Widder, J. | Search bioRxiv

bioRxiv2026

A protein language model unveils the E. coli pangenome functional landscape regulating host proteostasis

Understanding how bacterial diversity at strain level resolution shapes host physiology is a central challenge in microbiome research. The vast, functionally unknown genetic diversity within a species pangenome makes it difficult to connect genes to function and their impact on host physiology. Here, we explore how the functional landscape of the Escherichia coli pangenome impacts transcriptional responses in Caenorhabditis elegans and show that traditional gene-centric methods fail to provide significant functional associations with the host. Thus, we developed a pangenome framework that leverages the protein language model ProtT5 and generates unique strain embeddings representing the functional potential of each 9,558 E. coli isolate. Stratification of the pangenome into distinct functional guilds aligned with key host processes such as cell division, metabolism and proteostasis. Further, we identify a critical interplay between the extensive network of bacterial chaperones and proteases in regulating host proteostasis. We find that the bacterial chaperone DNAK/HSP70 and protease ClpX fine-tune the host ubiquitin-proteasome system by controlling propionate and vitamin B12 availability. These findings reveal a conserved co-proteostasis mechanism as a key phenomenon modulating host-microbe interactions through metabolic communication. Our pangenome-to-phenotype approach offers a powerful strategy to decode bacterial pangenome functional diversity, directly linking microbial genomic variation to host physiological outcomes.

systems biology↗

bioRxiv2025

Elucidating a potential role of the infant gut microbiome on the bioavailability of L-tyrosine in phenylketonuria

BackgroundPhenylketonuria (PKU) is an inherited metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency, leading to elevated L-phenylalanine and severe neurological damage if untreated. While phenylalanine-based biomarkers are diagnostic and phenylalanine levels correlate with disease severity, the clinical manifestations of PKU are heterogeneous. ResultsTo identify additional reliable, potentially novel biomarkers, we used germ-free sex-specific, organ-resolved infant whole-body metabolic models (infant-WBMs) to simulate PAH deficiency and predicted elevated L-phenylalanine and its derivatives, alongside reduced L-tyrosine fluxes, as the product of phenylalanine hydroxylation. To test the reliability of these predictions, we combined the infant-WBMs with gut microbiome models from 48 healthy infants. Upon integrating microbiome data, we found that microbial metabolism significantly increased L-tyrosine availability, obscuring its utility as a universal biomarker. In [~]23% of microbiome-PKU models, L-tyrosine fluxes remained low, indicating insufficient microbial compensation. These cases were enriched in Firmicutes and lacked specific Bifidobacterium and Escherichia strains linked to L-tyrosine biosynthesis via the pretyrosine pathway. Shadow price analysis identified microbial species critical for host L-tyrosine metabolism. However, some, such as Bifidobacterium dentium, also contributed to L-phenylalanine synthesis, potentially worsening the PKU phenotype. In contrast, L-phenylalanine, phenylpyruvate, and hydroxyphenylacetic acid remained reliably elevated across all models, validating their diagnostic relevance. ConclusionsOur study demonstrates that microbiome composition can modulate biomarker reliability in PKU, particularly for L-tyrosine. Integrating microbial metabolic models with whole-body physiology enables assessment of biomarker reliability and reveals subpopulations for whom secondary biomarkers or targeted probiotics may be beneficial. This approach offers a powerful framework for refining diagnostics and therapy monitoring in rare metabolic diseases and the development of possible targeted microbiome therapies.

systems biology↗