Host genetic regulation of human gut microbial structural variation.

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.

Coenzyme A precursors flow from mother to zygote and from microbiome to host.

Coenzyme A (CoA) is essential for metabolism and protein acetylation. Current knowledge holds that each cell obtains CoA exclusively through biosynthesis via the canonical five-step pathway, starting with pantothenate uptake. However, recent studies have suggested the presence of additional CoA-generating mechanisms, indicating a more complex system for CoA homeostasis. Here, we uncovered pathways for CoA generation through inter-organismal flows of CoA precursors. Using traceable compounds and fruit flies with a genetic block in CoA biosynthesis, we demonstrate that progeny survive embryonal and early larval development by obtaining CoA precursors from maternal sources. Later in life, the microbiome can provide the essential CoA building blocks to the host, enabling continuation of normal development. A flow of stable, long-lasting CoA precursors between living organisms is revealed. This indicates the presence of complex strategies to maintain CoA homeostasis.

Faecalibacterium wellingii sp. nov. and Faecalibacterium langellae sp. nov., description of two novel species aiding to the reclassification of Faecalibacterium species.

OBJECTIVES: The genus Faecalibacterium is one of the most important butyrate producers in the human intestinal tract and has been widely linked to health. Recently, several different species are described, but still more phylogroups have been identified, suggesting that additional species may exist. Four strains HTF-FT, HTF-128, HTF-75HT and HTF-76H, representing two different phylogenetic clusters, are evaluated in this study. METHODS: Phylogenomic analysis was performed using whole-genome sequences and 16S rRNA gene sequences. Chemotaxonomic analysis was done based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Physiological and phenotypical characteristics of these strains were also determined. All characteristics of these strains were compared with other validly published species within the genus Faecalibacterium. RESULTS: On a genomic level, the four strains shared an average nucleotide identity (ANI) of <95.0% and digital DNA-DNA hybridization (dDDH) of <70.0 with other Faecalibacterium species, while between HTF-FT and HTF-128 the ANI-value was 97.18% and the dDDH was 76.8%. HTF-75HT and HTF-76H had an ANI and dDDH value of 100% (99.96%) and 100% (99.99%) respectively. 16S rRNA gene and chemotaxonomic analysis were in accordance with the genomic data, confirming that the four strains represent two different Faecalibacterium species. CONCLUSIONS: Faecalibacterium strains HTF-FT (=DSM 117771T =NCIMB 15531T), HTF-128, HTF-75HT (=DSM 17770T =NCIMB 15530T) and HTF-76H represent two novel species. The names Faecalibacterium wellingii with HTF-FT as type strain and Faecalibacterium langellae with HTF-75HT as type strain are proposed.

Inulin-grown Faecalibacterium prausnitzii cross-feeds fructose to the human intestinal epithelium.

Many chronic diseases are associated with decreased abundance of the gut commensal Faecalibacterium prausnitzii. This strict anaerobe can grow on dietary fibers, e.g., prebiotics, and produce high levels of butyrate, often associated to epithelial metabolism and health. However, little is known about other F. prausnitzii metabolites that may affect the colonic epithelium. Here, we analyzed prebiotic cross-feeding between F. prausnitzii and intestinal epithelial (Caco-2) cells in a "Human-oxygen Bacteria-anaerobic" coculture system. Inulin-grown F. prausnitzii enhanced Caco-2 viability and suppressed inflammation- and oxidative stress-marker expression. Inulin-grown F. prausnitzii produced excess butyrate and fructose, but only fructose efficiently promoted Caco-2 growth. Finally, fecal microbial taxonomy analysis (16S sequencing) from healthy volunteers (n = 255) showed the strongest positive correlation for F. prausnitzii abundance and stool fructose levels. We show that fructose, produced and accumulated in a fiber-rich colonic environment, supports colonic epithelium growth, while butyrate does not.