Swine Enteric and Systemic Diseases: Dysentery, Fever, and Bloody Diarrhea in Pigs

Introduction

Swine enteric diseases represent a major cause of morbidity, mortality, and economic loss in global pig production. These conditions manifest clinically as diarrhea, dysentery (bloody or mucohemorrhagic feces), fever, dehydration, and in severe cases, systemic collapse and death [121, 141]. The etiological landscape is complex and includes bacterial pathogens such as Brachyspira hyodysenteriae, Lawsonia intracellularis, Salmonella enterica serovars, and enterotoxigenic Escherichia coli (ETEC), as well as viral agents like porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea syndrome coronavirus (SADS-CoV) [51, 103, 115]. Accurate differential diagnosis is critical because clinical signs overlap considerably, yet treatment and control strategies differ fundamentally between bacterial and viral etiologies [130, 137]. This article provides a detailed, publication-grade review of the major swine enteric and systemic diseases characterized by dysentery, fever, and bloody diarrhea, with a focus on bacterial and viral pathogenesis, host-pathogen interactions, diagnostic approaches, and control measures.

Bacterial Etiologies of Swine Dysentery and Hemorrhagic Enteritis

Swine Dysentery: Brachyspira hyodysenteriae

Swine dysentery is a classic mucohemorrhagic colitis caused by the anaerobic spirochete Brachyspira hyodysenteriae [89, 90]. The disease is characterized by severe inflammation of the large intestine, leading to profuse watery to mucoid diarrhea with fresh blood and mucus [62]. The pathogenesis involves colonization of the colonic mucosa, where the spirochete invades the crypt epithelium and induces a robust inflammatory response [62, 67]. B. hyodysenteriae produces hemolysins and lipooligosaccharides that damage epithelial cells and recruit neutrophils, resulting in crypt abscessation and mucosal erosion [90]. Transmission occurs via the fecal-oral route, and the organism can persist in the environment and in carrier pigs [89]. Recent field evidence indicates that the gut microbiota composition plays a significant role in predisposition to and recovery from infection, with specific microbial consortia associated with resilience [62]. Competitive exclusion using commensal probiotic candidates has been explored as a control strategy [67]. An avirulent strain of B. hyodysenteriae has been shown to elicit intestinal IgA responses and slow the spread of disease within herds [89]. Molecular epidemiology studies using techniques such as multilocus sequence typing and pulsed-field gel electrophoresis have revealed considerable genetic diversity among field isolates, which has implications for vaccine development and diagnostic surveillance [90].

Porcine Proliferative Enteropathy: Lawsonia intracellularis

Lawsonia intracellularis is an obligate intracellular bacterium that causes porcine proliferative enteropathy (PPE), a disease characterized by thickening of the intestinal mucosa due to enterocyte proliferation [31, 80]. The acute form, proliferative hemorrhagic enteropathy (PHE), presents with bloody diarrhea and sudden death, primarily in young adult pigs [31]. The bacterium infects the crypt epithelial cells of the ileum and colon, where it resides within membrane-bound vacuoles and modulates host cell cycle pathways to induce proliferation [80]. Transmission dynamics studies have demonstrated that L. intracellularis spreads efficiently within herds through fecal shedding, and subclinically infected pigs serve as important reservoirs [31]. Quantitative PCR (qPCR) assays have been developed and applied for detection and quantification of L. intracellularis in fecal samples, enabling accurate diagnosis and monitoring of shedding patterns [80].

Salmonellosis: Salmonella enterica Serovars

Salmonella enterica serovars, particularly Salmonella Typhimurium and the monophasic variant Salmonella I 4,[1],12:i:-, are important causes of enteric salmonellosis in swine [100, 133, 146]. These serovars are associated with lesions typical of enteric salmonellosis, including necrotizing colitis, typhlocolitis, and mesenteric lymphadenitis [133]. The pathogenesis involves invasion of the intestinal epithelium via M cells and enterocytes, followed by replication within macrophages and dissemination to systemic sites [146]. Salmonella Typhimurium temporally modulates the enteric microbiota and host responses to overcome colonization resistance, with acute stage infection characterized by elevated body temperature, reduced feed intake, and neutrophilic infiltration of the intestinal mucosa [146]. The bacterium induces a strong inflammatory response mediated by tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukin-8 (IL-8), which contributes to tissue damage and diarrhea [146]. Antimicrobial resistance is a growing concern, with multidrug resistance (MDR) detected in a substantial proportion of isolates, including resistance to tetracycline, ampicillin, and sulfonamides [100]. The monophasic variant Salmonella I 4,[1],12:i:- has emerged as a prevalent serotype in swine and is strongly associated with enteric lesions [133].

