Periodontitis

Complex MONDO:0005076 Pathograph 16 Show in embeddings browser Oral Cavity Disease Inflammatory Disease

Periodontitis is a chronic, biofilm-driven inflammatory disease of the tooth-supporting apparatus — gingiva, periodontal ligament, cementum and alveolar bone. It is not a classical infection by a single pathogen but a dysbiosis: an ecological shift in the subgingival plaque community that provokes a dysregulated host inflammatory response, and it is that host response — not the bacteria directly — that destroys the periodontium. A low-abundance keystone organism (canonically Porphyromonas gingivalis) can remodel an otherwise commensal community into a dysbiotic one by subverting complement and innate immune surveillance. The resulting IL-17/Th17-polarised, neutrophil-rich lesion drives osteoclast-mediated resorption of alveolar bone and degradation of the periodontal ligament, producing clinical attachment loss, periodontal pocketing and, eventually, tooth loss. Beyond the mouth, periodontitis is a persistent source of systemic inflammatory burden. Periodontal pathogens and inflammatory mediators disseminate haematogenously, and — the arm this entry models explicitly — amassed oral pathobionts are also swallowed, seeding the gut. This oral-gut route is mechanistically distinct from haematogenous spread and is the non-redundant core of the oral-gut axis framework (see notes).

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Mechanistic Hypotheses

Keystone-Pathogen / Polymicrobial Synergy and Dysbiosis Model

keystone_pathogen_polymicrobial_synergy CANONICAL

Evidence balance 2 support

The prevailing model: a low-abundance keystone organism (P. gingivalis) elevates the virulence of the whole subgingival community by subverting complement and innate immune surveillance, converting a commensal biofilm into a dysbiotic one that the host then over-responds to. Disease severity tracks the dysregulated host response rather than total bacterial load.

Pathograph links

Dysbiotic Subgingival Biofilm Formation -> Keystone-Pathogen Remodelling and Complement Subversion DIRECT The dysbiotic community is the substrate on which a keystone organism acts.

Keystone-Pathogen Remodelling and Complement Subversion -> Th17 Expansion and Neutrophil-Rich Periodontal Inflammation DIRECT

Th17 Expansion and Neutrophil-Rich Periodontal Inflammation -> Osteoclast-Mediated Alveolar Bone Resorption DIRECT

Show evidence (2 references)

PMID:22941505 SUPPORT Other

"The keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one."

States the hypothesis in its canonical form; periodontitis is its exemplar disease.

PMID:25534621 SUPPORT Other

"Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health."

Review framing of periodontitis as dysbiotic-inflammatory rather than classically infectious.

Oral-to-Gut Pathobiont Translocation Model

oral_gut_translocation_model EMERGING

Evidence balance 2 support

Periodontitis expands oral pathobionts (Klebsiella, Enterobacter) that are ingested and ectopically colonise the intestine, where they activate the inflammasome in colonic mononuclear phagocytes; in parallel, oral pathobiont-reactive Th17 cells generated in the mouth are imprinted with gut tropism and migrate to the intestine. This supplies an enteral, non-haematogenous route by which oral inflammation aggravates extra-oral disease. The causal chain is established in gnotobiotic and murine models; direct human causal verification is the open question (see the HUMAN_MODEL_MISMATCH discussion).

Pathograph links

Connective Tissue Attachment Loss and Pocket Formation -> Expansion and Ingestion of Oral Pathobionts DIRECT

Expansion and Ingestion of Oral Pathobionts -> Ectopic Intestinal Colonisation by Oral Pathobionts DIRECT

Expansion and Ingestion of Oral Pathobionts -> Gut-Homing Oral-Pathobiont-Reactive T Cell Induction DIRECT

Ectopic Intestinal Colonisation by Oral Pathobionts -> Chronic Systemic Inflammatory Burden and Comorbidity Risk INDIRECT KNOWN INTERMEDIATES

Gut-Homing Oral-Pathobiont-Reactive T Cell Induction -> Chronic Systemic Inflammatory Burden and Comorbidity Risk INDIRECT KNOWN INTERMEDIATES

Show evidence (2 references)

PMID:32758418 SUPPORT Model Organism

"Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells."

States the model's central claim as the study's own conclusion, in a murine periodontitis-colitis system.

PMID:42396665 SUPPORT INDIRECT Other

"It sustains systemic homeostasis through bidirectional microbial translocation, metabolite signaling and immune crosstalk."

The review that motivated this curation frames the axis as bidirectional; this entry models only the oral-to-gut direction, for which experimental causal evidence exists. Graded INDIRECT: the quote establishes that microbial translocation along the oral-gut axis occurs, and this model's premise follows from that by an inference step rather than being asserted by the sentence.

Periodontal Hypercitrullination Trigger of Autoimmunity

periodontal_citrullination_autoimmunity_model EMERGING

Evidence balance 1 support

A specific periodontal pathogen, Aggregatibacter actinomycetemcomitans, secretes the pore-forming leukotoxin A, which dysregulates neutrophil citrullinating enzymes and produces a citrullinome mirroring that of the rheumatoid joint — proposing the periodontium as a mucosal initiation site for anti-citrullinated protein autoimmunity. Candidate-trigger status, not established causation.

Pathograph links

Dysbiotic Subgingival Biofilm Formation -> Neutrophil Hypercitrullination by Leukotoxin A INDIRECT KNOWN INTERMEDIATES Periodontal dysbiosis supplies the Aggregatibacter actinomycetemcomitans burden whose leukotoxin drives neutrophil hypercitrullination.

Neutrophil Hypercitrullination by Leukotoxin A -> Chronic Systemic Inflammatory Burden and Comorbidity Risk INDIRECT UNKNOWN INTERMEDIATES Proposed route from a periodontal mucosal trigger to systemic anti-citrullinated protein autoimmunity; the intervening steps in humans are not established.

Show evidence (1 reference)

PMID:27974664 SUPPORT Human Clinical

"These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA."

The authors themselves stop at candidate trigger, which is the epistemic level recorded here.

Discussions and Knowledge Gaps

Does the oral-to-gut pathobiont translocation chain established in murine and gnotobiotic models operate causally in humans with periodontitis, or is the human oral-gut association confounded by shared risk factors (smoking, diet, glycaemic state) and by the fact that both niches are sampled from the same individual?

HUMAN MODEL MISMATCH OPEN oral_gut_axis_human_causality

Attached to

pathophysiology#Expansion and Ingestion of Oral Pathobionts pathophysiology#Ectopic Intestinal Colonisation by Oral Pathobionts pathophysiology#Gut-Homing Oral-Pathobiont-Reactive T Cell Induction

Every step of the chain modelled here — periodontitis-driven expansion of Klebsiella and Enterobacter, ingestion and gut translocation, inflammasome activation in colonic mononuclear phagocytes, and gut-tropic imprinting of oral pathobiont-reactive Th17 cells — rests on murine periodontitis-colitis models and gnotobiotic colonisation of germ-free mice. Human data are largely cross-sectional co-detection of oral taxa in stool. The review that motivated this curation names causal verification as the field's primary open challenge. This is a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP: the evidence exists and is mechanistically detailed, but its translational validity to human periodontitis is unresolved.

Proposed experiments

Paired oral-faecal strain-resolved metagenomics through periodontal therapy

longitudinal human strain-resolved metagenomic cohort study

exp_perio_oral_gut_strain_tracking

Longitudinally sample saliva/subgingival plaque and stool from patients with stage III-IV periodontitis before and after a full course of subgingival instrumentation, and use strain-resolved metagenomics to test whether oral-origin Klebsiella/Enterobacter strains detectable in stool decline as the periodontal lesion resolves. Untreated periodontitis patients and periodontally healthy controls serve as comparators.

Decision criterion

A treatment-associated fall in gut carriage of oral-origin strains, absent in untreated controls, would support directional oral-to-gut seeding in humans.

Would support

pathophysiology#Ectopic Intestinal Colonisation by Oral Pathobionts pathophysiology#Expansion and Ingestion of Oral Pathobionts

Would refute

pathophysiology#Ectopic Intestinal Colonisation by Oral Pathobionts

Supporting outcome

Oral pathobionts seed the human gut and the mouth is the upstream reservoir.

Refuting outcome

Gut carriage of oral-type strains is unchanged by periodontal resolution, indicating shared exposure or independent gut colonisation rather than seeding.

Periodontal therapy trial in inflammatory bowel disease with gut endpoints

randomised interventional clinical trial

exp_perio_therapy_ibd_endpoint_trial

Randomised trial of intensive versus standard periodontal therapy in patients with both periodontitis and inflammatory bowel disease, powered on intestinal inflammatory endpoints (faecal calprotectin, endoscopic activity) rather than on periodontal outcomes.

Decision criterion

A significant reduction in intestinal inflammatory activity in the intensive arm would establish a causal oral-to-gut contribution in humans.

Would support

mechanistic_hypotheses#oral_gut_translocation_model

Would refute

mechanistic_hypotheses#oral_gut_translocation_model

Supporting outcome

Oral inflammation causally aggravates human intestinal inflammation.

Refuting outcome

No gut benefit despite periodontal resolution, indicating the murine intermucosal connection does not dominate in human disease.

Antigen-specific tracking of oral pathobiont-reactive T cells in humans

human antigen-specific T cell phenotyping study

exp_perio_gut_homing_t_cell_tracking

Identify oral pathobiont-reactive T cells in blood and paired gut biopsies from patients with periodontitis, and test whether they carry gut-homing integrin and chemokine-receptor imprints, as reported in mice.

