For decades, the prevailing wisdom about heart disease has centered on a simple narrative: eating fatty foods leads to cholesterol-rich plaques that clog our arteries and jeopardize cardiovascular health.
This theory has shaped dietary guidelines, medical treatments, and public health policies worldwide. But what if this explanation doesn't tell the whole story? What if a significant contributor to atherosclerosis comes not from our diets but from within our own bodies—specifically, from the trillions of bacteria that inhabit our mouths and guts?
Groundbreaking research has revealed that certain bacteria produce distinctive fats that infiltrate our arterial walls, trigger inflammatory responses, and potentially accelerate the development of atherosclerotic plaques.
This article explores the fascinating relationship between serine dipeptide lipids produced by commensal Bacteroidetes bacteria and the process of atherosclerosis—a connection that could revolutionize our understanding of heart disease and open new avenues for prevention and treatment.
The human body hosts complex communities of microorganisms, particularly in the oral cavity and gastrointestinal tract. Among the most prevalent residents are bacteria of the phylum Bacteroidetes, which constitute approximately one-third of the cultivable bacteria in the human intestinal microbiota 1 . In the mouth, genera such as Porphyromonas, Prevotella, Tannerella and Capnocytophaga dominate among Bacteroidetes 1 . These bacteria are sometimes called "greasy bugs" because they constantly produce and shed substantial amounts of lipid molecules 5 .
| Bacterial Genus | Primary Location | Significance |
|---|---|---|
| Porphyromonas | Oral cavity | Includes P. gingivalis, associated with periodontal disease |
| Prevotella | Oral cavity, Gut | Common in oral and intestinal microbiomes |
| Tannerella | Oral cavity | Associated with periodontal disease |
| Bacteroides | Intestinal tract | Dominant intestinal bacteria, ~30% of cultivable gut flora |
| Capnocytophaga | Oral cavity | Common oral inhabitant |
Under normal conditions, these bacteria exist as commensal organisms, peacefully coexisting with their human hosts. However, when conditions change—due to factors like poor oral hygiene, dietary shifts, or immune compromise—some of these bacteria can contribute to disease processes. Porphyromonas gingivalis, for example, is considered a primary pathogen in chronic destructive periodontal disease 2 and has been implicated in the development of atherosclerosis in experimental animals 2 .
What makes these bacteria particularly interesting in the context of heart disease is their unique lipid production capability. Unlike human cells, Bacteroidetes bacteria manufacture distinctive serine dipeptide lipids with unusual chemical structures that may have profound effects on human health 5 .
The serine dipeptide lipids produced by Bacteroidetes bacteria are chemically distinct from the lipids humans produce or consume in their diets. These bacterial molecules contain unusual fatty acids with branched chains and odd numbers of carbon atoms—features not typically found in mammalian lipids 5 .
The deacylated product of Lipid 654, containing a single hydroxyl fatty acid linked to a serine-glycine dipeptide 2 .
These structural differences result in subtle weight variations that enable researchers to distinguish them from human lipids using modern mass spectrometry techniques 5 .
Though Bacteroidetes bacteria typically remain in the oral cavity and gastrointestinal tract without directly infecting blood vessels, their lipids can easily pass through cell walls and enter the bloodstream 5 . This transmission may occur through several mechanisms:
That occur during normal bodily functions like chewing or tooth brushing
Of bacterial products into the host
Caused by conditions like high-fat intake or obesity, which allows microbiota or their products to enter circulation 1
Once in the bloodstream, these foreign lipids can travel throughout the circulatory system and potentially accumulate in arterial walls.
In a pivotal 2017 study published in the Journal of Lipid Research, Nemati and colleagues set out to investigate whether these bacterial lipids could be detected in human arteries and whether they might contribute to atherosclerosis 2 7 . The research team employed a sophisticated analytical approach:
Carotid endarterectomy samples from patients with atherosclerosis, along with control carotid artery samples from young, healthy individuals 2
Using the Bligh and Dyer method to isolate lipids from arterial tissues and bacterial samples 2
Using HPLC and ESI-MRM mass spectrometry to identify and quantify specific lipid molecules 2
Testing various lipase enzymes for their ability to hydrolyze Lipid 654 to Lipid 430 2
The results of this comprehensive study revealed several crucial insights:
| Sample Type | Lipid 430/Lipid 654 Ratio | Significance |
|---|---|---|
| Carotid endarterectomy samples | Significantly elevated | Indicates active hydrolysis in diseased arteries |
| Control artery samples | Lower ratio | Baseline level of hydrolysis |
| Bacteroidetes bacteria | Variable but consistent | Ratio as produced by bacteria |
| Human serum samples | Lower ratio | Limited hydrolysis in blood |
| Human brain samples | Lower ratio | Limited hydrolysis in neural tissue |
These findings suggested that Lipid 654 deposition occurs in artery walls and that its hydrolysis to Lipid 640 increases significantly in diseased arteries, likely due to elevated PLA2 enzyme activity associated with atherosclerosis 2 7 .
