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Equine veterinary journal2025; 58(2); 601-618; doi: 10.1111/evj.70112

Beyond nocardioform: Transcriptionally active microbes and host responses in equine mucoid placentitis.

Abstract: Nocardioform placentitis (NP) is an understudied form of equine placentitis historically attributed to nocardioform bacteria, yet it remains uncertain whether these organisms are the sole pathogens involved. Objective: To elucidate the pathophysiology of NP and the host-pathogen interaction. Methods: In vivo clinical multi-omics study. Methods: Dual RNA sequencing was performed to profile transcriptionally active microbial communities and concurrent placental transcriptome responses in samples from 31 placentas with and without NP. Untargeted metabolomics was performed to study the associated metabolites in the placenta. Results: The most abundant microbial transcripts belonged to Amycolatopsis, Crossiella, Lentzea, Enterococcus, and Mycobacterium. Bacterial gene expression in NP-affected placentas was enriched in pathways related to ribosomal activity and metabolic processes involving amino acid, carbohydrate, and glycosphingolipid metabolism. Concurrently, placental transcripts demonstrated significant upregulation of inflammatory pathways and downregulation of pathways associated with blood vessel formation. Untargeted metabolomics highlighted an elevated abundance of metabolites such as beta-D-fucose, nervonic acid, and zymostenol in the placentitis samples. Significant correlations were found between microbial genes (mraW, rlmB, amy, afuA, and cysC) and host inflammation genes (CXCL14, IL15RA, TASL, and IFIH1). Additionally, elevated beta-D-fucose, a microbe-specific metabolite, showed a strong correlation with microbial genes involved in stress-adaptive metabolism and DNA repair (ydhP, ybgC, serC, puuE, and radA). The bacterial enzymes involved in beta-D-fucose were notably upregulated and predominantly expressed by Amycolatopsis and Lentzea. Conclusions: Classification based on RNA abundance limited the number of Crossiella cases (n = 3). Conclusions: Both nocardioform and non-nocardioform bacteria are involved in NP-diagnosed cases, challenging the current generalisation of the term 'nocardioform placentitis' and supporting the need to broaden diagnostic protocols for mucoid placentitis. Multi-omics profiling revealed potential host-microbe interactions mediated by microbial metabolites, offering mechanistic insights and opportunities for improved diagnostic strategies.
© 2025 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.
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Publication Date: 2025-11-18 PubMed ID: 41255097PubMed Central: PMC12892373DOI: 10.1111/evj.70112Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates the complex microbial communities and host immune responses in equine nocardioform placentitis (NP), revealing that a broader range of bacteria beyond nocardioform species contributes to this disease.
  • Researchers used advanced multi-omics approaches, including dual RNA sequencing and untargeted metabolomics, to understand microbial gene activity, placental responses, and metabolite changes associated with NP.

Background and Objective

  • Nocardioform placentitis (NP) is a disease affecting the placenta in horses, traditionally thought to be caused by nocardioform bacteria.
  • There is uncertainty whether only nocardioform bacteria cause NP or if other microbes are involved.
  • The study aimed to clarify the pathophysiology of NP, specifically investigating which microbes are active during infection and how the equine placenta responds at the transcriptional and metabolic levels.

Methods

  • Clinical samples were collected from 31 equine placentas, both affected by NP and healthy controls.
  • Dual RNA sequencing (dual RNA-seq) was employed to simultaneously profile:
    • Transcriptionally active microbes (i.e., bacteria actively expressing genes in the placenta), and
    • The host placental transcriptome (gene expression profiles in horse placenta cells).
  • Untargeted metabolomics analysis was conducted to identify and quantify metabolites present in the placental tissue, highlighting biochemical changes associated with infection.

Key Findings: Microbial Communities and Gene Expression

  • Multiple bacteria were transcriptionally active in NP, including:
    • Amycolatopsis
    • Crossiella
    • Lentzea
    • Enterococcus
    • Mycobacterium
  • This indicates involvement beyond just nocardioform bacteria, challenging the traditional classification.
  • Bacterial genes differentially expressed in NP placentas were enriched in functions including:
    • Ribosomal activity — indicating active protein synthesis
    • Metabolic processes involving amino acids, carbohydrates, and glycosphingolipids, suggesting that bacteria are metabolically active and adapting to the placental environment
  • Enzymes linked to beta-D-fucose metabolism were highly expressed particularly in Amycolatopsis and Lentzea, pointing to important microbial metabolic pathways during infection.

