The authors emphasize that the impact of Fusobacterium colonization cannot be predicted from bacterial abundance alone. Instead, disease outcomes depend on the interplay of bacterial localization, strain-specific metabolism, metabolite concentration, host genetics, immune status, tumor biology, and treatment context. This metabolite-centered framework distinguishes their synthesis from earlier reviews that focused on bacterial abundance, virulence factors, or broader host-microbe interactions. By organizing the evidence according to each metabolite’s demonstrated or proposed bacterial origin, experimental model, anatomical site, cellular target, and molecular pathway, the review offers one of the most granular pictures yet of how a single bacterial species can exert such divergent effects across the body.

In the periodontal pocket, the story begins with short-chain fatty acids. Unlike most saccharolytic oral bacteria, F. nucleatum ferments peptides and amino acids rather than carbohydrates, releasing high concentrations of acetate, propionate, and butyrate as end products. Liquid chromatography-tandem mass spectrometry measurements of bacterial culture supernatants revealed millimolar acetate and high micromolar propionate and butyrate. These metabolites act as chemoattractants for neutrophils through the free fatty acid receptor 2, also known as GPR43, a G protein-coupled receptor abundantly expressed on neutrophil surfaces. When researchers blocked FFAR2 with the specific antagonist CATPB, the calcium responses triggered by F. nucleatum fractions were nearly abolished, indicating that this receptor mediates much of the neutrophil recruitment characteristic of periodontitis. The same SCFA-FFAR2 axis may also contribute to peri-implantitis, where F. nucleatum has been identified as particularly relevant during the transition from mucositis to aggressive bone loss.

The review also highlights how F. nucleatum functions as a metabolic bridge organism within oral biofilms. In multispecies community models, Streptococcus gordonii converts arginine to ornithine via its arginine deiminase system and exports the product through the ArcD antiporter. F. nucleatum then decarboxylates that ornithine into putrescine, a reaction that consumes cytoplasmic protons, generates proton motive force, and increases acid resistance. Meanwhile, Veillonella parvula increases lysine availability, promoting cadaverine production. The resulting putrescine-rich biofilm microenvironment accelerates the maturation and dispersal of Porphyromonas gingivalis biofilms, potentially seeding the dysbiotic communities that drive periodontal disease. Metatranscriptomic studies add a further nuance: although the relative abundance of F. nucleatum is similar in healthy and diseased sites, its metabolic activity differs dramatically between the two states.

In colorectal cancer, the metabolite story becomes considerably more intricate. One of the most consequential findings concerns indole metabolism and the aryl hydrocarbon receptor, a ligand-activated transcription factor that integrates microbial, dietary, and endogenous signals. F. nucleatum culture supernatant and the indole derivative indole-3-propionic acid were reported to activate AhR in macrophages, driving their polarization toward an immunosuppressive, M2-like phenotype marked by CD206, CD163, IL-10, TGF-beta, and VEGF expression, alongside reduced CD8+ T-cell infiltration. Separately, a distinct team identified three previously unrecognized indole-containing metabolites, fusotrisindoline, streptindole, and trisindoline, as AhR agonists, with fusotrisindoline being the most potent. It activated an AhR-telomerase reverse transcriptase axis that promoted proliferation, migration, and invasion in susceptible CRC cell lines and enhanced xenograft growth. Notably, the two studies did not detect the same metabolites under their respective culture conditions, underscoring that the AhR-active metabolic profile of F. nucleatum depends on strain, substrate availability, and environment. Neither IPA nor fusotrisindoline should currently be considered clinically validated biomarkers.

Formate adds another layer to this metabolic-epigenetic web. Recent work summarized in the review shows that F. nucleatum-derived formic acid increases expression of the glucose transporter GLUT1 in colorectal cancer cells, boosting glucose uptake, glycolytic flux, and lactate accumulation. That lactate, in turn, drives histone lysine lactylation, an epigenetic modification associated with enhanced proliferation, migration, and invasion of tumor cells. Analyses of clinical tumor specimens provided the first reported association between intratumoral F. nucleatum abundance and histone lactylation in CRC cells. The authors of the review caution, however, that the proposed formate-GLUT1-lactate-lactylation pathway should be regarded as a supported mechanistic model with demonstrated links at individual steps rather than a fully established linear causal chain, since upstream pharmacological interventions affect multiple cellular processes simultaneously.

