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Digital dermatitis (DD) is an endemic infectious hoof disease causing lameness in dairy cattle. The aim of the present study was to investigate the genetic profile of DD development using phenotypic and genotypic data on 2192 Holstein cows. The feet of each cow were clinically examined four times: pre-calving, shortly after calving, near peak of milk production, and in late lactation. Presence or absence of disease and proportion of healthy feet per cow constituted two DD phenotypes of study. For each phenotype and timepoint of clinical examination, we conducted single-step genome-wide association analyses to identify individual markers and genomic regions linked to DD. We focused on the ten 1-Mb windows that explained the largest proportion of the total genetic variance as well as windows that enclosed significant markers. Functional enrichment analysis was also applied to determine functional candidate genes for DD. Significant ( P  < 0.05) genomic heritability estimates were derived ranging from 0.21 to 0.25. Results revealed two markers on chromosomes 7 and 15 that were related to both disease phenotypes. Furthermore, we identified three genomic windows on chromosome 14 and one window on chromosome 7 each explaining more than 1% of the trait additive genetic variance. Functional enrichment analysis revealed multiple promising candidate genes implicated in hoof health, wound healing, and inflammatory skin diseases. Collectively, our results provide novel insights into the biological mechanism of host resistance to DD development in dairy cattle and support genomic selection towards improving foot health.

Metagenomic methods amplifying 16S ribosomal RNA genes have been used to describe the microbial diversity of healthy skin and lesion stages of bovine digital dermatitis (DD) and to detect critical pathogens involved with disease pathogenesis. In this study, we characterized the microbiome and for the first time, the composition of functional genes of healthy skin (HS), active (ADD) and inactive (IDD) lesion stages using a whole-genome shotgun approach. Metagenomic sequences were annotated using MG-RAST pipeline. Six phyla were identified as the most abundant. Firmicutes and Actinobacteria were the predominant bacterial phyla in the microbiome of HS, while Spirochetes, Bacteroidetes and Proteobacteria were highly abundant in ADD and IDD. T. denticola-like, T. vincentii-like and T. phagedenis-like constituted the most abundant species in ADD and IDD. Recruitment plots comparing sequences from HS, ADD and IDD samples to the genomes of specific Treponema spp., supported the presence of T. denticola and T. vincentii in ADD and IDD. Comparison of the functional composition of HS to ADD and IDD identified a significant difference in genes associated with motility/chemotaxis and iron acquisition/metabolism. We also provide evidence that the microbiome of ADD and IDD compared to that of HS had significantly higher abundance of genes associated with resistance to copper and zinc, which are commonly used in footbaths to prevent and control DD. In conclusion, the results from this study provide new insights into the HS, ADD and IDD microbiomes, improve our understanding of the disease pathogenesis and generate unprecedented knowledge regarding the functional genetic composition of the digital dermatitis microbiome.

Background Polymicrobial infections represent a great challenge for the clarification of disease etiology and the development of comprehensive diagnostic or therapeutic tools, particularly for fastidious and difficult-to-cultivate bacteria. Using bovine digital dermatitis (DD) as a disease model, we introduce a novel strategy to study the pathogenesis of complex infections. Results The strategy combines meta-transcriptomics with high-density peptide-microarray technology to screen for in vivo -expressed microbial genes and the host antibody response at the site of infection. Bacterial expression patterns supported the assumption that treponemes were the major DD pathogens but also indicated the active involvement of other phyla (primarily Bacteroidetes ). Bacterial genes involved in chemotaxis, flagellar synthesis and protection against oxidative and acidic stress were among the major factors defining the disease. Conclusions The extraordinary diversity observed in bacterial expression, antigens and host antibody responses between individual cows pointed toward microbial variability as a hallmark of DD. Persistence of infection and DD reinfection in the same individual is common; thus, high microbial diversity may undermine the host’s capacity to mount an efficient immune response and maintain immunological memory towards DD. The common antigenic markers identified here using a high-density peptide microarray address this issue and may be useful for future preventive measures against DD.