Decision criterion

Detection of oral pathobiont-reactive, gut-homing-imprinted T cells in human gut tissue would translate the murine T cell arm.

Would support

pathophysiology#Gut-Homing Oral-Pathobiont-Reactive T Cell Induction

Would refute

pathophysiology#Gut-Homing Oral-Pathobiont-Reactive T Cell Induction

Supporting outcome

The cellular arm of the oral-gut axis operates in humans.

Refuting outcome

No such population is detectable, leaving only the microbial arm as a candidate human mechanism.

Show evidence (1 reference)

PMID:42396665 SUPPORT Other

"Current challenges include difficulties in causal verification, substantial interindividual variability in intervention efficacy"

The source review identifies causal verification as the unresolved problem, which is the substance of this mismatch.

Does treating periodontitis improve hard clinical outcomes in the associated comorbidities, or only surrogate markers?

KNOWLEDGE GAP OPEN periodontal_therapy_comorbidity_outcomes

Attached to

pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk

The interventional evidence base for the periodontal-systemic link is largely built on surrogate endpoints. The one quantified outcome curated here is a roughly 0.4% HbA1c reduction in diabetes; for cardiovascular disease the joint EFP/WHF consensus stops at independent association. Without event-driven trials the direction and magnitude of any causal benefit remain open, and the comorbidity node should not be read as asserting that periodontitis causes its associated diseases.

Proposed experiments

Event-driven periodontal therapy trial with cardiovascular endpoints

event-driven randomised outcome trial

exp_perio_mace_outcome_trial

Randomised trial of intensive versus standard periodontal therapy in patients at elevated cardiovascular risk, with major adverse cardiovascular events as the primary endpoint rather than surrogate markers such as endothelial function or C-reactive protein.

Decision criterion

A significant reduction in major adverse cardiovascular events in the intensive arm.

Would support

pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk

Would refute

pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk

Supporting outcome

Periodontal inflammation causally contributes to cardiovascular events.

Refuting outcome

Surrogate-marker improvement without event reduction, indicating the association is largely confounded or non-causal.

Mendelian randomisation of periodontitis against cardio-metabolic outcomes

Mendelian randomisation analysis

exp_perio_mendelian_randomisation

Use periodontitis-associated germline variants as instruments to estimate the causal effect of periodontitis liability on cardio-metabolic outcomes, separating association from shared-risk-factor confounding.

Decision criterion

A significant instrumented effect surviving pleiotropy-robust sensitivity analyses.

Would support

pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk

Would refute

pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk

Supporting outcome

A causal contribution of periodontitis liability to cardio-metabolic disease.

Refuting outcome

A null instrumented effect, favouring confounding by smoking and metabolic state.

Show evidence (1 reference)

PMID:33510490 SUPPORT Other

"Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions."

Explicitly characterises the interventional evidence as acting on surrogate markers, which is the gap recorded here.

Should the oral-gut translocation arm be promoted from disease-level pathophysiology to a `kb/modules/` mechanism module?

CURATION TODO OPEN oral_gut_axis_module_scope

Issue 6098 asked whether the published barrier-metabolism-immunity oral-gut framework warrants a module. The barrier and immunity dimensions are already covered by `intestinal_barrier_dysfunction`, `epithelial_barrier_dysfunction`, `gut_dysbiosis` and `molecular_mimicry_autoimmunity`, so a three-dimensional module would largely duplicate them. The non-redundant kernel is the directional oral-to-gut pathobiont route curated here. A module becomes worthwhile once a second conformer exists — the natural candidates are `Inflammatory_Bowel_Disease` (the gut end of the same chain) and `Rheumatoid_Arthritis` (which already names Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans in the notes of its mucosal-immune-activation node without modelling them structurally). Until then, one disease entry does not justify a module.

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Pathophysiology

Dysbiotic Subgingival Biofilm Formation

Accumulation of supragingival and subgingival plaque, unchecked by oral hygiene, permits an ecological shift in the resident periodontal community away from health-associated taxa. Disease initiation and propagation follow from this dysbiosis interacting with host immune defences, rather than from acquisition of an exogenous pathogen.

Keystone-Pathogen / Polymicrobial Synergy and Dysbiosis Model Periodontal Hypercitrullination Trigger of Autoimmunity

subgingival plaque biofilm formation GO:0042710 ↑ INCREASED

gingiva UBERON:0001828

Downstream

Keystone-Pathogen Remodelling and Complement Subversion The dysbiotic community is the substrate on which a keystone organism acts.

Neutrophil Hypercitrullination by Leukotoxin A Periodontal dysbiosis supplies the Aggregatibacter actinomycetemcomitans burden whose leukotoxin drives neutrophil hypercitrullination.

Show evidence (1 reference)

PMID:28805207 SUPPORT Human Clinical

"Periodontal disease initiation and propagation is through a dysbiosis of the commensal oral microbiota (dental plaque), which then interacts with the immune defences of the host, leading to inflammation and disease."

Disease-primer statement that dysbiosis of the commensal plaque community, not exogenous infection, initiates and propagates periodontal disease.

Keystone-Pathogen Remodelling and Complement Subversion

Porphyromonas gingivalis, present at very low abundance, disproportionately raises the pathogenicity of the whole community by manipulating complement receptor signalling (C3a/C5a receptors) and innate immune surveillance. In experimental periodontitis both an intact commensal microbiota and an intact complement system are required for P. gingivalis to cause bone loss, establishing that the organism acts through the community and the host rather than by direct tissue damage.

Keystone-Pathogen / Polymicrobial Synergy and Dysbiosis Model

complement activation GO:0006956 ↑ INCREASED

Downstream

Th17 Expansion and Neutrophil-Rich Periodontal Inflammation

Show evidence (2 references)

PMID:22036469 SUPPORT Model Organism

"Here we show that P. gingivalis, at very low colonization levels, triggers changes to the amount and composition of the oral commensal microbiota leading to inflammatory periodontal bone loss."

Demonstrates the keystone effect in mice: a low-abundance species remodels the community and causes bone loss.

PMID:22036469 SUPPORT Model Organism

"The commensal microbiota and complement were both required for P. gingivalis-induced bone loss, as germ-free mice or conventionally raised C3a and C5a receptor-deficient mice did not develop bone loss after inoculation with P. gingivalis."

Genetic requirement for C3aR/C5aR establishes complement as an obligatory intermediate in the keystone mechanism.

Th17 Expansion and Neutrophil-Rich Periodontal Inflammation

The dysbiotic community drives local proliferation of resident memory Th17 cells in the gingiva in an IL-6- and IL-23-dependent manner, with accompanying neutrophil accumulation. This IL-17-polarised infiltrate — not bacterial burden per se — is the proximate effector of periodontal tissue destruction. Human genetic experiments of nature run in both directions: individuals with defective Th17 differentiation show diminished periodontal inflammation and bone loss, while individuals with defective neutrophil recruitment (leukocyte adhesion deficiency type I) show excessive local IL-17 and severe bone loss.

Keystone-Pathogen / Polymicrobial Synergy and Dysbiosis Model

T-helper 17 cell CL:0000899 neutrophil CL:0000775 gingival epithelial cell CL:0002621

T-helper 17 cell differentiation GO:0072539 ↑ INCREASED interleukin-17 production GO:0032620 ↑ INCREASED neutrophil chemotaxis GO:0030593 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Osteoclast-Mediated Alveolar Bone Resorption

Connective Tissue Attachment Loss and Pocket Formation

Show evidence (5 references)

PMID:30333238 SUPPORT Human Clinical

"Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis."

Establishes the Th17 expansion in human, not just murine, periodontitis.

PMID:30333238 SUPPORT Model Organism

"periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23"

Places the Th17 expansion causally downstream of dysbiosis and identifies the required cytokines.

PMID:30333238 SUPPORT Human Clinical

"In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections."

Loss-of-function human evidence that Th17 cells are required for periodontal immunopathology.

+ 2 more references

Osteoclast-Mediated Alveolar Bone Resorption

Sustained IL-17-driven inflammation in the periodontium recruits and activates osteoclasts at the alveolar crest, tipping remodelling toward net resorption. Bone loss is the structural readout by which experimental periodontitis is quantified and the basis of radiographic staging in patients.

osteoclast CL:0000092

osteoclast differentiation GO:0030316 ↑ INCREASED bone resorption GO:0045453 ↑ INCREASED

Downstream

Connective Tissue Attachment Loss and Pocket Formation

Show evidence (1 reference)

PMID:30333238 SUPPORT Model Organism

"TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis."

Establishes the immune infiltrate as necessary for the destructive phase that includes bone loss.

Connective Tissue Attachment Loss and Pocket Formation

Proteolytic degradation of the periodontal ligament and gingival connective tissue detaches the soft tissue from the root surface, converting the physiological gingival sulcus into a pathological periodontal pocket. Pocket depth and clinical attachment loss are the defining measurements of the disease and drive the 2017 staging system; the pocket itself is an anaerobic niche that further favours the dysbiotic community.

Oral-to-Gut Pathobiont Translocation Model

extracellular matrix disassembly GO:0022617 ↑ INCREASED

periodontal ligament UBERON:0008266

Downstream

Systemic Dissemination of Periodontal Pathogens and Inflammatory Mediators

Expansion and Ingestion of Oral Pathobionts

Show evidence (2 references)

PMID:28805207 SUPPORT Human Clinical

"Periodontal diseases comprise a wide range of inflammatory conditions that affect the supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead to tooth loss and contribute to systemic inflammation."

