The Oral–Vascular–Neural Axis
Bacterial extracellular vesicles as a candidate oral–systemic disease interface
S. Thaddeus Connelly, DDS, MD, PhD, FACS
San Francisco Veteran's Affairs Healthcare System
University of California San Francisco • GengyeUSA • 2026
How to Read This Deck
This presentation distinguishes established evidence from supported mechanisms and working hypotheses that still require causal testing.
✅ Established
  • Periodontitis generates systemic inflammatory and microbial exposure
  • Periodontal disease is associated with ASCVD and chronic outcomes
  • Periodontal therapy can improve endothelial or inflammatory biomarkers
⚠️ Supported, Not Settled
  • P. gingivalis OMVs carry virulence cargo and injure host cells in models
  • OMVs can promote endothelial activation and mitochondrial stress
  • P. gingivalis is associated with certain cancers and neurodegenerative pathways
🔬 Hypothesis Under Test
  • A conserved OMV-driven program contributes across vascular, tumor, and brain disease
  • Salivary/blood OMV signals can serve as scalable upstream biomarkers
  • Upstream oral intervention can change long-term systemic trajectories

Read this deck as a disciplined translational hypothesis — not a proven unifying law.
Why the Mouth–Body Interface Matters
The opportunity is not to collapse diseases into one disease, but to identify shared upstream interfaces worth measuring and testing.
32%
CVD Global Deaths
Cardiovascular disease is the leading cause of global mortality
1 in 6
Cancer Deaths
Cancer accounts for nearly 1 in 6 deaths worldwide
~1B
Dementia Burden
Dementia is a major cause of disability and death globally
Even a modest upstream risk signal could matter clinically if it is measurable and modifiable.
Why Periodontitis Creates Systemic Exposure
Chronic Oral Exposure
Periodontitis creates a persistently inflamed, ulcerated pocket surface — providing repeated opportunities for bacterial products, inflammatory mediators, and extracellular vesicles to enter the circulation.
Why Vesicles Are Plausible Long-Range Effectors
  • Smaller and more mobile than whole bacteria
  • Package concentrated virulence cargo
  • Can enter host cells and alter signaling without viable bacterial colonization at the distal site
  • Provide a tractable biomarker and intervention interface
Candidate Effector: P. gingivalis Outer Membrane Vesicles
Plausible Messenger — Not Yet a Proven Master Cause
What They Are
20–250 nm bilayer vesicles shed from Gram-negative bacteria. They package concentrated virulence factors and move through tissues and fluids more easily than intact bacteria.
Typical Cargo
  • Gingipains
  • Heterogeneous LPS / lipid A species
  • PPAD and adhesins / fimbrial components
  • Nucleic acids
Cargo composition matters — different components likely drive different phenotypes.
Cargo with the Strongest Mechanistic Support
Specifying which cargo class drives which phenotype — and where evidence is strongest — tightens the biology.

Avoid universal statements like "Pg LPS = TLR2 agonist / TLR4 antagonist." The receptor biology is context- and preparation-dependent.
A Working Five-Step Cascade
Useful for organizing experiments; risky if presented as already-proven causality.
Step 1 — Barrier Disruption
Preclinical + Translational
Barrier injury is the gatekeeping step that makes distal effects plausible. If OMVs cannot alter barriers, the distal-disease narrative gets much weaker.
Vascular Endothelium
P. gingivalis cells and OMVs increase CXCL8 and E-selectin signaling, promote monocyte adhesion, and perturb endothelial integrity and inflammatory tone.
Mucosal / Epithelial Interface
Long-term P. gingivalis infection in primary oral epithelial cells induces EMT-like changes: E-cadherin loss and increases in vimentin, Slug, Snail, and ZEB1.
Brain Interface
Oral microbial or host EVs can reach the brain in animal models and perturb BBB-related tight-junction signals. Human relevance is plausible but still incomplete.
Step 2 — Mitochondrial Dysfunction
High-Value Mechanistic Node
A strong mechanistic node and reasonable translational target — but not yet proof of cross-disease efficacy.
What Is Directly Supported
In endothelial models, P. gingivalis exposure increases mitochondrial fragmentation and mtROS, lowers membrane potential, and decreases ATP via Drp1-dependent fission — a concrete bioenergetic mechanism beyond vague "inflammation."
Downstream Readouts
  • Vascular: Bioenergetic stress sensitizes endothelium to dysfunction, inflammatory signaling, and remodeling
  • Neural: Pg OMVs can induce neuroinflammation, BBB tight-junction loss, tau phosphorylation, and memory effects in mice