Hydrogen sulfide and succinate extend the pathogenic repertoire further. F. nucleatum metabolizes L-cysteine into hydrogen sulfide, and experimental exposure of HCT116 and DLD-1 colorectal cancer cells increased their migratory capacity, induced inflammatory and autophagy-related gene expression changes, and reshaped the gut microbiome of mice by enriching pathogenic bacteria and depleting beneficial ones. Succinate, historically viewed as a simple tricarboxylic acid cycle intermediate, has emerged as a genuine immunometabolite. In metastatic CRC models, F. nucleatum-derived succinate suppressed the cGAS-interferon beta pathway, reducing antitumor immune activation and limiting CD8+ T-cell trafficking into tumors. Disrupting the bacterial frdA gene, which impairs succinate production, eliminated this effect, and metronidazole depletion of F. nucleatum lowered circulating succinate and restored sensitivity to anti-PD-1 therapy. Complementary work on Fusobacterium varium in ulcerative colitis showed that succinate activates SUCNR1 on neutrophils, triggering NF-kappaB signaling and CXCL8 production, though the review stresses this finding should not be extrapolated to F. nucleatum biology.

Perhaps the most striking theme is how profoundly context determines whether these metabolites help or harm immunotherapy. Intestinal F. nucleatum and its circulating succinate are associated with resistance to anti-PD-1 treatment, yet intratumoral F. nucleatum has been shown to enhance anti-PD-1 responses in microsatellite-stable colorectal cancer, a tumor subtype that normally responds poorly to checkpoint inhibitors. In that setting, locally produced butyrate inhibits the histone deacetylases HDAC3 and HDAC8, increasing H3K27 acetylation at the Tbx21 promoter. Elevated TBX21 then represses PD-1 expression in CD8+ tumor-infiltrating lymphocytes, reducing T-cell exhaustion and restoring cytotoxic function. A butyrate biosynthesis-deficient mutant of F. nucleatum abolished this effect, while purified butyric acid reproduced it. In a separate line of evidence, F. nucleatum-associated butyrate was reported to reduce MLH1 protein levels through an autophagy-lysosomal mechanism, potentially pushing tumors toward mismatch-repair deficiency and microsatellite instability, phenotypes associated with greater immunotherapy responsiveness. Combined butyrate and PD-L1 blockade produced greater tumor regression than either treatment alone in a subcutaneous mouse model, though direct conversion from MSS to MSI status remains to be demonstrated.

The review also documents metabolic effects beyond immunity. F. nucleatum was shown to stimulate host cholesterol biosynthesis in colorectal cancer by activating NF-kappaB and upregulating microRNA-130a-3p, which suppresses the AMPK signaling pathway and thereby activates SREBF2, increasing expression of cholesterol biosynthesis genes including FDPS, FDFT1, and SQLE. Butyrate counteracted this pathway, suppressing cholesterol accumulation. Elevated fecal F. nucleatum and miR-130a-3p were associated with colorectal cancer and hypercholesterolemia, although the retrospective nature of the cohort and incomplete documentation of dietary and medication confounders limit interpretation. Dietary composition may also tip the balance of Fusobacterium activity: in vitro fermentation with the fibers polydextrose and Fibersol-2 boosted F. nucleatum butyrate production by roughly 206 percent and 153 percent respectively, and the fiber-conditioned fermentation broth inhibited Caco-2 colorectal cancer cell growth in a dose-dependent manner, suggesting diet can shift bacterial activity toward an antitumor phenotype.

The authors are careful to delineate the limits of translation. Most mechanistic evidence derives from in vitro systems and animal models, while human data are largely associative. Metabolite concentrations measured in culture supernatants cannot be assumed to reflect free concentrations at host cell surfaces in vivo, where pH, dilution, transport, protein binding, and spatial localization all modify exposure. Strain, diet, host genetics, microbiota composition, disease stage, and treatment all shape metabolite production and activity, and measurements of fecal bacterial abundance or circulating succinate remain hypothesis-generating candidates rather than validated predictive biomarkers. Prospective studies with standardized, compartment-specific assays will be needed to determine whether Fusobacterium-derived metabolites can guide diagnosis or therapy. What the review establishes, however, is a conceptual shift: the pathogenicity of Fusobacterium is written not only in its adhesins and surface proteins but in the small molecules it releases, chemical mediators that connect microbial ecology to inflammation, tumor metabolism, epigenetics, and the success or failure of cancer immunotherapy.

Subject of Research: Metabolite-mediated mechanisms by which Fusobacterium nucleatum influences periodontal disease, colorectal cancer progression, and immunotherapy response

Article Title: Fusobacterium nucleatum-associated metabolites in disease pathogenesis: from cancer to immunotherapy

Article References: Farah, H., PadmaPriya, G., Sahoo, S., Alhasso, B., Srivastav, S. K., Rani, A., Singh, R., & Khdyr, A. H. (2026). Fusobacterium nucleatum-associated metabolites in disease pathogenesis: from cancer to immunotherapy. Frontiers in Microbiology, 17, 1996310. https://doi.org/10.3389/fmicb.2026.1996310

Image Credits: AI Generated

DOI: 10.3389/fmicb.2026.1996310

Keywords: Fusobacterium nucleatum, colorectal cancer, short-chain fatty acids, butyrate, succinate, indole derivatives, aryl hydrocarbon receptor, hydrogen sulfide, immunotherapy, anti-PD-1, periodontitis, microbiome