Enterotoxigenic Escherichia coli (ETEC)

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of neonatal and post-weaning diarrhea in pigs [114, 124]. ETEC strains express fimbrial adhesins (F4/K88, F5/K99, F6/987P, F18, F41) that mediate attachment to specific receptors on porcine intestinal brush border epithelial cells [124]. Following colonization, ETEC produces enterotoxins, including heat-stable toxin a (STa), heat-stable toxin b (STb), and heat-labile toxin (LT), which stimulate fluid and electrolyte secretion into the intestinal lumen, resulting in diarrhea, dehydration, and acidosis [114, 124]. Post-weaning diarrhea (PWD) is particularly problematic and is most commonly associated with F4- and F18-positive ETEC strains [124, 129]. The emergence of MDR ETEC clones, including those carrying mcr genes conferring colistin resistance, poses a significant therapeutic challenge [125, 129, 131]. Genomic characterization of prevalent ETEC lineages in Spain has revealed the dominance of clonal complex 10 (CC10) strains, including serotypes O157:HNM and O108:HNM, which are associated with high rates of antimicrobial resistance [125, 129]. Alternative control strategies, including bacteriophage therapy, probiotics, prebiotics, and phytogenic substances, are under active investigation [114, 119].

Other Bacterial Enteric Pathogens

Clostridium perfringens type A and type C are associated with enteric disease in swine, particularly necrotic enteritis and hemorrhagic enteritis in neonatal piglets [25, 140]. Clostridium perfringens type C produces beta toxin, which causes segmental hemorrhagic necrosis of the small intestine [140]. Clostridioides difficile (formerly Clostridium difficile) is also frequently detected in diarrheic piglets, although its role as a primary pathogen is debated [140]. Pan-genomic analyses of C. perfringens isolates have revealed extensive genetic diversity in resistance, virulence, and stress adaptation genes [25]. Antimicrobial susceptibility testing for C. perfringens is method-dependent, with agar dilution and broth microdilution methods showing variable agreement [34].

Viral Etiologies of Swine Enteric Disease

Porcine Epidemic Diarrhea Virus (PEDV)

Porcine epidemic diarrhea virus (PEDV) is an enveloped, positive-sense single-stranded RNA virus belonging to the genus Alphacoronavirus within the family Coronaviridae [51, 103, 115]. PEDV causes acute, watery diarrhea, vomiting, dehydration, and high mortality in neonatal piglets [121, 141]. The virus infects and destroys enterocytes lining the villi of the small intestine, leading to villous atrophy, malabsorption, and osmotic diarrhea [106, 147]. PEDV enters host cells via interaction between its spike (S) protein and cellular receptors, including aminopeptidase N (APN) and the cholesterol transporter Niemann-Pick C1 (NPC1) [1, 55]. The virus has been shown to exploit multiple entry pathways, including clathrin-mediated endocytosis and macropinocytosis [55]. Recent studies have identified tight junction protein claudin-1 as a novel internalization factor for swine enteric coronaviruses, including PEDV [69].

PEDV infection triggers a complex interplay of host cell responses. The virus promotes its own replication by inducing reactive oxygen species (ROS) and stabilizing hypoxia-inducible factor 1 alpha (HIF-1α), which drives glycolytic flux [68]. PEDV also activates sterol regulatory element-binding protein 2 (SREBP2) and induces RORγ expression to enhance cholesterol biosynthesis, which is required for viral replication [40]. The virus suppresses host innate immune responses by inhibiting DHX9-mediated antiviral transcription through its nucleocapsid protein [2]. Cross-talk between pyroptosis and ferroptosis promotes intestinal inflammation and barrier failure during PEDV infection [9]. PEDV nsp5 induces apoptosis by targeting GATA zinc finger domain-containing protein 2A (GATAD2A/p66α) [3]. Gasdermin B-mediated pyroptosis serves as a host defense mechanism against swine enteric coronaviruses, but PEDV has evolved strategies to antagonize this response [81].