"Mitochondria matter" is well supported. "One mitochondrial intervention will work across ASCVD, cancer, and AD" is still an inference.
Step 3 — Phenotypic Reprogramming
Selected Tissues — Avoid Over-Generalizing
VSMCs
Pg OMVs can induce ERK1/2 → Runx2 signaling, alkaline phosphatase activity, and osteogenic calcification in vascular smooth-muscle cells in vitro.
Oral / Orodigestive Epithelium
Chronic P. gingivalis exposure drives EMT-like programs linked to invasion and altered apoptosis — most convincing in oral and upper-GI contexts, not as a universal solid-tumor rule.
Microglia / Neurons
OMV exposure can amplify inflammatory phenotypes including NLRP3-related signaling and tau-associated changes in mouse models. Human translation remains uncertain.
Step 4 — Secondary EV Signals & Mitochondrial Transfer
Emerging — Most Context-Dependent Step
What Is Supported
  • P. gingivalis infection can alter host EV release and cargo
  • EVs can propagate tau-related pathology in AD models
  • Mitochondrial transfer occurs in cancer and can affect chemoresistance, immune biology, and metabolic fitness
What Remains Uncertain
  • Whether OMV injury triggers a conserved EV/organelle relay across vascular, tumor, and neural tissues
  • Which transfer events are harmful versus reparative
  • How to block pathological transfer without suppressing beneficial repair
  • Whether these pathways are measurable and clinically actionable in humans
Step 5 — Tissue-Level Endpoints Are Real, But Not Identical
Guardrail

Use "shared upstream interface, tissue-specific endpoints" — not "one disease in three organs."
Vascular Calcification
OMV-induced VSMC calcification is real in vitro and clinically relevant. Microcalcification may destabilize lesions; macrocalcification can reflect healing or stabilization — nuance matters.
Cancer Progression
Best P. gingivalis evidence is in oral and selected GI/upper-GI cancers. Enough biology to take seriously — not enough to claim a universal solid-tumor mechanism.
AD-Like Pathology
OMV exposure can worsen neuroinflammation and tau-related changes in animals. Direct human causal proof remains absent. Describe as association plus biological plausibility.
Clinical Implications Justified Today
Be ambitious in screening and collaboration; be conservative in causal claims and treatment promises.
✅ Supported Now
  • Treat periodontitis as a systemic health issue, not just a local dental problem
  • Capture periodontal status in cardiometabolic and geriatric histories where relevant
  • Expect local benefit and some biomarker or endothelial improvement after periodontal therapy
❌ Not Yet Justified
  • Claiming periodontal disease is a fully validated causal driver of ASCVD, cancer, or AD
  • Telling patients gingipain inhibition or oral therapy is proven to slow dementia
  • Presenting the AHA statement as if it resolved the causal question
The Atuzaginstat Lesson
What the GAIN Trial Showed
Target engagement and subgroup signals make the biology interesting. However, GAIN missed its co-primary endpoints in the overall cohort.
Atuzaginstat is a tractability signal — not clinical validation of the OVN thesis.
Best Near-Term Move
Build integrated dental-medical workflows, biomarker panels, and prospective studies that measure whether treating the mouth moves systemic biology.
That is a stronger story than claiming one hidden cause of three diseases.
Upstream Therapeutic Opportunities
Translation
The most defensible strategy: reduce source burden and prove biomarker movement first.
01
Source Reduction
Highest-credibility path: periodontal therapy, biofilm disruption, precise subgingival delivery, and oral-care formulations that measurably reduce P. gingivalis burden or virulence output.
02
Cargo Neutralization
Gingipain inhibition is the clearest cargo-target concept. Vaccine, antibody, and OMV-binding decoy ideas are attractive but early — platform possibilities, not established therapies.
03
Host-Response Modulation
NLRP3 and mitochondrial-resilience approaches may blunt downstream injury. Position as adjunctive pathway ideas unless paired with source-control biomarkers.

