Distinct Campylobacter fetus lineages adapted as livestock pathogens and human pathobionts in the intestinal microbiota

Abstract

Campylobacter fetus is a venereal pathogen of cattle and sheep, and an opportunistic human pathogen. It is often assumed that C. fetus infection occurs in humans as a zoonosis through food chain transmission. Here we show that mammalian C. fetus consists of distinct evolutionary lineages, primarily associated with either human or bovine hosts. We use whole-genome phylogenetics on 182 strains from 17 countries to provide evidence that C. fetus may have originated in humans around 10,500 years ago and may have "jumped" into cattle during the livestock domestication period. We detect C. fetus genomes in 8% of healthy human fecal metagenomes, where the human-associated lineages are the dominant type (78%). Thus, our work suggests that C. fetus is an unappreciated human intestinal pathobiont likely spread by human to human transmission. This genome-based evolutionary framework will facilitate C. fetus epidemiology research and the development of improved molecular diagnostics and prevention schemes for this neglected pathogen.

Fig. 1

Phylogenetic structure and transmission. a Time-scaled phylogeny of the C. fetus population constructed from the core genome alignment (980 genes). Branches are colored according the most probable ancestral host. Vertical color strips are colored according to host type and to BAPS clustering, respectively. b Bar plot showing the distribution of hosts in each BAPS cluster, bar width is proportional to the percentage of strains present at each cluster. c Asymmetric graph showing significant host-to-host transmissions. Arrows redness is proportional to the transmission rate and the width is proportional to the Bayes factor

Fig. 2

Positive selection in the core genome. a The scatter plot shows genes with Ka/Ks>1 in the bovine or human lineages. For better visualization the values are showed as the logarithm of the Ka/Ks ratio. b The pie charts show the distribution of biological process assignments to the genes with positive selection exclusively in bovine and human lineages. Categories involved in bacterial virulence are highlighted in violet. Categories with at least two genes were plotted

Fig. 3

Accessory genome analysis. a Hierarchical clustering based on pairwise Jaccard distances, the distribution of hosts in the two main groups is presented as pie charts. The vertical color strip shows the correspondence of the accessory genome groups with the BAPS clusters identified with the core genome. The presence of virulence genes is shown as heatmap blocks whose opacity is proportional to the copy number. b Discriminant analysis of principal components (DAPC) showing the complete separation between bovine and human lineages based on the accessory genome. c Boxplots showing the abundance of virulence genes (gray) and all the accessory genes (black) in bovine and human lineages

Fig. 4

Human gut microbiome analysis. a Prevalence of C. fetus strains of human and bovine origin compared to prevalence of common pathogenic Campylobacter species (C. jejuni and C. coli) and E. coli in the gut microbiota of healthy humans. b Prevalence of C. fetus genotypes found in the intestinal microbiota of healthy individuals