Genetic diversity among PEDV strains is extensive, with variant GII-a strains currently predominant in China [11, 104]. Recombination between PEDV and TGEV has given rise to chimeric swine enteric coronaviruses (SeCoVs), which have been detected in Europe since the 1990s [128, 132, 138]. These recombinant viruses contain the S gene and 3a sequences from PEDV within a TGEV backbone and can cause disease indistinguishable from PED [138]. PEDV can also disseminate from the nasal cavity to the intestinal mucosa via dendritic cells and CD3+ T cells, providing a mechanism for airborne transmission [147].

Transmissible Gastroenteritis Virus (TGEV)

Transmissible gastroenteritis virus (TGEV) is an alphacoronavirus that causes severe gastroenteritis in pigs of all ages, with high mortality in neonates [51, 103, 115]. TGEV infects enterocytes of the small intestine, causing villous atrophy and malabsorption [106]. The virus enters cells via APN and has been shown to activate the RIG-I/IFN-β/STAT1 axis to promote NLRC5-mediated SLA-I upregulation [39]. TGEV infection induces robust type I and III interferon responses and upregulates antigen-presentation genes in intestinal enteroids [105]. The virus also modulates host gene expression through m6A RNA methylation [64]. Recombinant Bacillus subtilis expressing LTB-fused protective antigens of TGEV has been evaluated for immunogenicity [66]. TGEV has largely been controlled through vaccination, but the emergence of recombinant SeCoVs complicates diagnosis and control [82, 101].

Porcine Deltacoronavirus (PDCoV)

Porcine deltacoronavirus (PDCoV) is an emerging enteric coronavirus that causes acute diarrhea and vomiting in piglets [51, 84, 103, 115]. PDCoV belongs to the genus Deltacoronavirus and has a broad host tropism, including the ability to infect human cells in vitro [95, 107]. The virus enters cells via APN and heparan sulfate [55, 70]. PDCoV nonstructural protein 5 (nsp5) cleaves host HDAC6 to dampen its antiviral activity, a strategy shared among swine enteric coronaviruses [99]. The host protein SERPINB1 promotes PDCoV replication by targeting the viral accessory protein NS7a [71]. Swine guanylate-binding protein 1 (GBP1) restricts PDCoV replication by disrupting the replication and transcription complex [24]. The A20 protein restricts PDCoV release through negative regulation of PANoptosis [42]. ANKFY1 suppresses PDCoV replication by degrading viral nsp8 via p62-dependent selective autophagy [43]. Deletion of the NS6 gene attenuates PDCoV pathogenicity without compromising immunogenicity, suggesting a target for live attenuated vaccine development [27]. PDCoV has been detected in multiple countries and is often found in co-infections with PEDV [94, 104].

Swine Acute Diarrhea Syndrome Coronavirus (SADS-CoV)

Swine acute diarrhea syndrome coronavirus (SADS-CoV), also known as swine enteric alphacoronavirus (SeACoV), is a bat-origin alphacoronavirus that emerged in China in 2017 [111, 118]. SADS-CoV causes severe diarrhea and high mortality in neonatal piglets [51, 111]. The virus has an extensive cell species tropism in vitro, raising concerns about its zoonotic potential [107, 111]. SADS-CoV nsp5 induces apoptosis by targeting GATAD2A [3]. The virus triggers caspase-1/GSDMD-mediated pyroptotic cell death in human cells [109]. Heat shock protein 90 (Hsp90) has been identified as an antiviral target, as its inhibition significantly reduces SADS-CoV infection [109]. SADS-CoV has been detected in limited geographic regions, primarily in southern China, and its adaptive evolution in pigs appears incomplete [107, 111].

Porcine Rotaviruses

Porcine rotaviruses, particularly species A (RVA) and species C (RVC), are important causes of diarrhea in suckling and weaned piglets [47, 54, 63, 140]. Rotaviruses are non-enveloped, double-stranded RNA viruses belonging to the family Reoviridae [63]. They infect and destroy mature enterocytes at the tips of intestinal villi, leading to malabsorptive diarrhea [140]. Genetic diversity among porcine RVA strains is extensive, with multiple G and P genotypes circulating globally [63, 140]. In Europe, RVC genotypes have been characterized, and their distribution is being mapped [54]. Mixed rotavirus infections are common in large-scale pig farms [47]. Bivalent inactivated vaccines have been developed and evaluated for immunogenicity [63]. Therapeutic antibody strategies are also being explored for rotavirus prevention and control [4].