Identifies the destroyed tissues and the two downstream consequences modelled here — tooth loss and systemic inflammation.

PMID:29926952 SUPPORT Other

"Stage I to IV of periodontitis is defined based on severity (primarily periodontal breakdown with reference to root length and periodontitis-associated tooth loss), complexity of management (pocket depth, infrabony defects, furcation involvement, tooth hypermobility, masticatory dysfunction) and..."

Confirms that periodontal breakdown, pocket depth and attachment/tooth loss are the operative clinical measurements of this node.

Systemic Dissemination of Periodontal Pathogens and Inflammatory Mediators

The ulcerated pocket epithelium is a large, chronically breached surface through which periodontal bacteria and locally generated inflammatory mediators enter the circulation. Disseminated pathogens and periodontitis-associated systemic inflammation — including adaptation of bone marrow haematopoietic progenitors — are the proposed mechanistic bridge to extra-oral comorbidity.

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Chronic Systemic Inflammatory Burden and Comorbidity Risk

Show evidence (2 references)

PMID:33510490 SUPPORT Other

"Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of..."

Names the two dissemination channels — organisms and systemic inflammation — modelled by this node.

PMID:30746447 SUPPORT INDIRECT Model Organism

"Oral P. gingivalis infection in mice resulted in brain colonization"

Demonstration that an oral periodontal pathogen can reach an extra-oral organ after oral infection. Cited for the dissemination step only; this entry does not assert the paper's causal claim about Alzheimer disease. Graded INDIRECT because the dissemination is shown in mice, so it reaches this node's claim about human periodontitis by an inference step.

Expansion and Ingestion of Oral Pathobionts

Periodontal inflammation expands specific oral pathobionts — notably Klebsiella and Enterobacter species — in the oral cavity. Because saliva is continuously swallowed, this amassed oral population is delivered enterally to the gut. This is the entry point of the oral-gut axis and is mechanistically distinct from the haematogenous dissemination node above.

Oral-to-Gut Pathobiont Translocation Model

Downstream

Ectopic Intestinal Colonisation by Oral Pathobionts

Gut-Homing Oral-Pathobiont-Reactive T Cell Induction

Show evidence (1 reference)

PMID:32758418 SUPPORT Model Organism

"Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation."

States both halves of this node: periodontitis-driven oral expansion, and ingestion as the route to the gut.

Ectopic Intestinal Colonisation by Oral Pathobionts

Oral-derived strains that reach the intestine can colonise it ectopically when the resident gut community is already dysbiotic, activating the inflammasome in colonic mononuclear phagocytes and inducing intestinal T helper 1 responses. Salivary Klebsiella isolates are strong TH1 inducers in gnotobiotic colonisation, are multi-drug resistant, and elicit severe gut inflammation in a genetically susceptible host.

Oral-to-Gut Pathobiont Translocation Model

colonic mononuclear phagocyte CL:0000235

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Chronic Systemic Inflammatory Burden and Comorbidity Risk

Show evidence (2 references)

PMID:29051379 SUPPORT Model Organism

"we show that strains of Klebsiella spp. isolated from the salivary microbiota are strong inducers of T helper 1 (TH1) cells when they colonize in the gut"

Gnotobiotic evidence that salivary-origin organisms colonising the gut drive a distinct intestinal T cell response.

PMID:29051379 SUPPORT Model Organism

"Our findings suggest that the oral cavity may serve as a reservoir for potential intestinal pathobionts that can exacerbate intestinal disease."

States the reservoir model that this node encodes.

Gut-Homing Oral-Pathobiont-Reactive T Cell Induction

In parallel with the microbial route, periodontitis generates oral pathobiont-reactive Th17 cells in the oral cavity that are imprinted with gut tropism and migrate to the inflamed intestine. Once there they are activated by the translocated oral pathobionts — but not by gut-resident microbes — so the cellular and the microbial arms are jointly required.

Oral-to-Gut Pathobiont Translocation Model

T-helper 17 cell CL:0000899

T-helper 17 cell differentiation GO:0072539 ↑ INCREASED

Downstream

Chronic Systemic Inflammatory Burden and Comorbidity Risk

Show evidence (1 reference)

PMID:32758418 SUPPORT Model Organism

"In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut."

Establishes the T cell arm and its gut-homing imprint.

Neutrophil Hypercitrullination by Leukotoxin A

Aggregatibacter actinomycetemcomitans secretes the pore-forming toxin leukotoxin A, which permeabilises neutrophils and dysregulates their citrullinating enzymes. The resulting periodontal citrullinome mirrors the hypercitrullination pattern of the rheumatoid joint, and neutrophil morphological changes resembling extracellular trap formation release the hypercitrullinated cargo into the periodontal tissue.

Periodontal Hypercitrullination Trigger of Autoimmunity

neutrophil CL:0000775

Downstream

Chronic Systemic Inflammatory Burden and Comorbidity Risk Proposed route from a periodontal mucosal trigger to systemic anti-citrullinated protein autoimmunity; the intervening steps in humans are not established.

Show evidence (2 references)

PMID:27974664 SUPPORT Human Clinical

"Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA."

Human gingival crevicular fluid proteomics showing the periodontal citrullinome.

PMID:27974664 SUPPORT In Vitro

"We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint."

Identifies the molecular effector modelled by this node.

Chronic Systemic Inflammatory Burden and Comorbidity Risk

The convergent endpoint of the haematogenous, enteral and autoimmune arms: a sustained systemic inflammatory state epidemiologically associated with cardio-metabolic, neurodegenerative and autoimmune disease and with cancer. The relationship with diabetes is explicitly bidirectional — diabetes roughly triples periodontitis susceptibility, and periodontal inflammation worsens glycaemic control.

inflammatory response GO:0006954 ↑ INCREASED

Show evidence (3 references)

PMID:33510490 SUPPORT Other

"Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer."

Scope statement for the comorbidity set represented by this node.

PMID:22057194 SUPPORT Human Clinical

"There is emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycaemic control."

Supports the bidirectional framing rather than a one-way periodontitis-to-diabetes claim.

PMID:32011025 SUPPORT DIRECT Human Clinical

"There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD."

Consensus statement of association. This node claims an epidemiological association and no more, which is exactly what the quoted sentence asserts, so it is graded DIRECT for that claim. The workshop stops short of causation, and this node should not be upgraded to a causal assertion on the strength of it.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 1

Gingival Inflammation and Bleeding Gingival bleeding HP:0000225

Show evidence (1 reference)

PMID:32383274 SUPPORT Human Clinical

"Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of..."

Gingival inflammation is named as an explicit therapeutic target, confirming it as a clinical feature of the disease.

Head and Neck 4

Periodontitis HP:0000704

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:28805207 SUPPORT Human Clinical

Defines the phenotype in terms of the affected supporting structures.

Alveolar Bone Loss Alveolar bone loss around teeth HP:0410027

Show evidence (1 reference)

PMID:24670684 SUPPORT Human Clinical

"LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection."

Documents severe periodontal bone loss as the clinical phenotype in a human immunodeficiency presenting with the periodontitis phenotype.

Tooth Loss Premature loss of teeth HP:0006480

Show evidence (1 reference)

PMID:29926952 SUPPORT Other

Periodontitis-associated tooth loss is an explicit staging criterion.

Gingival Recession HP:0030816

Constitutional 1

Halitosis HP:0100812

🧬

Genetic Associations

ITGB2

Gene: ITGB2 hgnc:6155 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24670684 SUPPORT Human Clinical

"LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection."

Establishes the invariable periodontal phenotype of the ITGB2/CD18 deficiency syndrome.

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Medical Actions

Subgingival Instrumentation

Action: Periodontal Scaling and Root Planing NCIT:C63714

Mechanical removal of the supra- and subgingival biofilm (scaling and root planing) is the cornerstone of cause-related periodontal therapy and the second step of the EFP stepwise protocol. It acts directly on the dysbiotic biofilm node.

Mechanism Target:

INHIBITS Dysbiotic Subgingival Biofilm Formation — Physically disrupts and removes the subgingival biofilm, removing the trigger of the inflammatory cascade.

Show evidence (1 reference)

PMID:32383274 SUPPORT Human Clinical

Sub-gingival instrumentation is a guideline-recommended intervention directed at the biofilm.

Show evidence (1 reference)

PMID:32383274 SUPPORT Human Clinical

"The S3 CPG approaches the treatment of periodontitis (stages I, II and III) using a pre-established stepwise approach to therapy that, depending on the disease stage, should be incremental, each including different interventions."

Establishes the stepwise framework within which instrumentation sits.

Periodontal Surgery

Action: periodontal surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Access, resective or regenerative periodontal surgery for sites that do not respond to non-surgical instrumentation; the third step of the EFP stepwise protocol.

Show evidence (1 reference)

PMID:32383274 SUPPORT Human Clinical

Periodontal surgical interventions are a guideline-recommended treatment category.

Oral Hygiene and Professional Biofilm Removal

Action: dental prophylaxis Ontology label: Dental Prophylaxis NCIT:C62548

Daily self-performed plaque control plus professional removal of the microbial biofilm on a quarterly or bi-annual basis. This is the mainstay of prevention and the supragingival-biofilm component of the first step of the EFP stepwise protocol.

Mechanism Target:

INHIBITS Dysbiotic Subgingival Biofilm Formation — Self-performed and professional biofilm removal prevents the plaque accumulation from which dysbiosis develops.