Commercially, "reduces upstream oral signal and moves measurable biomarkers" is a much stronger first claim than "prevents heart disease, cancer, and dementia."
Downstream / Repurposable Opportunities
Downstream
Useful pathway-adjacent bets — but not proof of the OVN thesis.
Calcification Modulation
SNF472 slowed coronary artery calcium progression in hemodialysis phase 2b. Its phase 3 calciphylaxis program did not meet primary endpoints — pathway-adjacent evidence, not a validated cardiovascular OVN therapy.
EV Interception
Exosome inhibition, EV decoys, and nanoparticle "sponges" are conceptually attractive. They remain early, and their value is strongest when paired with a measurable pathogenic EV signal.
Mitochondrial Transfer Modulation
Tunneling-nanotube or gap-junction blockade may matter in oncology, but selectivity is the central challenge — some mitochondrial transfer is reparative rather than pathological.
Five Priority De-Risking Experiments
Execution
Goal: move from plausible narrative to measurable, targetable biology.
1
Human Saliva → Systemic Biomarker Study
Quantify OMV load, gingipain activity, antibodies, and inflammatory markers; correlate with hsCRP, endothelial markers, CAC/IMT, and cognition.
2
Cargo Deconvolution
Compare wild-type vs. gingipain-deficient vs. PPAD-deficient OMVs across endothelium, VSMCs, microglia, and tumor cells.
3
Parallel Tri-Tissue Platform
Run the same OMV prep through a BBB chip, vascular coculture, and tumor-invasion model to test whether the cascade is actually conserved.
4
Intervention Biomarker-Movement Trial
Measure salivary and systemic changes before and after periodontal therapy, with and without an adjunct source-control formulation.
5
Prospective Enrichment Cohort
Test whether baseline oral biomarker signatures predict vascular progression, frailty, or cognitive decline better than dental measures alone.
Five Scalable Commercialization Paths
The smartest early businesses do not require proving full cross-disease causality first.
1. Salivary OMV / Gingipain Assay
RUO → CLIA/LDT path; recurring consumables and a biomarker data asset.
2. Dental-Medical Risk SaaS
Combine periodontal status, biomarkers, and referrals into workflow software for dental and medical groups.
3. Precision Oral-Care Platform
Office-dispensed rinses, gels, or adjuncts positioned around source reduction plus biomarker tracking.
4. Companion Diagnostic / Trial Enrichment
Identify oral-pathogen-high patients for neurology, inflammation, or oncology trials.
5. Registry + Longitudinal Evidence Network
Turn real-world dental-medical data into publications, payer leverage, and future defensibility.

Best sequence: biomarker → workflow → source-control product → trial-enrichment platform.
Bottom Line
Best Current Claim
Oral bacterial EVs are plausible systemic effectors and a tractable upstream biomarker interface — strong enough to justify measurement, intervention studies, and disciplined translational development now.
Strongest Evidence
Periodontitis ↔ ASCVD association; OMV endothelial effects; mitochondrial stress; selected neural and cancer-related model systems.
Biggest Gaps
Human causality, cargo attribution, prospective biomarker validation, and proof that the proposed cascade is truly conserved across tissues.
Winning Strategy: Prove an upstream signal, show that intervention moves it, and only then claim disease modification. That path is scientifically stronger and commercially more credible.
Thank You — Questions & Discussion
This revised deck distinguishes established evidence from supported mechanisms and working hypotheses.
Email
Web
Affiliation
University of California, San Francisco
SFVAMC