Diagnostic Approaches

Accurate diagnosis of swine enteric diseases requires a combination of clinical, pathological, and laboratory methods [23, 130]. Fecal sample collection from acutely affected pigs is essential for pathogen detection [23]. Bacterial culture, isolation, and antimicrobial susceptibility testing remain important for bacterial pathogens such as Brachyspira hyodysenteriae, Salmonella spp., and ETEC [34, 124]. Molecular methods, including conventional PCR, real-time quantitative PCR (qPCR), and multiplex RT-qPCR panels, enable rapid and sensitive detection of multiple enteric pathogens simultaneously [77, 80, 110]. A 5-plex real-time RT-PCR has been developed for simultaneous detection and differentiation of PEDV, PDCoV, TGEV, and SADS-CoV [110]. Quadruple RT-qPCR methods for porcine enteric coronaviruses have also been established [77]. Isothermal amplification methods, such as reverse transcription loop-mediated isothermal amplification (RT-LAMP) and recombinase polymerase amplification (RPA) combined with CRISPR-Cas12a, offer point-of-care testing capabilities [14, 98]. Microfluidic-RT-LAMP chips enable rapid, high-throughput detection of PEDV, PDCoV, and SADS-CoV in field settings [144]. Immunoassays, including enzyme-linked immunosorbent assays (ELISAs) based on viral S proteins, are used for serological surveillance and vaccine response monitoring [32, 74, 79]. Bifunctional nanobodies and quantum dot-labeled antibody fluorescent immunoassay strips have been developed for ultrasensitive antigen detection [20, 36]. High-throughput sequencing and metagenomics provide comprehensive insights into the enteric virome and can identify unexpected or novel pathogens [30, 117, 143].

Differential Diagnosis

The clinical presentation of swine enteric diseases overlaps considerably, making differential diagnosis essential. The following table summarizes key differentiating features of major enteric pathogens.

Pathogenesis and Host-Pathogen Interactions

The pathogenesis of swine enteric diseases involves complex interactions between pathogens and the host intestinal epithelium, immune system, and microbiota [65, 92, 103, 115]. Bacterial pathogens such as B. hyodysenteriae and Salmonella Typhimurium induce robust inflammatory responses that contribute to tissue damage and diarrhea [62, 146]. ETEC enterotoxins activate intracellular signaling pathways that stimulate chloride secretion and inhibit sodium absorption, leading to secretory diarrhea [114, 124]. Viral pathogens, particularly coronaviruses, directly destroy enterocytes, causing villous atrophy and malabsorptive diarrhea [106, 121]. Coronaviruses also modulate host cell death pathways, including apoptosis, pyroptosis, and ferroptosis, to facilitate viral replication and dissemination [3, 9, 42, 81, 103]. The interplay between pyroptosis and ferroptosis promotes intestinal inflammation and barrier failure during PEDV infection [9]. The gut microbiota plays a critical role in host resilience to enteric infections, with specific microbial consortia associated with resistance or susceptibility [45, 62, 65, 92]. Fecal microbiome profiling has identified putative biomarkers for piglets resilient to post-weaning diarrhea [45]. Intestinal organoids have emerged as a valuable in vitro model for studying pathogen-host interactions, as they recapitulate the cellular diversity and architecture of the intestinal epithelium [93, 97, 108, 112]. Apical-out organoid models enable direct viral infection via the physiologically relevant apical surface [112]. Mucus layers derived from organoid air-liquid interface monolayers have been shown to attenuate coronavirus infection through the antiviral activity of Mucin 2 (Muc2) [97].