Show evidence (1 reference)

PMID:28805207 SUPPORT Human Clinical

"Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi-annual basis."

States the preventive mechanism as biofilm removal.

Show evidence (1 reference)

PMID:28805207 SUPPORT Human Clinical

"Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi-annual basis."

Primary-prevention recommendation from the disease primer.

Behavioural Change and Risk-Factor Control

Action: behavioural counselling Ontology label: Behavioral Counseling NCIT:C181743

Platform: Behavioral / lifestyle

Counselling for behaviour change and control of modifiable risk factors — above all smoking cessation, plus glycaemic control in people with diabetes. This is the risk-factor component of the first step of the EFP stepwise protocol.

Mechanism Target:

INHIBITS Connective Tissue Attachment Loss and Pocket Formation — Removing the smoking exposure removes the principal modifiable determinant of periodontal breakdown severity.

Show evidence (1 reference)

PMID:28805207 SUPPORT Human Clinical

"The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility)."

Identifies smoking as the modifiable severity determinant this treatment targets.

Show evidence (1 reference)

PMID:32383274 SUPPORT Human Clinical

Behavioural change and risk-factor control are the first named intervention category in the guideline.

Supportive Periodontal Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Structured maintenance recall after active therapy, required to sustain the treatment benefit over time; the fourth step of the EFP stepwise protocol.

Show evidence (1 reference)

PMID:32383274 SUPPORT Human Clinical

Supportive periodontal care is named as necessary to extend benefits over time.

Periodontal Therapy for Glycaemic Control

Action: Periodontal Treatment NCIT:C63747

Treating periodontitis in people with diabetes produces a modest but reproducible improvement in glycaemic control, and is the clearest interventional evidence that the periodontal-systemic link is at least partly causal in that direction.

Mechanism Target:

INHIBITS Chronic Systemic Inflammatory Burden and Comorbidity Risk — Reducing the periodontal inflammatory burden improves a systemic comorbidity outcome (HbA1c).

Show evidence (1 reference)

PMID:22057194 SUPPORT Human Clinical

"Treatment of periodontitis is associated with HbA(1c) reductions of approximately 0.4%."

Quantifies the systemic benefit of treating the oral disease.

Show evidence (1 reference)

PMID:22057194 SUPPORT Human Clinical

"Oral and periodontal health should be promoted as integral components of diabetes management."

Recommendation to integrate periodontal care into diabetes management.

🌍

Environmental Factors

Tobacco smoking

Smoking is the principal modifiable environmental risk factor for periodontitis severity and is an explicit target of risk-factor control in first-step therapy.

Show evidence (2 references)

PMID:28805207 SUPPORT Human Clinical

"The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility)."

Supports the first clause of this entry: smoking is an environmental, modifiable determinant of periodontal disease severity. Note the primer names it as the exemplar modifiable factor and does not rank the modifiable factors against each other, so it does not by itself establish the word "principal" in the description above.

PMID:32383274 SUPPORT Human Clinical

Supports the second clause: risk-factor control is the first named intervention category in the guideline's stepwise protocol, which is what makes this exposure an explicit therapeutic target rather than only a descriptive risk factor. The same sentence carries the corresponding claim on the 'Behavioural Change and Risk-Factor Control' treatment.

Mechanism Target:

EXACERBATES Connective Tissue Attachment Loss and Pocket Formation — Smoking increases the severity of periodontal breakdown; the mediating steps are not resolved by the cited source, which reports it as a modifiable severity determinant.

Show evidence (1 reference)

PMID:28805207 SUPPORT Human Clinical

"The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility)."

Names smoking as the exemplar modifiable environmental determinant of periodontal disease severity.

📊

Prevalence

Worldwide

Point Prevalence 11200.0 per 100,000 (10500.0–12000.0) >1 in 1,000

Severe periodontitis only. Global age-standardised prevalence, GBD 2010 modelling; the reported 95% uncertainty interval for 2010 is 10.5%-12.0%. Non-severe periodontitis is substantially more common and is not covered by this estimate.

Show evidence (2 references)

PMID:25261053 SUPPORT Human Clinical

"Between 1990 and 2010, the global age-standardized prevalence of SP was static at 11.2%"

Source of the 11.2% age-standardised global prevalence of severe periodontitis.

PMID:25261053 SUPPORT Human Clinical

"SP was the sixth-most prevalent condition in the world."

Contextualises the global burden ranking.

Worldwide

Annual Incidence 701.0 per 100,000 (599.0–823.0) >1 in 1,000 per year

Severe periodontitis, age-standardised incidence in 2010 (95% uncertainty interval 599-823 per 100,000 person-years). Do not compare directly with the point-prevalence record above.

Show evidence (1 reference)

PMID:25261053 SUPPORT Human Clinical

"The age-standardized incidence of SP in 2010 was 701 cases per 100,000 person-years"

Source of the annual incidence estimate.

{ }

Source YAML

click to show

name: Periodontitis
creation_date: "2026-08-07T00:00:00Z"
category: Complex
disease_term:
  preferred_term: periodontitis
  term:
    id: MONDO:0005076
    label: periodontitis
parents:
- Oral Cavity Disease
- Inflammatory Disease

synonyms:
- Chronic Periodontitis
- Aggressive Periodontitis
- Periodontal Disease

description: >
  Periodontitis is a chronic, biofilm-driven inflammatory disease of the tooth-supporting
  apparatus — gingiva, periodontal ligament, cementum and alveolar bone. It is not a
  classical infection by a single pathogen but a dysbiosis: an ecological shift in the
  subgingival plaque community that provokes a dysregulated host inflammatory response,
  and it is that host response — not the bacteria directly — that destroys the
  periodontium. A low-abundance keystone organism (canonically Porphyromonas gingivalis)
  can remodel an otherwise commensal community into a dysbiotic one by subverting
  complement and innate immune surveillance. The resulting IL-17/Th17-polarised,
  neutrophil-rich lesion drives osteoclast-mediated resorption of alveolar bone and
  degradation of the periodontal ligament, producing clinical attachment loss, periodontal
  pocketing and, eventually, tooth loss.

  Beyond the mouth, periodontitis is a persistent source of systemic inflammatory burden.
  Periodontal pathogens and inflammatory mediators disseminate haematogenously, and — the
  arm this entry models explicitly — amassed oral pathobionts are also swallowed, seeding
  the gut. This oral-gut route is mechanistically distinct from haematogenous spread and
  is the non-redundant core of the oral-gut axis framework (see notes).
notes: >
  **Scope and modelling decisions.**

  1. *Periodontitis versus dental caries.* Both are oral-biofilm dysbiosis diseases and
     share ecological framing with the `Dental_Caries` entry, but the microbial shift,
     the host response and the destroyed tissue differ: caries is an acidogenic,
     acid-tolerant community demineralising tooth hard tissue; periodontitis is an
     anaerobic, Gram-negative-enriched community driving inflammatory destruction of the
     tooth-supporting soft tissue and bone.

  2. *Necrotizing periodontal diseases, endodontic-periodontal lesions and periodontal
     abscesses* remain distinct categories in the 2017 World Workshop classification
     (PMID:29926951) and are deliberately out of scope here.

  3. *Chronic versus aggressive periodontitis.* The 2017 classification collapsed these
     into a single periodontitis category characterised by stage (I-IV) and grade (A-C)
     rather than by named subtype, so this entry does not model them as `has_subtypes`.
     The synonyms are retained because most of the cited literature predates the
     reclassification.

  4. *Oral-gut axis.* This entry curates the oral-to-gut translocation arm as explicit
     pathophysiology nodes rather than deferring to a new oral-gut axis module. The
     barrier and immunity dimensions of the published three-dimensional framework
     (PMID:42396665) are already covered by existing dismech modules
     (`intestinal_barrier_dysfunction`, `epithelial_barrier_dysfunction`, `gut_dysbiosis`,
     `molecular_mimicry_autoimmunity`); the genuinely non-redundant mechanism is the
     directional one — oral pathobionts amassed in the mouth being ingested and
     ectopically colonising the intestine. See issue 6098 and the
     `oral_gut_axis_module_scope` discussion below.