Background For infectious diseases, the probability that an animal gets infected depends on its own susceptibility, and on the number of infectious herd mates and their infectivity. Together with the duration of the infectious period, susceptibility and infectivity determine the basic reproduction ratio of the disease ( R 0 ). R 0 is the average number of secondary cases caused by a typical infectious individual in an otherwise uninfected population. An infectious disease dies out when R 0 is lower than 1. Thus, breeding strategies that aim at reducing disease prevalence should focus on reducing R 0 , preferably to a value lower than 1. In animal breeding, however, R 0 has received little attention. Here, we estimate the additive genetic variance in host susceptibility, host infectivity, and R 0 for the endemic claw disease digital dermatitis (DD) in Holstein Friesian dairy cattle, and estimate genomic breeding values (GEBV) for these traits. We recorded DD disease status of both hind claws of 1513 cows from 12 Dutch dairy farms, every 2 weeks, 11 times. The genotype data consisted of 75,904 single nucleotide polymorphisms (SNPs) for 1401 of the cows. We modelled the probability that a cow got infected between recordings, and compared four generalized linear mixed models. All models included a genetic effect for susceptibility; Models 2 and 4 also included a genetic effect for infectivity, while Models 1 and 2 included a farm*period interaction. We corrected for variation in exposure to infectious herd mates via an offset. Results GEBV for R 0 from the model that included genetic effects for susceptibility only had an accuracy of ~ 0.39 based on cross-validation between farms, which is very high given the limited amount of data and the complexity of the trait. Models with a genetic effect for infectivity showed a larger bias, but also a slightly higher accuracy of GEBV. Additive genetic standard deviation for R 0 was large, i.e. ~ 1.17, while the mean R 0 was 2.36. Conclusions GEBV for R 0 showed substantial variation. The mean R 0 was only about one genetic standard deviation greater than 1. These results suggest that lowering DD prevalence by selective breeding is promising.

Background Lameness is a collective term for multiple foot diseases in cattle including, but not limited to, foot rot (FR), digital dermatitis (DD), and toe tip necrosis (TTN), which is a critical welfare concern. The diagnosis of specific phenotypes of lameness in feedlot cattle is challenging and primarily relies on visual assessments. However, different lameness phenotypes share similar clinical symptoms and there is a limited understanding of potential biomarkers relating to such disease for further molecular diagnosis. This study aimed to identify blood miRNA profiles of feedlot cattle with various lameness phenotypes and whether they could be potential diagnostic markers to differentiate lameness phenotypes and predictive lameness recovery. Results MicroRNAome profiles were generated for the whole blood samples collected from feedlot cattle at Week 0 (W0) before treatment ( n  = 106) and longitudinal miRNA expression profiles relating to lameness recovery from W0 to W2 ( n  = 140) using RNA-seq. Ten miRNAs were selected to verify miRNA sequencing accuracy using stem-loop RT-qPCR. A total of 321 miRNAs were identified to be expressed in bovine blood samples with three (all downregulated, average log 2 fold change = -1.32), seven (two downregulated with average log 2 fold change = -1.15, five upregulated with average log 2 fold change = 1.68), six (three downregulated with average log 2 fold change = -1.23, three upregulated with average log 2 fold change = 3.31), and fourteen (eight downregulated with average log 2 fold change = -1.24, six upregulated with average log 2 fold change = 1.26) miRNAs differentially expressed (DE) miRNAs in DD, FR, TTN, and FR combined with DD (FRDD) compared to healthy control at W0 (defined as pre-treatment DE miRNAs), respectively. The predicted functions of identified DE miRNAs among different lameness phenotypes were mainly related to Zinc-finger, muscle cell development, and host inflammatory responses. Furthermore, the longitudinal miRNA expression profiles revealed that a total of eight miRNA changed patterns from W0 to W2, with the BTB/POZ-like domain being the most enriched function by longitudinal miRNA expression profiles in both unrecovered and recovered cattle. A total of nine miRNAs (five downregulated with average log 2 fold change = -2.4, four upregulated with average log 2 fold change = 3.7) from W0 to W2 were differentially expressed in unrecovered cattle compared to the recovered cattle, with functions associated with transcription regulation and Zinc-finger. Moreover, the area under the receiver operating characteristics (ROC) curve (AUC) revealed that pre-treatment DE miRNAs could serve as good diagnostic markers to differentiate any two of four phenotypes of lameness, with bta-miR-339b being able to differentiate all lameness phenotypes. Moreover, pre-treatment DE miRNAs could also predict the recovery of three lameness phenotypes (DD, FRDD, TTN) with good to excellent predictiveness. Conclusion Our results comprehensively assessed the blood miRNAomes in response to various lameness phenotypes, promoting the understanding of miRNA-regulated mechanisms of lameness in feedlot cattle. The diagnostic miRNA markers were also identified to differentiate within lameness phenotypes and predictive lameness recovery, shedding light on accurate on-farm lameness detection.