Control and Prevention

Control of swine enteric diseases relies on a combination of biosecurity, vaccination, antimicrobial stewardship, and management practices [10, 51, 76, 101, 121]. Biosecurity measures, including all-in/all-out production, cleaning and disinfection, and control of fomites and vectors, are critical for preventing introduction and spread of pathogens [76, 121]. Vaccination is a key tool for viral enteric diseases, with commercial vaccines available for PEDV, TGEV, and rotavirus [63, 82, 101]. Next-generation vaccines, including nucleic acid platforms, mucosal delivery systems, and AI-driven antigen design, are under development [82]. mRNA vaccines encoding double proline-substituted full-length spike protein have shown enhanced immunogenicity and protective efficacy compared to conventional inactivated vaccines [15]. Adenovirus-vectored strategies expressing IFN-λ3 and IL-22 have demonstrated protection against PEDV in neonatal piglets [50]. For bacterial diseases, autogenous vaccines and commercial bacterins are used, although efficacy can be variable [124]. Antimicrobial therapy remains important for bacterial enteric infections, but the emergence of MDR pathogens necessitates judicious use and susceptibility testing [10, 124]. Alternative strategies, including probiotics, prebiotics, organic acids, bacteriophages, and phytogenic substances, are being explored to reduce reliance on antibiotics [5, 6, 17, 26, 33, 35, 46, 60, 114, 119]. Probiotic Bacillus subtilis strains and their cell-free supernatants have shown inhibitory activity against Clostridium perfringens [46]. Native swine probiotics have demonstrated prophylactic effects against Salmonella Typhimurium infection by modulating immune responses and stabilizing the gut microbiome [5]. Yeast-derived postbiotics are being investigated for prevention of enteric diseases [33]. Natural products, including luteolin, phloretin, celastrol, and (-)-epigallocatechin-3-gallate, have demonstrated broad-spectrum antiviral activity against swine enteric coronaviruses by targeting viral proteases or modulating host pathways [26, 48, 56, 60, 86, 102]. Octyl gallate, a food additive, has shown potent antiviral activity against PEDV and other coronaviruses by targeting 3C-like protease [102].

Decision Tree for Diagnostic Workup

The following Mermaid diagram outlines a diagnostic decision tree for swine enteric diseases presenting with dysentery, fever, and bloody diarrhea.

flowchart TD
    A[Pig presents with diarrhea, dysentery, fever] --> B{Clinical assessment}
    B --> C[Fecal sample collection]
    C --> D{Microscopy & culture}
    D --> E[Anaerobic culture for Brachyspira]
    D --> F[Aerobic culture for Salmonella & E. coli]
    D --> G[PCR/qPCR panels]
    G --> H{Bacterial targets}
    H --> I[B. hyodysenteriae positive]
    H --> J[L. intracellularis positive]
    H --> K[Salmonella spp. positive]
    H --> L[ETEC virulence genes positive]
    G --> M{Viral targets}
    M --> N[PEDV positive]
    M --> O[TGEV positive]
    M --> P[PDCoV positive]
    M --> Q[SADS-CoV positive]
    M --> R[Rotavirus positive]
    E & I --> S["Diagnosis: Swine Dysentery"]
    J --> T["Diagnosis: Proliferative Enteropathy"]
    K --> U["Diagnosis: Salmonellosis"]
    L --> V["Diagnosis: Colibacillosis"]
    N --> W["Diagnosis: PED"]
    O --> X["Diagnosis: TGE"]
    P --> Y["Diagnosis: PDCoV infection"]
    Q --> Z["Diagnosis: SADS-CoV infection"]
    R --> AA["Diagnosis: Rotavirus infection"]
    S & T & U & V & W & X & Y & Z & AA --> AB[Antimicrobial susceptibility testing if bacterial]
    AB --> AC[Implement targeted treatment & control measures]

Conclusions

Swine enteric and systemic diseases characterized by dysentery, fever, and bloody diarrhea represent a complex diagnostic and therapeutic challenge. The etiological spectrum includes bacterial pathogens such as Brachyspira hyodysenteriae, Lawsonia intracellularis, Salmonella serovars, and ETEC, as well as viral pathogens including PEDV, TGEV, PDCoV, SADS-CoV, and rotaviruses. Accurate diagnosis requires a multifaceted approach combining clinical, pathological, and molecular methods. Understanding the detailed mechanisms of pathogenesis, host-pathogen interactions, and antimicrobial resistance patterns is essential for developing effective control and prevention strategies. Continued surveillance, vaccine development, and exploration of alternative therapeutics are critical for mitigating the impact of these diseases on swine health and production.

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Disclaimer: This article is for educational and informational purposes only. It is not intended to substitute for professional veterinary advice, diagnosis, treatment, or regulatory guidance. Always consult a licensed veterinarian or qualified specialist regarding animal health, disease diagnosis, and therapeutic decisions.