  5. *Genetic architecture.* Periodontitis is a complex trait; no common-variant locus is
     curated here because the entry's evidence standard requires a verified quotable
     snippet per claim. The monogenic entry point retained is leukocyte adhesion
     deficiency type I (ITGB2/CD18), in which severe periodontal bone loss is invariable
     and mechanistically informative — it demonstrates that defective neutrophil
     recruitment, not neutrophil excess, can drive IL-17-dependent bone loss.

mechanistic_hypotheses:
- hypothesis_group_id: keystone_pathogen_polymicrobial_synergy
  hypothesis_label: Keystone-Pathogen / Polymicrobial Synergy and Dysbiosis Model
  status: CANONICAL
  description: >
    The prevailing model: a low-abundance keystone organism (P. gingivalis) elevates the
    virulence of the whole subgingival community by subverting complement and innate
    immune surveillance, converting a commensal biofilm into a dysbiotic one that the
    host then over-responds to. Disease severity tracks the dysregulated host response
    rather than total bacterial load.
  evidence:
  - reference: PMID:22941505
    reference_title: "The keystone-pathogen hypothesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one."
    explanation: >
      States the hypothesis in its canonical form; periodontitis is its exemplar disease.
  - reference: PMID:25534621
    reference_title: "Periodontitis: from microbial immune subversion to systemic inflammation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health."
    explanation: >
      Review framing of periodontitis as dysbiotic-inflammatory rather than classically
      infectious.
- hypothesis_group_id: oral_gut_translocation_model
  hypothesis_label: Oral-to-Gut Pathobiont Translocation Model
  status: EMERGING
  description: >
    Periodontitis expands oral pathobionts (Klebsiella, Enterobacter) that are ingested
    and ectopically colonise the intestine, where they activate the inflammasome in
    colonic mononuclear phagocytes; in parallel, oral pathobiont-reactive Th17 cells
    generated in the mouth are imprinted with gut tropism and migrate to the intestine.
    This supplies an enteral, non-haematogenous route by which oral inflammation
    aggravates extra-oral disease. The causal chain is established in gnotobiotic and
    murine models; direct human causal verification is the open question (see the
    HUMAN_MODEL_MISMATCH discussion).
  evidence:
  - reference: PMID:32758418
    reference_title: "The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells."
    explanation: >
      States the model's central claim as the study's own conclusion, in a murine
      periodontitis-colitis system.
  - reference: PMID:42396665
    reference_title: "Oral-gut axis in systemic disease: A barrier-metabolism-immunity three-dimensional regulatory model (Review)."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "It sustains systemic homeostasis through bidirectional microbial translocation, metabolite signaling and immune crosstalk."
    explanation: >
      The review that motivated this curation frames the axis as bidirectional; this
      entry models only the oral-to-gut direction, for which experimental causal
      evidence exists. Graded INDIRECT: the quote establishes that microbial
      translocation along the oral-gut axis occurs, and this model's premise follows
      from that by an inference step rather than being asserted by the sentence.
- hypothesis_group_id: periodontal_citrullination_autoimmunity_model
  hypothesis_label: Periodontal Hypercitrullination Trigger of Autoimmunity
  status: EMERGING
  description: >
    A specific periodontal pathogen, Aggregatibacter actinomycetemcomitans, secretes the
    pore-forming leukotoxin A, which dysregulates neutrophil citrullinating enzymes and
    produces a citrullinome mirroring that of the rheumatoid joint — proposing the
    periodontium as a mucosal initiation site for anti-citrullinated protein autoimmunity.
    Candidate-trigger status, not established causation.
  evidence:
  - reference: PMID:27974664
    reference_title: "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA."
    explanation: >
      The authors themselves stop at candidate trigger, which is the epistemic level
      recorded here.

pathophysiology:
- name: Dysbiotic Subgingival Biofilm Formation
  role: trigger
  biological_scale: TISSUE
  description: >
    Accumulation of supragingival and subgingival plaque, unchecked by oral hygiene,
    permits an ecological shift in the resident periodontal community away from
    health-associated taxa. Disease initiation and propagation follow from this dysbiosis
    interacting with host immune defences, rather than from acquisition of an exogenous
    pathogen.
  biological_processes:
  - preferred_term: subgingival plaque biofilm formation
    term:
      id: GO:0042710
      label: biofilm formation
    modifier: INCREASED
  locations:
  - preferred_term: gingiva
    term:
      id: UBERON:0001828
      label: gingiva
  downstream:
  - target: Keystone-Pathogen Remodelling and Complement Subversion
    causal_link_type: DIRECT
    hypothesis_groups:
    - keystone_pathogen_polymicrobial_synergy
    description: >
      The dysbiotic community is the substrate on which a keystone organism acts.
  - target: Neutrophil Hypercitrullination by Leukotoxin A
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - periodontal_citrullination_autoimmunity_model
    description: >
      Periodontal dysbiosis supplies the Aggregatibacter actinomycetemcomitans burden
      whose leukotoxin drives neutrophil hypercitrullination.
  evidence:
  - reference: PMID:28805207
    reference_title: "Periodontal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periodontal disease initiation and propagation is through a dysbiosis of the commensal oral microbiota (dental plaque), which then interacts with the immune defences of the host, leading to inflammation and disease."
    explanation: >
      Disease-primer statement that dysbiosis of the commensal plaque community, not
      exogenous infection, initiates and propagates periodontal disease.

- name: Keystone-Pathogen Remodelling and Complement Subversion
  role: mechanism
  biological_scale: CELLULAR
  description: >
    Porphyromonas gingivalis, present at very low abundance, disproportionately raises the
    pathogenicity of the whole community by manipulating complement receptor signalling
    (C3a/C5a receptors) and innate immune surveillance. In experimental periodontitis both
    an intact commensal microbiota and an intact complement system are required for
    P. gingivalis to cause bone loss, establishing that the organism acts through the
    community and the host rather than by direct tissue damage.
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  downstream:
  - target: Th17 Expansion and Neutrophil-Rich Periodontal Inflammation
    causal_link_type: DIRECT
    hypothesis_groups:
    - keystone_pathogen_polymicrobial_synergy
  evidence:
  - reference: PMID:22036469
    reference_title: "Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that P. gingivalis, at very low colonization levels, triggers changes to the amount and composition of the oral commensal microbiota leading to inflammatory periodontal bone loss."
    explanation: >
      Demonstrates the keystone effect in mice: a low-abundance species remodels the
      community and causes bone loss.
  - reference: PMID:22036469
    reference_title: "Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The commensal microbiota and complement were both required for P. gingivalis-induced bone loss, as germ-free mice or conventionally raised C3a and C5a receptor-deficient mice did not develop bone loss after inoculation with P. gingivalis."
    explanation: >
      Genetic requirement for C3aR/C5aR establishes complement as an obligatory
      intermediate in the keystone mechanism.
  notes: >
    Both supporting experiments are murine; the complement requirement has not been
    demonstrated by genetic ablation in humans.

- name: Th17 Expansion and Neutrophil-Rich Periodontal Inflammation
  role: mechanism
  biological_scale: CELLULAR
  description: >
    The dysbiotic community drives local proliferation of resident memory Th17 cells in
    the gingiva in an IL-6- and IL-23-dependent manner, with accompanying neutrophil
    accumulation. This IL-17-polarised infiltrate — not bacterial burden per se — is the
    proximate effector of periodontal tissue destruction. Human genetic experiments of
    nature run in both directions: individuals with defective Th17 differentiation show
    diminished periodontal inflammation and bone loss, while individuals with defective
    neutrophil recruitment (leukocyte adhesion deficiency type I) show excessive local
    IL-17 and severe bone loss.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: gingival epithelial cell
    term:
      id: CL:0002621
      label: gingival epithelial cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: INCREASED
  - preferred_term: interleukin-17 production
    term:
      id: GO:0032620
      label: interleukin-17 production
    modifier: INCREASED
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Osteoclast-Mediated Alveolar Bone Resorption
    causal_link_type: DIRECT
    hypothesis_groups:
    - keystone_pathogen_polymicrobial_synergy
  - target: Connective Tissue Attachment Loss and Pocket Formation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30333238
    reference_title: "A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis."
    explanation: >
      Establishes the Th17 expansion in human, not just murine, periodontitis.
  - reference: PMID:30333238
    reference_title: "A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23"
    explanation: >
      Places the Th17 expansion causally downstream of dysbiosis and identifies the
      required cytokines.
  - reference: PMID:30333238
    reference_title: "A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections."
    explanation: >
      Loss-of-function human evidence that Th17 cells are required for periodontal
      immunopathology.
  - reference: PMID:24670684
    reference_title: "Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection."
    explanation: >
      The LAD-I phenotype anchors the counterintuitive direction: impaired neutrophil
      recruitment, not neutrophil excess, produces severe bone loss.
  - reference: PMID:24670684
    reference_title: "Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Local treatment with antibodies to IL-17 or IL-23 in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis."
    explanation: >
      Interventional murine evidence that IL-17/IL-23 blockade is sufficient to block
      periodontal bone loss.

- name: Osteoclast-Mediated Alveolar Bone Resorption
  role: consequence
  biological_scale: CELLULAR
  conforms_to: "osteoporosis_bone_resorption#Increased Osteoclastic Bone Resorption"
  description: >
    Sustained IL-17-driven inflammation in the periodontium recruits and activates
    osteoclasts at the alveolar crest, tipping remodelling toward net resorption. Bone
    loss is the structural readout by which experimental periodontitis is quantified and
    the basis of radiographic staging in patients.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: INCREASED
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  downstream:
  - target: Connective Tissue Attachment Loss and Pocket Formation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30333238
    reference_title: "A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis."
    explanation: >
      Establishes the immune infiltrate as necessary for the destructive phase that
      includes bone loss.
  notes: >
    Conforms to the shared osteoclastic-resorption node of
    `osteoporosis_bone_resorption`; the substituted context is the alveolar crest and an
    IL-17/dysbiosis-driven rather than oestrogen-withdrawal/ageing driver. No verified
    quotable RANKL/OPG-ratio snippet was available at curation time, so the specific
    RANKL mechanism is deliberately not asserted here.

