The discovery, made thanks to an experiment involving hundreds of bank employees in Spain, opens the door to new treatments beyond reducing cholesterol
Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors1. However, individuals at risk for early vascular disease often remain unidentified2. Recent research has identified new molecules in the pathophysiology of atherosclerosis3, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImPâI1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImPâI1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.
Wow, this is genuinely exciting, they say there is a causal relationship between that bacteria and atherosclerosis.
Sancho stresses that the work has been made possible thanks to the collaboration of thousands of volunteer employees of Banco Santander in Madrid, but also thanks to grants of âŹ1 million from the âla Caixaâ Foundation, âŹ150,000 from the European Research Council and âŹ100,000 from the State Research Agency.
If thatâs all it took in terms of funding, thatâs also pretty impressive too!
Researchers have discovered that gut bacteria produce a molecule that not only induces but also causes atherosclerosis, the accumulation of fat and cholesterol in the arteries that can lead to heart attacks and strokes. This unexpected link between microbes and cardiovascular disease â the leading cause of death in humanity â is a paradigm shift. The work was published Wednesday in the journal Nature, a showcase for the worldâs best science.
another microbiome paper:
Open access paper:
Tanshinone regulated gut microbiota and TMAO to improve high-fat diet induced atherosclerosis in APOEâ/â mice
Conclusion
Tanshinone has the potential to ameliorate atherosclerosis induced by a high-fat diet by promoting the proliferation of lactobacillus, reducing the abundance of lachnospiraceae, enhancing lipid metabolism, and diminishing the production of TMAO.
Tanshinone does not seem to be readily available but the plant extract Danshen (used in TCM) from which it is derived is available as a supplement Danshen 500mg and often recommended for cancer in TCM. However, Danshen only contains 0.02% to 0.32% of Tanshinone Danshen global quality.
What they used in the study is AGN192403, have not done enough reading to see if there is a known human dose.
These results demonstrate that the administration of AGN192403, which inhibits the ImPâI1R axis, prevents atherosclerosis linked to immune cell activation without affecting cholesterol concentration in plasma, suggesting a novel approach for atherosclerosis therapy. Imidazole propionate is a driver and therapeutic target in atherosclerosis | Nature
Itâs fairly âoldâ and has been studied for quite a while with regards to being a
Protective effects of rilmenidine and AGN 192403 on oxidative cytotoxicity and mitochondrial inhibitor-induced cytotoxicity in astrocytes
â94.3% of the US population do not meet the daily requirement for vitamin D, 88.5% for vitamin E, 52.2% for magnesium, 44.1% for calcium, 43.0% for vitamin A, and 38.9% for vitamin C.â
The magnesium study above does say that additional work is needed to determine âwhether Mg treatment specifically changes the production of ImP by microbiota.â
The new study shows that blood levels of imidazole propionate are lower in people with diets rich in vegetables, fruits, whole grains, fish, tea, and low-fat dairy products.
Elements of the Japanese diet. Could be Mediterranean as well, without the tea.
It seems to me that another and more direct path may exist to reduce imidazole propionate. Via ChatGPT:
Koh et al. (Nature, 2018), identify several Clostridial species as likely producers of imidazole propionate, including:
Clostridium bolteae
Clostridium symbiosum
Eggerthella lenta (a non-Clostridial Actinobacteria, but often associated)
Dorea longicatena
Ruminococcus gnavus
These microbes convert histidine â urocanate â imidazole propionate through anaerobic fermentation pathways.
It further appears that dysbiosis - involving the overgrowth or imbalance of the above Clostridial species can lead to increased imidazole propionate production
Histidine Metabolism Pathway These microbes metabolize dietary histidine into urocanate, then into imidazole propionate (ImP) under anaerobic conditions.
Dysbiosis Context In healthy individuals, histidine may pass through the gut without significant microbial conversion.In dysbiosis (especially when Clostridial species and Eggerthella lenta are overrepresented), more histidine gets diverted into the ImP pathway.
Clinical Implications
Elevated ImP levels have been observed in individuals with type 2 diabetes and obesity.
ImP interferes with insulin signaling via activation of mTORC1 and p38Îł pathways.
Dysbiosis may lower microbial diversity, reducing checks on overactive histidine fermenters.
I make no claims any of us would find it easy, but I think this raises the question(s) of defining:
An optimal microbiome and
Interventions to shift sub-optimal microbiomes toward optimal ones.
Diet could help. Possible antibiotic interventions might include:
Bacterium
Common Susceptible Antibiotics
Resistance Notes
Clostridium bolteae
Metronidazole, Vancomycin, Rifaximin
May resist β-lactams, especially in biofilm form
Clostridium symbiosum
Metronidazole, Clindamycin, Rifaximin
Similar to other Clostridia; variable
Eggerthella lenta
Metronidazole, Linezolid, Rifaximin
Frequently resistant to β-lactams (e.g. penicillins, cephalosporins)
Dorea longicatena
Vancomycin, Rifaximin, Clindamycin (variable)
Less well-characterized; possible resistance to ampicillin
Ruminococcus gnavus
Rifaximin, Metronidazole
Often resistant to aminoglycosides and some cephalosporins
Whoâs going to be the first volunteer? Iâm curious, but my last coronary calcification score was zero, so the risk/reward doesnât work out for me.
Agmatine is an imidazoline I2 receptor agonist. Iâve been using with some slight benefit for neuropathy and sciatica pain. I also have familial hypercholesterolemia, but have not noticed this making a dent as yet.
The original article speaks of the imidazole I1R receptor and blocking the I1R receptor eliminates the damage caused by imidazole. Even if the imidazole I2 and I1R receptors are similar, wouldnât using a I2 receptor agonist make the problem worse, by causing problems even without any imidazole production in the gut ?
Youâre absolutely correct. Wishful thinking on my part and ignoring that detail. It also is reported to act on I1 receptor as well, but I have not seen any studies on the effects of this action specifically.