Host Placental Responses

  • Placental tissue showed upregulation of genes involved in inflammation:
    • Indicating an active immune response to infection
    • Genes such as CXCL14, IL15RA, TASL, and IFIH1 were correlated with microbial genes, showing close host-microbe interaction
  • There was a downregulation of pathways related to blood vessel formation (angiogenesis), which may contribute to impaired placental function and pathology.

Metabolomics Results

  • Untargeted metabolomics revealed increased abundance of specific metabolites in NP placentas, including:
    • Beta-D-fucose — a sugar metabolite associated with microbial activity
    • Nervonic acid — a fatty acid possibly related to inflammation or cell membrane changes
    • Zymostenol — a sterol intermediate that may reflect altered lipid metabolism
  • Elevated beta-D-fucose was strongly correlated with bacterial genes involved in stress adaptation and DNA repair, suggesting it has a role in bacterial survival and pathogenicity.

Interpretations and Conclusions

  • The study redefines NP as a polymicrobial condition involving both nocardioform and non-nocardioform bacteria rather than exclusively nocardioform pathogens.
  • This challenges the current clinical diagnostic category of ‘nocardioform placentitis’ and suggests that diagnostic protocols should be broadened to detect a wider variety of bacterial species.
  • Integrated multi-omics profiling provided mechanistic insights into how microbial metabolites can mediate host immune responses, potentially informing the development of new diagnostic markers or therapeutic targets.
  • Importantly, the work demonstrates the power of dual RNA sequencing combined with metabolomics to dissect complex host-microbe interactions in infectious diseases.

Implications for Future Research and Veterinary Practice

  • Refined diagnosis: Multi-species involvement suggests that diagnostics need to screen for a broader bacterial spectrum in mucoid placentitis.
  • Potential biomarkers: Microbial metabolites like beta-D-fucose and host inflammation genes could serve as biomarkers for early detection or monitoring disease progression.
  • Therapeutic advances: Understanding metabolic pathways and host responses could lead to more targeted antimicrobial or anti-inflammatory treatments.
  • Further studies are needed to validate findings in larger cohorts and explore the causal roles of specific microbes and metabolites in NP pathogenesis.

Cite This Article

APA
van Heule M, Verstraete M, Norris JK, Graniczkowsa KB, Scoggin KE, Ali HE, Ball BA, De Spiegelaere W, Daels P, Weimer BC, Dini P. (2025). Beyond nocardioform: Transcriptionally active microbes and host responses in equine mucoid placentitis. Equine Vet J, 58(2), 601-618. https://doi.org/10.1111/evj.70112

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English
Volume: 58
Issue: 2
Pages: 601-618

Researcher Affiliations

van Heule, Machteld
  • School of Veterinary Medicine, University of California Davis, Davis, California, USA.
  • Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Verstraete, Margo
  • School of Veterinary Medicine, University of California Davis, Davis, California, USA.
  • Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Norris, Jamie Kaj
  • School of Veterinary Medicine, University of California Davis, Davis, California, USA.
Graniczkowsa, Kinga Barbara
  • School of Veterinary Medicine, University of California Davis, Davis, California, USA.
Scoggin, Kirsten E
  • Gluck Research Center, University of Kentucky, Lexington, Kentucky, USA.
Ali, Hossam El-Sheikh
  • Gluck Research Center, University of Kentucky, Lexington, Kentucky, USA.
  • Mansoura University, Mansoura, Egypt.
Ball, Barry A
  • Gluck Research Center, University of Kentucky, Lexington, Kentucky, USA.
De Spiegelaere, Ward
  • Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Daels, Peter
  • Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Weimer, Bart C
  • School of Veterinary Medicine, University of California Davis, Davis, California, USA.
  • 100K Pathogen Genome Project, UCDavis, Davis, California, USA.
Dini, Pouya
  • School of Veterinary Medicine, University of California Davis, Davis, California, USA.

MeSH Terms

  • Animals
  • Horses
  • Horse Diseases / microbiology
  • Female
  • Pregnancy
  • Placenta Diseases / veterinary
  • Placenta Diseases / microbiology
  • Transcriptome
  • Actinomycetales Infections / veterinary
  • Actinomycetales Infections / microbiology

Grant Funding

  • UC Davis Center for Equine Health
  • Special Research Fund at University of Ghent (BOF)
  • Clay Endowment at UKY
  • John Hughes Endowment at UCDavis
  • Foundation for the Horse
  • Grayson-Jockey Club Research Foundation

Conflict of Interest Statement

The authors have declared no conflicting interests.

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