- name: Connective Tissue Attachment Loss and Pocket Formation
  role: consequence
  biological_scale: TISSUE
  description: >
    Proteolytic degradation of the periodontal ligament and gingival connective tissue
    detaches the soft tissue from the root surface, converting the physiological gingival
    sulcus into a pathological periodontal pocket. Pocket depth and clinical attachment
    loss are the defining measurements of the disease and drive the 2017 staging system;
    the pocket itself is an anaerobic niche that further favours the dysbiotic community.
  locations:
  - preferred_term: periodontal ligament
    term:
      id: UBERON:0008266
      label: periodontal ligament
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: INCREASED
  downstream:
  - target: Systemic Dissemination of Periodontal Pathogens and Inflammatory Mediators
    causal_link_type: DIRECT
  - target: Expansion and Ingestion of Oral Pathobionts
    causal_link_type: DIRECT
    hypothesis_groups:
    - oral_gut_translocation_model
  evidence:
  - reference: PMID:28805207
    reference_title: "Periodontal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periodontal diseases comprise a wide range of inflammatory conditions that affect the supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead to tooth loss and contribute to systemic inflammation."
    explanation: >
      Identifies the destroyed tissues and the two downstream consequences modelled
      here — tooth loss and systemic inflammation.
  - reference: PMID:29926952
    reference_title: "Staging and grading of periodontitis: Framework and proposal of a new classification and case definition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Stage I to IV of periodontitis is defined based on severity (primarily periodontal breakdown with reference to root length and periodontitis-associated tooth loss), complexity of management (pocket depth, infrabony defects, furcation involvement, tooth hypermobility, masticatory dysfunction) and additionally described as extent (localized or generalized)."
    explanation: >
      Confirms that periodontal breakdown, pocket depth and attachment/tooth loss are
      the operative clinical measurements of this node.

- name: Systemic Dissemination of Periodontal Pathogens and Inflammatory Mediators
  role: consequence
  biological_scale: ORGANISM
  description: >
    The ulcerated pocket epithelium is a large, chronically breached surface through which
    periodontal bacteria and locally generated inflammatory mediators enter the
    circulation. Disseminated pathogens and periodontitis-associated systemic inflammation
    — including adaptation of bone marrow haematopoietic progenitors — are the proposed
    mechanistic bridge to extra-oral comorbidity.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Chronic Systemic Inflammatory Burden and Comorbidity Risk
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33510490
    reference_title: "Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities."
    explanation: >
      Names the two dissemination channels — organisms and systemic inflammation —
      modelled by this node.
  - reference: PMID:30746447
    reference_title: "Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Oral P. gingivalis infection in mice resulted in brain colonization"
    explanation: >
      Demonstration that an oral periodontal pathogen can reach an extra-oral organ
      after oral infection. Cited for the dissemination step only; this entry does not
      assert the paper's causal claim about Alzheimer disease. Graded INDIRECT because
      the dissemination is shown in mice, so it reaches this node's claim about human
      periodontitis by an inference step.
  notes: >
    The P. gingivalis / Alzheimer citation is included as dissemination evidence only.
    Its disease-causation claim is contested; do not upgrade this to a causal assertion
    about neurodegeneration without new human evidence.

- name: Expansion and Ingestion of Oral Pathobionts
  role: mechanism
  biological_scale: ORGANISM
  description: >
    Periodontal inflammation expands specific oral pathobionts — notably Klebsiella and
    Enterobacter species — in the oral cavity. Because saliva is continuously swallowed,
    this amassed oral population is delivered enterally to the gut. This is the entry
    point of the oral-gut axis and is mechanistically distinct from the haematogenous
    dissemination node above.
  downstream:
  - target: Ectopic Intestinal Colonisation by Oral Pathobionts
    causal_link_type: DIRECT
    hypothesis_groups:
    - oral_gut_translocation_model
  - target: Gut-Homing Oral-Pathobiont-Reactive T Cell Induction
    causal_link_type: DIRECT
    hypothesis_groups:
    - oral_gut_translocation_model
  evidence:
  - reference: PMID:32758418
    reference_title: "The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation."
    explanation: >
      States both halves of this node: periodontitis-driven oral expansion, and
      ingestion as the route to the gut.

- name: Ectopic Intestinal Colonisation by Oral Pathobionts
  role: consequence
  biological_scale: CELLULAR
  description: >
    Oral-derived strains that reach the intestine can colonise it ectopically when the
    resident gut community is already dysbiotic, activating the inflammasome in colonic
    mononuclear phagocytes and inducing intestinal T helper 1 responses. Salivary
    Klebsiella isolates are strong TH1 inducers in gnotobiotic colonisation, are
    multi-drug resistant, and elicit severe gut inflammation in a genetically susceptible
    host.
  cell_types:
  - preferred_term: colonic mononuclear phagocyte
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Chronic Systemic Inflammatory Burden and Comorbidity Risk
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - oral_gut_translocation_model
  evidence:
  - reference: PMID:29051379
    reference_title: "Ectopic colonization of oral bacteria in the intestine drives T(H)1 cell induction and inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that strains of Klebsiella spp. isolated from the salivary microbiota are strong inducers of T helper 1 (TH1) cells when they colonize in the gut"
    explanation: >
      Gnotobiotic evidence that salivary-origin organisms colonising the gut drive a
      distinct intestinal T cell response.
  - reference: PMID:29051379
    reference_title: "Ectopic colonization of oral bacteria in the intestine drives T(H)1 cell induction and inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings suggest that the oral cavity may serve as a reservoir for potential intestinal pathobionts that can exacerbate intestinal disease."
    explanation: >
      States the reservoir model that this node encodes.
  notes: >
    The `preferred_term` is the source study's own cell description; CL has no dedicated
    colonic mononuclear phagocyte class, so it is bound to the nearest suitable ancestor,
    CL:0000235 macrophage.

- name: Gut-Homing Oral-Pathobiont-Reactive T Cell Induction
  role: mechanism
  biological_scale: CELLULAR
  description: >
    In parallel with the microbial route, periodontitis generates oral pathobiont-reactive
    Th17 cells in the oral cavity that are imprinted with gut tropism and migrate to the
    inflamed intestine. Once there they are activated by the translocated oral
    pathobionts — but not by gut-resident microbes — so the cellular and the microbial
    arms are jointly required.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: INCREASED
  downstream:
  - target: Chronic Systemic Inflammatory Burden and Comorbidity Risk
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - oral_gut_translocation_model
  evidence:
  - reference: PMID:32758418
    reference_title: "The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut."
    explanation: >
      Establishes the T cell arm and its gut-homing imprint.

- name: Neutrophil Hypercitrullination by Leukotoxin A
  role: mechanism
  biological_scale: MOLECULAR
  description: >
    Aggregatibacter actinomycetemcomitans secretes the pore-forming toxin leukotoxin A,
    which permeabilises neutrophils and dysregulates their citrullinating enzymes. The
    resulting periodontal citrullinome mirrors the hypercitrullination pattern of the
    rheumatoid joint, and neutrophil morphological changes resembling extracellular trap
    formation release the hypercitrullinated cargo into the periodontal tissue.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  downstream:
  - target: Chronic Systemic Inflammatory Burden and Comorbidity Risk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - periodontal_citrullination_autoimmunity_model
    description: >
      Proposed route from a periodontal mucosal trigger to systemic anti-citrullinated
      protein autoimmunity; the intervening steps in humans are not established.
  evidence:
  - reference: PMID:27974664
    reference_title: "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA."
    explanation: >
      Human gingival crevicular fluid proteomics showing the periodontal citrullinome.
  - reference: PMID:27974664
    reference_title: "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint."
    explanation: >
      Identifies the molecular effector modelled by this node.

- name: Chronic Systemic Inflammatory Burden and Comorbidity Risk
  role: outcome
  biological_scale: ORGANISM
  description: >
    The convergent endpoint of the haematogenous, enteral and autoimmune arms:
    a sustained systemic inflammatory state epidemiologically associated with
    cardio-metabolic, neurodegenerative and autoimmune disease and with cancer. The
    relationship with diabetes is explicitly bidirectional — diabetes roughly triples
    periodontitis susceptibility, and periodontal inflammation worsens glycaemic control.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:33510490
    reference_title: "Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer."
    explanation: >
      Scope statement for the comorbidity set represented by this node.
  - reference: PMID:22057194
    reference_title: "Periodontitis and diabetes: a two-way relationship."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycaemic control."
    explanation: >
      Supports the bidirectional framing rather than a one-way periodontitis-to-diabetes
      claim.
  - reference: PMID:32011025
    reference_title: "Periodontitis and cardiovascular diseases: Consensus report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD."
    explanation: >
      Consensus statement of association. This node claims an epidemiological
      association and no more, which is exactly what the quoted sentence asserts, so
      it is graded DIRECT for that claim. The workshop stops short of causation, and
      this node should not be upgraded to a causal assertion on the strength of it.

