022 and has no longer been developed since August 2022. There is no approved agent that protects the heart or brain via the oral microbiome. There is no relevance to doping.

Safety

Intensive periodontitis treatment proceeded without serious side effects; the deterioration after 24 hours reversed. The risk consists essentially of the time spent on appointments. With the drug, it was different: dose-dependent liver value elevations led to the development stop, even though all values returned to normal. Bleeding gums when brushing are not normal, but the point at which an appointment is due.

Sources

• Dominy et al., Science Advances 2019
• GAIN study on atuzaginstat (COR388), phase 2/3 with 643 participants, registry entry NCT03823404
• Tonetti et al., New England Journal of Medicine 2007
• Cochrane review on periodontitis treatment and cardiovascular endpoints — Ye et al., 2022
• Scientific statement of the American Heart Association on periodontitis and cardiovascular disease — Lockhart et al., Circulation 2012