The oral-amplifier hypothesis: linking oral inflammation to intestinal microbial activity in autism spectrum disorder

The oral-amplifier hypothesis proposes a testable sequence linking oral inflammation to intestinal microbial activity. Gingival or periodontal inflammation may alter the identity and quantity of strains released into saliva. Gastrointestinal conditions may then clear those strains, permit repeated passage, or support local activity. A participant-matched strain is an oral and intestinal population from the same person that meets prespecified genomic, coverage, and contamination criteria. The hypothesis predicts that greater inflammation-associated oral strain output will precede increased abundance or activity of the genomically matched intestinal strain. The lag is calibrated to the participant’s measured gastrointestinal transit time. The first proposed study tests this lagged within-person relationship, termed source-to-activity coupling. It asks whether community resistance, mucosal immunity, and local resources modify the relationship’s magnitude, delay, or persistence. The second proposed study is a controlled oral-health intervention in which reduced gingival inflammation must accompany a verified reduction in candidate-strain salivary output. It then tests whether matched intestinal activity declines after that verified source reduction. ASD is methodologically informative because oral-care needs, diet, medication exposure, gastrointestinal symptoms, immune state, and transit time may vary together within individuals. This variation provides measurable contrasts for testing oral output and gastrointestinal filtering but does not make the mechanism ASD-specific or causal in ASD. Together, the two proposed studies test whether increased oral output precedes transit-calibrated matched intestinal activity and verified source reduction produces downstream decline. Concordance would support a reversible, strain-specific oral contribution, whereas failure of either temporal pattern would constrain or refute the hypothesis.