phenotypes:
- category: Oral
  name: Periodontitis
  description: >
    The defining clinical phenotype: inflammatory destruction of the tooth-supporting
    apparatus with clinical attachment loss and periodontal pocketing.
  phenotype_term:
    preferred_term: Periodontitis
    term:
      id: HP:0000704
      label: Periodontitis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28805207
    reference_title: "Periodontal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periodontal diseases comprise a wide range of inflammatory conditions that affect the supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead to tooth loss and contribute to systemic inflammation."
    explanation: >
      Defines the phenotype in terms of the affected supporting structures.
- category: Oral
  name: Gingival Inflammation and Bleeding
  description: >
    Gingival inflammation with bleeding on probing is the earliest and most accessible
    clinical sign, and controlling it is an explicit target of first-step therapy.
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:32383274
    reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time."
    explanation: >
      Gingival inflammation is named as an explicit therapeutic target, confirming it as
      a clinical feature of the disease.
- category: Dental
  name: Alveolar Bone Loss
  description: >
    Radiographic loss of alveolar bone height around the affected teeth; the structural
    readout of the osteoclastic resorption node and a component of 2017 staging.
  phenotype_term:
    preferred_term: Alveolar bone loss around teeth
    term:
      id: HP:0410027
      label: Alveolar bone loss around teeth
  evidence:
  - reference: PMID:24670684
    reference_title: "Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection."
    explanation: >
      Documents severe periodontal bone loss as the clinical phenotype in a human
      immunodeficiency presenting with the periodontitis phenotype.
- category: Dental
  name: Tooth Loss
  description: >
    Loss of teeth from loss of periodontal support; periodontitis-associated tooth loss is
    a severity criterion in the 2017 staging framework.
  phenotype_term:
    preferred_term: Premature loss of teeth
    term:
      id: HP:0006480
      label: Premature loss of teeth
  evidence:
  - reference: PMID:29926952
    reference_title: "Staging and grading of periodontitis: Framework and proposal of a new classification and case definition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Stage I to IV of periodontitis is defined based on severity (primarily periodontal breakdown with reference to root length and periodontitis-associated tooth loss), complexity of management (pocket depth, infrabony defects, furcation involvement, tooth hypermobility, masticatory dysfunction) and additionally described as extent (localized or generalized)."
    explanation: >
      Periodontitis-associated tooth loss is an explicit staging criterion.
- category: Oral
  name: Gingival Recession
  description: >
    Apical migration of the gingival margin exposing the root surface, a common
    consequence of attachment loss and of its treatment.
  phenotype_term:
    preferred_term: Gingival recession
    term:
      id: HP:0030816
      label: Gingival recession
- category: Oral
  name: Halitosis
  description: >
    Oral malodour arising from volatile sulphur compounds produced by the anaerobic
    subgingival community.
  phenotype_term:
    preferred_term: Halitosis
    term:
      id: HP:0100812
      label: Halitosis

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 11200.0
  rate_low: 10500.0
  rate_high: 12000.0
  notes: >
    Severe periodontitis only. Global age-standardised prevalence, GBD 2010 modelling;
    the reported 95% uncertainty interval for 2010 is 10.5%-12.0%. Non-severe
    periodontitis is substantially more common and is not covered by this estimate.
  evidence:
  - reference: PMID:25261053
    reference_title: "Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Between 1990 and 2010, the global age-standardized prevalence of SP was static at 11.2%"
    explanation: >
      Source of the 11.2% age-standardised global prevalence of severe periodontitis.
  - reference: PMID:25261053
    reference_title: "Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SP was the sixth-most prevalent condition in the world."
    explanation: >
      Contextualises the global burden ranking.
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 701.0
  rate_low: 599.0
  rate_high: 823.0
  notes: >
    Severe periodontitis, age-standardised incidence in 2010 (95% uncertainty interval
    599-823 per 100,000 person-years). Do not compare directly with the point-prevalence
    record above.
  evidence:
  - reference: PMID:25261053
    reference_title: "Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age-standardized incidence of SP in 2010 was 701 cases per 100,000 person-years"
    explanation: >
      Source of the annual incidence estimate.

genetic:
- name: ITGB2
  gene_term:
    preferred_term: ITGB2
    term:
      id: hgnc:6155
      label: ITGB2
  relationship_type: CAUSATIVE
  notes: >
    Biallelic ITGB2 (CD18) loss of function causes leukocyte adhesion deficiency type I,
    in which severe periodontal bone loss is an invariable feature. This is a syndromic,
    monogenic route to the periodontitis phenotype rather than a susceptibility locus for
    common periodontitis; it is curated here because the mechanism it exposes —
    IL-17-driven bone loss secondary to failed neutrophil recruitment — constrains the
    model of the common disease.
  evidence:
  - reference: PMID:24670684
    reference_title: "Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection."
    explanation: >
      Establishes the invariable periodontal phenotype of the ITGB2/CD18 deficiency
      syndrome.

environmental:
- name: Tobacco smoking
  description: >
    Smoking is the principal modifiable environmental risk factor for periodontitis
    severity and is an explicit target of risk-factor control in first-step therapy.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  evidence:
  - reference: PMID:28805207
    reference_title: "Periodontal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility)."
    explanation: >
      Supports the first clause of this entry: smoking is an environmental,
      modifiable determinant of periodontal disease severity. Note the primer names
      it as the exemplar modifiable factor and does not rank the modifiable factors
      against each other, so it does not by itself establish the word "principal" in
      the description above.
  - reference: PMID:32383274
    reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time."
    explanation: >
      Supports the second clause: risk-factor control is the first named
      intervention category in the guideline's stepwise protocol, which is what
      makes this exposure an explicit therapeutic target rather than only a
      descriptive risk factor. The same sentence carries the corresponding claim on
      the 'Behavioural Change and Risk-Factor Control' treatment.
  influences_mechanisms:
  - target: Connective Tissue Attachment Loss and Pocket Formation
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Smoking increases the severity of periodontal breakdown; the mediating steps are
      not resolved by the cited source, which reports it as a modifiable severity
      determinant.
    evidence:
    - reference: PMID:28805207
      reference_title: "Periodontal diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility)."
      explanation: >
        Names smoking as the exemplar modifiable environmental determinant of
        periodontal disease severity.

treatments:
- name: Subgingival Instrumentation
  description: >
    Mechanical removal of the supra- and subgingival biofilm (scaling and root planing) is
    the cornerstone of cause-related periodontal therapy and the second step of the EFP
    stepwise protocol. It acts directly on the dysbiotic biofilm node.
  treatment_term:
    preferred_term: Periodontal Scaling and Root Planing
    term:
      id: NCIT:C63714
      label: Periodontal Scaling and Root Planing
  target_mechanisms:
  - target: Dysbiotic Subgingival Biofilm Formation
    treatment_effect: INHIBITS
    description: >
      Physically disrupts and removes the subgingival biofilm, removing the trigger of
      the inflammatory cascade.
    evidence:
    - reference: PMID:32383274
      reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time."
      explanation: >
        Sub-gingival instrumentation is a guideline-recommended intervention directed at
        the biofilm.
  evidence:
  - reference: PMID:32383274
    reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The S3 CPG approaches the treatment of periodontitis (stages I, II and III) using a pre-established stepwise approach to therapy that, depending on the disease stage, should be incremental, each including different interventions."
    explanation: >
      Establishes the stepwise framework within which instrumentation sits.
- name: Periodontal Surgery
  description: >
    Access, resective or regenerative periodontal surgery for sites that do not respond to
    non-surgical instrumentation; the third step of the EFP stepwise protocol.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: periodontal surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:32383274
    reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time."
    explanation: >
      Periodontal surgical interventions are a guideline-recommended treatment category.
- name: Oral Hygiene and Professional Biofilm Removal
  description: >
    Daily self-performed plaque control plus professional removal of the microbial biofilm
    on a quarterly or bi-annual basis. This is the mainstay of prevention and the
    supragingival-biofilm component of the first step of the EFP stepwise protocol.
  treatment_term:
    preferred_term: dental prophylaxis
    term:
      id: NCIT:C62548
      label: Dental Prophylaxis
  target_mechanisms:
  - target: Dysbiotic Subgingival Biofilm Formation
    treatment_effect: INHIBITS
    description: >
      Self-performed and professional biofilm removal prevents the plaque accumulation
      from which dysbiosis develops.
    evidence:
    - reference: PMID:28805207
      reference_title: "Periodontal diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi-annual basis."
      explanation: >
        States the preventive mechanism as biofilm removal.
  evidence:
  - reference: PMID:28805207
    reference_title: "Periodontal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi-annual basis."
    explanation: >
      Primary-prevention recommendation from the disease primer.
- name: Behavioural Change and Risk-Factor Control
  description: >
    Counselling for behaviour change and control of modifiable risk factors — above all
    smoking cessation, plus glycaemic control in people with diabetes. This is the
    risk-factor component of the first step of the EFP stepwise protocol.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: behavioural counselling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  target_mechanisms:
  - target: Connective Tissue Attachment Loss and Pocket Formation
    treatment_effect: INHIBITS
    description: >
      Removing the smoking exposure removes the principal modifiable determinant of
      periodontal breakdown severity.
    evidence:
    - reference: PMID:28805207
      reference_title: "Periodontal diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility)."
      explanation: >
        Identifies smoking as the modifiable severity determinant this treatment targets.
  evidence:
  - reference: PMID:32383274
    reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time."
    explanation: >
      Behavioural change and risk-factor control are the first named intervention
      category in the guideline.
- name: Supportive Periodontal Care
  description: >
    Structured maintenance recall after active therapy, required to sustain the treatment
    benefit over time; the fourth step of the EFP stepwise protocol.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32383274
    reference_title: "Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consensus was achieved on recommendations covering different interventions, aimed at (a) behavioural changes, supragingival biofilm, gingival inflammation and risk factor control; (b) supra- and sub-gingival instrumentation, with and without adjunctive therapies; (c) different types of periodontal surgical interventions; and (d) the necessary supportive periodontal care to extend benefits over time."
    explanation: >
      Supportive periodontal care is named as necessary to extend benefits over time.
- name: Periodontal Therapy for Glycaemic Control
  description: >
    Treating periodontitis in people with diabetes produces a modest but reproducible
    improvement in glycaemic control, and is the clearest interventional evidence that
    the periodontal-systemic link is at least partly causal in that direction.
  treatment_term:
    preferred_term: Periodontal Treatment
    term:
      id: NCIT:C63747
      label: Periodontal Treatment
  target_mechanisms:
  - target: Chronic Systemic Inflammatory Burden and Comorbidity Risk
    treatment_effect: INHIBITS
    description: >
      Reducing the periodontal inflammatory burden improves a systemic comorbidity
      outcome (HbA1c).
    evidence:
    - reference: PMID:22057194
      reference_title: "Periodontitis and diabetes: a two-way relationship."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment of periodontitis is associated with HbA(1c) reductions of approximately 0.4%."
      explanation: >
        Quantifies the systemic benefit of treating the oral disease.
  evidence:
  - reference: PMID:22057194
    reference_title: "Periodontitis and diabetes: a two-way relationship."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral and periodontal health should be promoted as integral components of diabetes management."
    explanation: >
      Recommendation to integrate periodontal care into diabetes management.