Disclosure: Commercial affiliations and institutional disclosures remain as stated in the original deck. Scientific statements in this revision were rewritten to better separate evidence from inference.
Appendix — References: Framing, Burden & Epidemiology
Appendix
WHO CVD Fact Sheet, 2025
Source for the ~32% global-mortality figure used to frame vascular burden.
WHO Cancer Fact Sheet, 2025
Source for the "nearly 1 in 6 deaths" cancer-burden statement.
WHO Dementia Report, 2021
Supports describing dementia as a major cause of disability and death.
Tonetti et al., J Clin Periodontol, 2017 (PMID 28419559)
Establishes periodontal disease as a globally important health and wellbeing burden.
Tran et al., Circulation, 2025 (PMID 41399933)
AHA statement anchoring the deck's association-focused ASCVD framing.
Arbildo-Vega et al., BMC Oral Health, 2024 (PMID 39468505)
Umbrella review supporting a real but still non-causal periodontitis-CVD signal.
Appendix — References: OMV Cargo, Innate Sensing & Vascular Entry
Appendix
These sources support the strongest mechanistic claims in the endothelial / barrier section.
Vermilyea et al., mSphere, 2021 (PMID 33257525)
Shows PPAD activity can promote OMV biogenesis and surface translocation.
Darveau et al., Infect Immun, 2004 (PMC517442)
Key cautionary paper: P. gingivalis lipid A interacts variably with TLR2 and TLR4.
Ho et al., Front Cell Infect Microbiol, 2016 (PMID 27826542)
Direct evidence for endothelial activation induced by P. gingivalis and derived OMVs.
Farrugia et al., 2020 (PMID 32726180)
Important barrier paper: OMVs increase vascular permeability.
Xu et al., Int J Oral Sci, 2021 (PMID 34475379)
Supports Drp1-dependent mitochondrial fission, mtROS, and ATP loss in endothelial models.
Yang et al., 2016 (PMID 28255538)
Most on-point paper for VSMC osteogenic differentiation and calcification via ERK1/2-Runx2.
Appendix — References: Neural, Epithelial, EV & Cancer Context
Appendix
This group supports the deck's more cautious framing around BBB biology, AD-like effects, EMT, and selected cancer contexts.
Lee et al., 2017 (PMID 29250491)
Shows long-term P. gingivalis infection can drive EMT-like epithelial changes.
Elashiry et al., 2024 (PMID 38674094)
Model-system evidence that orally induced small EVs can cross the blood-brain barrier.
Gong et al., 2022 (PMID 36017373)
Key mouse-model paper for NLRP3 activation, tau phosphorylation, and memory effects after OMV exposure.
Lamont et al., 2022 (PMID 35244980)
Helps narrow the cancer claim to oral / orodigestive squamous-cell settings.
Chalmers et al., Periodontol 2000, 2025 (PMID 40495582)
Important guardrail: AD relevance is biologically plausible, but direct human causality is unproven.
Guan et al., 2024 (PMID 38769583)
Frames mitochondrial transfer as a real oncology mechanism and possible target.
Appendix — References: Human Intervention & Trial Guardrails
Appendix
These sources explain why the revised deck separates tractable biology from proven clinical efficacy.
Tonetti et al., N Engl J Med, 2007 (PMID 17329698)
Seminal human study showing periodontal treatment can improve endothelial-function-related readouts.
Asher et al., 2022 (PMID 36073186)
Supports describing dementia links as association plus biological plausibility rather than settled causality.
Sabbagh & Decourt, 2022 (PMID 36003033)
Useful reference for gingipain inhibition as a tractable target concept.
Raggi et al., 2020 (PMID 31707860)
Phase 2b evidence that SNF472 slowed coronary calcium progression in hemodialysis.
Sinha et al., 2024 (PMID 39252867)
Phase 3 CALCIPHYX result — keeps the deck honest about pathway-adjacent rather than validated therapy.
Baldwin et al., Cell, 2024 (PMID 39276774)
Important counterweight: mitochondrial transfer can be beneficial, so blocking it requires selectivity.

The experiment and commercialization slides are strategic synthesis built on the evidence above — not claims copied from any single paper.