Higher-order metabolic interactions among oral commensals gate pathobiont expansion through succinate-driven pH modulation

Despite advances in defining microbiome shifts associated with inflammatory mucosal diseases, the ecological interactions that constrain or facilitate pathobiont expansion remain poorly understood. Using a six-species synthetic oral microbial community and factorial interaction screening, we identified a higher-order interaction governing the growth of the periodontal pathobiont Porphyromonas gingivalis. The core community member Veillonella parvula was the strongest positive determinant of P. gingivalis growth, but this effect was substantially reduced by the health-associated commensal Actinomyces oris. A. oris-mediated antagonism resulted from extracellular acidification and was enhanced under anaerobic conditions. Genetic dissection of A. oris fermentation revealed that lactate dehydrogenase (ldh1) contributes to anaerobic lactate production, but ldh1 deletion only partially relieved P. gingivalis inhibition. Instead, succinate, produced through a succinate dehydrogenase/fumarate reductase pathway (sdh2), emerged as the principal driver of acidification and P. gingivalis suppression. At high cell densities, however, V. parvula consumed both lactate and succinate, reversing acidification and restoring conditions permissive for P. gingivalis growth. To assess the relevance of these interactions in vivo, we analyzed subgingival microbiome from 1,355 adults, including 555 with detectable P. gingivalis. Among these individuals, P. gingivalis abundance was negatively associated with Actinomyces abundance after adjustment for periodontitis severity, whereas this association was attenuated at high V. parvula abundance, consistent with the interaction observed in vitro. Together, these findings identify succinate as a previously unrecognized mediator of interbacterial antagonism and reveal how higher-order metabolic interactions among oral commensals regulate pathobiont expansion through pH modulation, with protective effects shaped by oxygen availability and metabolic cross-feeding.