discussions:
- discussion_id: oral_gut_axis_human_causality
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#Expansion and Ingestion of Oral Pathobionts"
  - "pathophysiology#Ectopic Intestinal Colonisation by Oral Pathobionts"
  - "pathophysiology#Gut-Homing Oral-Pathobiont-Reactive T Cell Induction"
  prompt: >
    Does the oral-to-gut pathobiont translocation chain established in murine and
    gnotobiotic models operate causally in humans with periodontitis, or is the human
    oral-gut association confounded by shared risk factors (smoking, diet, glycaemic
    state) and by the fact that both niches are sampled from the same individual?
  rationale: >
    Every step of the chain modelled here — periodontitis-driven expansion of Klebsiella
    and Enterobacter, ingestion and gut translocation, inflammasome activation in colonic
    mononuclear phagocytes, and gut-tropic imprinting of oral pathobiont-reactive Th17
    cells — rests on murine periodontitis-colitis models and gnotobiotic colonisation of
    germ-free mice. Human data are largely cross-sectional co-detection of oral taxa in
    stool. The review that motivated this curation names causal verification as the
    field's primary open challenge. This is a HUMAN_MODEL_MISMATCH rather than a
    KNOWLEDGE_GAP: the evidence exists and is mechanistically detailed, but its
    translational validity to human periodontitis is unresolved.
  proposed_experiments:
  - experiment_id: exp_perio_oral_gut_strain_tracking
    name: Paired oral-faecal strain-resolved metagenomics through periodontal therapy
    description: >
      Longitudinally sample saliva/subgingival plaque and stool from patients with
      stage III-IV periodontitis before and after a full course of subgingival
      instrumentation, and use strain-resolved metagenomics to test whether
      oral-origin Klebsiella/Enterobacter strains detectable in stool decline as the
      periodontal lesion resolves. Untreated periodontitis patients and periodontally
      healthy controls serve as comparators.
    experiment_type:
      preferred_term: longitudinal human strain-resolved metagenomic cohort study
    decision_criterion: >
      A treatment-associated fall in gut carriage of oral-origin strains, absent in
      untreated controls, would support directional oral-to-gut seeding in humans.
    would_support:
    - pathophysiology#Ectopic Intestinal Colonisation by Oral Pathobionts
    - pathophysiology#Expansion and Ingestion of Oral Pathobionts
    supporting_outcome:
    - >
      Oral pathobionts seed the human gut and the mouth is the upstream reservoir.
    would_refute:
    - pathophysiology#Ectopic Intestinal Colonisation by Oral Pathobionts
    refuting_outcome:
    - >
      Gut carriage of oral-type strains is unchanged by periodontal resolution, indicating
      shared exposure or independent gut colonisation rather than seeding.
  - experiment_id: exp_perio_therapy_ibd_endpoint_trial
    name: Periodontal therapy trial in inflammatory bowel disease with gut endpoints
    description: >
      Randomised trial of intensive versus standard periodontal therapy in patients
      with both periodontitis and inflammatory bowel disease, powered on intestinal
      inflammatory endpoints (faecal calprotectin, endoscopic activity) rather than on
      periodontal outcomes.
    experiment_type:
      preferred_term: randomised interventional clinical trial
    decision_criterion: >
      A significant reduction in intestinal inflammatory activity in the intensive arm
      would establish a causal oral-to-gut contribution in humans.
    would_support:
    - mechanistic_hypotheses#oral_gut_translocation_model
    supporting_outcome:
    - >
      Oral inflammation causally aggravates human intestinal inflammation.
    would_refute:
    - mechanistic_hypotheses#oral_gut_translocation_model
    refuting_outcome:
    - >
      No gut benefit despite periodontal resolution, indicating the murine intermucosal
      connection does not dominate in human disease.
  - experiment_id: exp_perio_gut_homing_t_cell_tracking
    name: Antigen-specific tracking of oral pathobiont-reactive T cells in humans
    description: >
      Identify oral pathobiont-reactive T cells in blood and paired gut biopsies from
      patients with periodontitis, and test whether they carry gut-homing integrin and
      chemokine-receptor imprints, as reported in mice.
    experiment_type:
      preferred_term: human antigen-specific T cell phenotyping study
    decision_criterion: >
      Detection of oral pathobiont-reactive, gut-homing-imprinted T cells in human gut
      tissue would translate the murine T cell arm.
    would_support:
    - pathophysiology#Gut-Homing Oral-Pathobiont-Reactive T Cell Induction
    supporting_outcome:
    - >
      The cellular arm of the oral-gut axis operates in humans.
    would_refute:
    - pathophysiology#Gut-Homing Oral-Pathobiont-Reactive T Cell Induction
    refuting_outcome:
    - >
      No such population is detectable, leaving only the microbial arm as a candidate
      human mechanism.
  evidence:
  - reference: PMID:42396665
    reference_title: "Oral-gut axis in systemic disease: A barrier-metabolism-immunity three-dimensional regulatory model (Review)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Current challenges include difficulties in causal verification, substantial interindividual variability in intervention efficacy"
    explanation: >
      The source review identifies causal verification as the unresolved problem, which
      is the substance of this mismatch.
- discussion_id: periodontal_therapy_comorbidity_outcomes
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk"
  prompt: >
    Does treating periodontitis improve hard clinical outcomes in the associated
    comorbidities, or only surrogate markers?
  rationale: >
    The interventional evidence base for the periodontal-systemic link is largely built
    on surrogate endpoints. The one quantified outcome curated here is a roughly 0.4%
    HbA1c reduction in diabetes; for cardiovascular disease the joint EFP/WHF consensus
    stops at independent association. Without event-driven trials the direction and
    magnitude of any causal benefit remain open, and the comorbidity node should not be
    read as asserting that periodontitis causes its associated diseases.
  proposed_experiments:
  - experiment_id: exp_perio_mace_outcome_trial
    name: Event-driven periodontal therapy trial with cardiovascular endpoints
    description: >
      Randomised trial of intensive versus standard periodontal therapy in patients at
      elevated cardiovascular risk, with major adverse cardiovascular events as the
      primary endpoint rather than surrogate markers such as endothelial function or
      C-reactive protein.
    experiment_type:
      preferred_term: event-driven randomised outcome trial
    decision_criterion: >
      A significant reduction in major adverse cardiovascular events in the intensive
      arm.
    would_support:
    - pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk
    supporting_outcome:
    - >
      Periodontal inflammation causally contributes to cardiovascular events.
    would_refute:
    - pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk
    refuting_outcome:
    - >
      Surrogate-marker improvement without event reduction, indicating the association is
      largely confounded or non-causal.
  - experiment_id: exp_perio_mendelian_randomisation
    name: Mendelian randomisation of periodontitis against cardio-metabolic outcomes
    description: >
      Use periodontitis-associated germline variants as instruments to estimate the
      causal effect of periodontitis liability on cardio-metabolic outcomes, separating
      association from shared-risk-factor confounding.
    experiment_type:
      preferred_term: Mendelian randomisation analysis
    decision_criterion: >
      A significant instrumented effect surviving pleiotropy-robust sensitivity
      analyses.
    would_support:
    - pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk
    supporting_outcome:
    - >
      A causal contribution of periodontitis liability to cardio-metabolic disease.
    would_refute:
    - pathophysiology#Chronic Systemic Inflammatory Burden and Comorbidity Risk
    refuting_outcome:
    - >
      A null instrumented effect, favouring confounding by smoking and metabolic state.
  evidence:
  - reference: PMID:33510490
    reference_title: "Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions."
    explanation: >
      Explicitly characterises the interventional evidence as acting on surrogate
      markers, which is the gap recorded here.
- discussion_id: oral_gut_axis_module_scope
  kind: CURATION_TODO
  status: OPEN
  prompt: >
    Should the oral-gut translocation arm be promoted from disease-level pathophysiology
    to a `kb/modules/` mechanism module?
  rationale: >-
    Issue 6098 asked whether the published barrier-metabolism-immunity oral-gut
    framework warrants a module. The barrier and immunity dimensions are already covered
    by `intestinal_barrier_dysfunction`, `epithelial_barrier_dysfunction`, `gut_dysbiosis`
    and `molecular_mimicry_autoimmunity`, so a three-dimensional module would largely
    duplicate them. The non-redundant kernel is the directional oral-to-gut pathobiont
    route curated here. A module becomes worthwhile once a second conformer exists — the
    natural candidates are `Inflammatory_Bowel_Disease` (the gut end of the same chain)
    and `Rheumatoid_Arthritis` (which already names Porphyromonas gingivalis and
    Aggregatibacter actinomycetemcomitans in the notes of its mucosal-immune-activation
    node without modelling them structurally). Until then, one disease entry does not
    justify a module.

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