Background Chronic systemic inflammation is a pivotal driver of colorectal carcinogenesis. While gut dysbiosis influences inflammation, the specific microbial species, functional pathways, and metabolic mediators bridging the "microbiota-inflammation-neoplasia" axis remain to be fully characterized.

Objectives This study aimed to (1) identify specific gut microbial species and functional pathways associated with systemic inflammation (high-sensitivity C-reactive protein, hs-CRP); (2) assess the causal relationships using Mendelian Randomization (MR); and (3) elucidate the metabolic mediators bridging gut dysbiosis and inflammation-driven tumorigenesis.

Methods We utilized a multi-stage design integrating metagenomics, plasma metabolomics, and epidemiology. In the discovery cohort (TARGET-C, n=786), we identified inflammation-associated microbial features using multivariable regression. These features were validated in an independent cohort (n=237) and seven external public datasets (n=1,135). Causal inference was assessed using MR and bidirectional mediation analyses. Plasma metabolomics was integrated to identify circulating metabolites mediating the microbe-host interaction.

Results We identified five inflammation-associated species: Flavonifractor plautii and Clostridium butyricum (positively associated with hs-CRP); and Mediterraneibacter butyricigenes, Eubacteriaceae bacterium, and GGB79734 SGB15291 (negatively associated). Two functional pathways were identified: all-trans-farnesol biosynthesis (PWY-6859, pro-inflammatory) and methylerythritol phosphate pathway II (PWY-7560, anti-inflammatory). Mendelian Randomization suggested a potential causal effect of Flavonifractor plautii on increased hs-CRP levels (OR=1.15, P=0.046). Mediation analysis indicated that hs-CRP significantly mediated the associations of Flavonifractor plautii and GGB79734 SGB15291 with advanced colorectal neoplasia. Integrative metabolomics revealed specific mechanistic axes: the pro-inflammatory effect of Flavonifractor plautii was mediated by elevated gamma-glutamylisoleucine (16.4%) and pantothenic acid (8.1%). Conversely, the protective pathway PWY-7560 was linked to elevated threonic acid (15.0%), while the pro-inflammatory pathway PWY-6859 was linked to L-asparagine depletion (19.2%).

Conclusions/Implications for practice or policy This study establishes a robust "microbiota-metabolite-inflammation-neoplasia" axis, highlighting Flavonifractor plautii as a key pro-inflammatory driver supported by potential causal evidence. The identification of specific metabolic mediators—including oxidative stress markers and nutrient depletion—provides novel mechanistic insights into how gut dysbiosis promotes an inflammatory microenvironment favorable for colorectal tumorigenesis.

Integration of plasma metabolomics reveals the mechanistic link between inflammation-associated microbial features and colorectal neoplasia