Background Claw diseases and mastitis represent the most important health issues in dairy cattle with a frequently mentioned connection to milk production. Although many studies have aimed at investigating this connection in more detail by estimating genetic correlations, they do not provide information about causality. An alternative is to carry out Mendelian randomization (MR) studies using genetic variants to investigate the effect of an exposure on an outcome trait mediated by genetic variants. No study has yet investigated the causal association of milk yield (MY) with health traits in dairy cattle. Hence, we performed a MR analysis of MY and seven health traits using imputed whole-genome sequence data from 34,497 German Holstein cows. We applied a method that uses summary statistics and removes horizontal pleiotropic variants (having an effect on both traits), which improves the power and unbiasedness of MR studies. In addition, genetic correlations between MY and each health trait were estimated to compare them with the estimates of causal effects that we expected. Results All genetic correlations between MY and each health trait were negative, ranging from − 0.303 (mastitis) to − 0.019 (digital dermatitis), which indicates a reduced health status as MY increases. The only non-significant correlation was between MY and digital dermatitis. In addition, each causal association was negative, ranging from − 0.131 (mastitis) to − 0.034 (laminitis), but the number of significant associations was reduced to five nominal and two experiment-wide significant results. The latter were between MY and mastitis and between MY and digital phlegmon. Horizontal pleiotropic variants were identified for mastitis, digital dermatitis and digital phlegmon. They were located within or nearby variants that were previously reported to have a horizontal pleiotropic effect, e.g., on milk production and somatic cell count. Conclusions Our results confirm the known negative genetic connection between health traits and MY in dairy cattle. In addition, they provide new information about causality, which for example points to the negative energy balance mediating the connection between these traits. This knowledge helps to better understand whether the negative genetic correlation is based on pleiotropy, linkage between causal variants for both trait complexes, or indeed on a causal association.

A newly-discovered foot disease of unknown origin in captive European Bison ( Bison bonasus ) was recently detected at Berne Animal Park. Dermatitis of the interdigital cleft of varying degrees of severity was diagnosed in all animals ( n = 10). The aim of this study was to describe the gross and histological lesions of the interdigital cleft found in 10 captive European bison and to identify involved potential pathogens in affected feet using molecular-based methods for Treponema spp., Dichelobacter nodosus and Fusobacterium necrophorum . Lesions were scored according to the degree of gross pathology at limb level. In a single animal, the gross lesions were restricted to focal lesions on the dorsal aspect of the digital skin of each foot (score 1), whereas all other animals showed at least one foot with extended lesions including the interdigital cleft (score 2). The presence of viable spirochaetes was observed in all animals using dark field microscopy. Applying fluorescence in situ hybridisation (FISH) on biopsies, Treponema spp. were identified, infiltrating the skin lesions in varying numbers in nine animals. Nested PCRs for Treponema medium , Treponema phagedenis and Treponema pedis of swab samples showed three positive animals out of ten for the latter two, whereas pooled biopsy samples were positive in all ten animals for at least T . phagedenis (9/10) and/or T . pedis (7/10), while all samples were negative for T . medium . However, none of these Treponema species could be isolated and sequence analysis of the amplified products showed 100% match of 365 base pairs (bp) to Treponema phylotype PT3 and almost full match (530 of 532 bp, 99.6%) to Treponema phylotype PT13. The presence of T . phagedenis , PT3 and PT13 phylotypes was confirmed by FISH analyses. The phylotypes of T . phagedenis were present in all hybridized positive biopsies of Treponema spp., and PT13 and PT3 were less abundant. Neither D . nodosus nor F . necrophorum were detected. The histological Treponema score was mostly mild. Digital dermatitis in captive European Bison is contagious and differs from bovine digital dermatitis, concerning associated pathogens as well as gross appearance.