| Reagent/Method | Function/Purpose | Example Sources |
|---|---|---|
| ESI-MRM Mass Spectrometry | Detection and quantification of specific lipid molecules | Modern mass spectrometers with electrospray ionization |
| HPLC Fractionation | Separation of complex lipid mixtures | Normal phase HPLC with neutral/acidic solvents |
| Bligh and Dyer Extraction | Comprehensive lipid extraction from biological samples | Chlorform:methanol:water mixture |
| Phospholipase A2 | Enzyme that hydrolyzes Lipid 654 to Lipid 430 | Porcine pancreatic, honey bee venom, human recombinant |
| Synthetic D9-Lipid 654 | Internal standard for mass spectrometry analysis | Chemically synthesized labeled compound |
| TLR2 Assays | Testing lipid immunostimulatory activity | Cell cultures with TLR2 reporting systems |
The immune system appears to play a crucial role in how these bacterial lipids contribute to atherosclerosis. The unique chemical structure of Bacteroidetes lipids makes them recognizable as foreign molecules to immune cells called macrophages that reside in arterial walls 5 .
When these immune cells encounter the bacterial lipids, they likely perceive them as signs of bacterial invasion and sound the alarm by activating inflammatory pathways 5 . Specifically, Lipid 654 functions as an agonist for Toll-like receptor 2 (TLR2), a pattern recognition receptor that plays an important role in innate immunity and has been implicated in the development of atherosclerosis 1 2 .
These bacterial lipids may damage blood vessels through two simultaneous mechanisms:
The immune system recognizes the lipids as foreign and mounts an inflammatory response 5
Enzymes in the artery walls break down Lipid 654 to Lipid 430, generating pro-inflammatory metabolites 5
This "double whammy" effect may create a vicious cycle of inflammation and tissue damage that accelerates the development and progression of atherosclerotic plaques.
The enzyme phospholipase A2 (PLA2) appears to play a particularly important role in this process. Expression of PLA2 is increased in atherosclerotic arteries concomitant with chronic inflammation associated with the formation of atheromas 1 . The conversion of Lipid 654 to Lipid 430 by PLA2 may promote atherogenesis through continued engagement of TLR2 1 2 .
| Enzyme | Source | Hydrolysis Activity | Significance |
|---|---|---|---|
| Phospholipase A2 (PLA2) | Various sources | Yes | Associated with macrophage activation and atherosclerosis |
| Phospholipase A1 | Thermomyces lanuginosus | No | Contrast for enzyme specificity |
| Phospholipase C | Clostridium perfringens | No | Contrast for enzyme specificity |
| Phospholipase D | Arachis hypogaea | No | Contrast for enzyme specificity |
| Lipoprotein lipase | Pseudomonas sp. | No | Contrast for enzyme specificity |
These findings challenge conventional wisdom about the relationship between dietary fats and heart disease. As Frank Nichols, a UConn Health periodontist and lead researcher on the study, noted: "Many think that atherosclerosis is caused by eating fatty foods, but it is now apparent that other lipids produced by oral and intestinal bacteria accumulate in diseased arteries" 4 .
This doesn't mean that dietary factors are irrelevant—conditions like obesity and high-fat intake can weaken gut integrity, potentially allowing more bacterial products to enter circulation 1 . However, it does suggest that the focus exclusively on dietary cholesterol and saturated fats may have been oversimplified.
The discovery of bacterial lipids in arterial plaques opens up several promising avenues for clinical applications:
The unique chemical signature of bacterial lipids might serve as biomarkers for early detection of atherosclerosis risk 5
Interventions aimed at maintaining healthy oral and gut microbiomes might help reduce the production of problematic lipids 7
This research adds to the growing body of evidence linking oral health to overall systemic health. The association between periodontal disease and cardiovascular conditions—once considered controversial—now has a potential mechanistic explanation through the transmission and effects of bacterial lipids 3 .
As Caroline Genco from Tufts University noted, "What [this study] adds to therapeutics is that atherosclerosis is a multi-factorial disease. There are other factors that are involved in the disease, and you need to think of those" 3 .
The discovery that serine dipeptide lipids from commensal Bacteroidetes bacteria accumulate in human arteries and potentially contribute to atherosclerosis represents a paradigm shift in our understanding of heart disease. While not dismissing the role of genetic factors, lifestyle choices, and dietary patterns, this research adds another layer of complexity to the multifaceted development of cardiovascular pathology.
As scientists continue to unravel the relationships between our microbiomes, immune systems, and vascular health, we move closer to a more comprehensive understanding of atherosclerosis—one that may lead to improved prevention strategies, earlier detection methods, and novel treatment approaches that target not just our own biology, but that of the microbial communities we host.
As research in this field progresses, we may discover that maintaining heart health involves not just watching what we eat, but also tending to the complex ecosystems of bacteria that call our bodies home.
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