Background Bovine Digital Dermatitis (BDD) is a prevalent infectious disease, causing painful foot skin lesions and lameness in cattle. We describe herein the bovine foot skin microbiota and its associations with BDD using 16S rRNA gene amplicon and shotgun metagenomic sequencing on samples from 259 dairy cows from three UK dairy farms. Results We show evidence of dysbiosis, and differences in taxonomy and functional profiles in the bovine foot skin microbiome of clinically healthy animals that subsequently develop BDD lesions, compared to those that do not. Our results suggest that taxonomical and functional differences together with alterations in ecological interactions between bacteria in the normal foot skin microbiome may predispose an animal to develop BDD lesions. Using genome-wide association and regional heritability mapping approaches, we provide first evidence for interactions between host genotype and certain members of the foot skin microbiota. We show the existence of significant genetic variation in the relative abundance of Treponema spp. and Peptoclostridium spp. and identify regions in the bovine genome that explain a significant proportion of this variation. Conclusions Collectively this work shows early changes in taxonomic and functional profiles of the bovine foot-skin microbiota in clinically healthy animals which are associated with subsequent development of BDD and could be relevant to prevention of disease. The description of host genetic control of members of the foot skin microbiota, combined with the association of the latter with BDD development offer new insights into a complex relationship that can be exploited in selective breeding programmes. ApfTUdsqPmkzyTqVTTd38- Video Abstract

Background The primary infectious foot diseases in cattle, bovine foot rot (BFR) and bovine digital dermatitis (BDD), commonly associated with Fusobacterium necrophorum and Treponema spp., respectively, are considered polybacterial in etiology with several additional bacteria involved such as Porphyromonas levii , Bacteroides pyogenes , and Fusobacterium mortiferum . BDD is further classified into several M-stages (M2: active and ulcerative; M4: chronic proliferative). Using quantitative real-time PCR and 16S rRNA gene (V3-V4 region) sequencing, we quantified several specific bacteria and analyzed bacterial communities present in biopsies of visually diagnosed cases of BFR ( n  = 32), M2 ( n  = 17), and M4 ( n  = 12) stages of BDD in feedlot cattle in contrast to inconclusive ( n  = 14) clinical cases and healthy ( n  = 25) cattle. Results Bacterial composition of healthy skin differed significantly from that of skin lesions, and between BFR and both lesion stages of BDD, which also differed from each other. All animal groups had generally the same bacterial species, albeit in distinct ratios. Differential abundance analysis relative to the healthy group identified a higher abundance of Fusobacterium spp. in BFR and Treponema spp. in both BDD-M2 and BDD-M4. P. levii had the highest absolute abundance in all animal groups. A significantly higher abundance of F. necrophorum was observed in BFR compared to BDD-M2, and F. mortiferum in both stages of BDD compared to the inconclusive group. Both BDD M-stages had a significantly higher abundance of Treponema phagedenis and Treponema pedis. Treponema medium was significantly more abundant in BDD-M4 compared to BDD-M2. Conclusion These results further the evidence of the involvement of Treponema spp., in BDD in feedlot cattle. However, it suggests further exploration of the role of Fusobacterium spp. in BFR and BDD. Importantly, a discriminating polybacterial involvement in these infections was evident demonstrated by changes in the population of multiple bacteria when compared to healthy animals.