1. Introduction
Crohn’s disease (CD) and ulcerative colitis (UC) are two principal forms of inflammatory bowel disease (IBD) defined by chronic, severe, and progressive conditions that result in recurrent gastrointestinal inflammation [1]. CD can affect any part of the digestive tract, commonly impacting the ileum and proximal colon, and is characterized by significant inflammation. Conversely, UC mainly impacts the colon and rectum, typically presenting as superficial inflammation limited to the mucosal layer of the colon [2].
Although global age‐standardized rates of prevalence, mortality, and disability‐adjusted life‐years (DALYs) for IBD declined modestly from 1990 to 2019, the absolute number of affected individuals increased in 147 of the 204 countries and territories examined, underscoring the continuing rise in the global burden of IBD [3]. In 2019, IBD was estimated to affect more than 4.9 million individuals worldwide. Traditionally seen as a “Western disease,” this viewpoint is evolving as incidence rates stabilize in Western nations while increasing in parts of Asia, South America, and the Middle East [4].
The etiology of IBD remains incompletely elucidated, though it is thought to result from a complicated interaction of genetic, environmental factors (such as physiological stress, diet, and smoking), immunological abnormalities, and microbial influences [5, 6].
Microbial imbalances can trigger an abnormal immune response, leading to inflammation of the gastrointestinal system [7]. Numerous studies have demonstrated that the composition of enteric microorganisms is altered in individuals with IBD, characterized by an excess of specific bacteria, such as Bacteroides, Escherichia coli (E. coli), and Enterococcus, alongside a reduction in beneficial bacteria, including Prevotella and Akkermansia [8–10]. Research indicates that imbalances in microbial families, including Rikenellaceae, Christensenellaceae, Veillonellaceae, Bacteroidaceae, and Ruminococcaceae, contribute to the worsening of IBD [11–15].
Recent advances have expanded the concept of dysbiosis beyond broad taxonomic shifts to include disease‐associated pathobionts, such as adherent‐invasive E. coli (AIEC) and Ruminococcus gnavus, which contribute to epithelial barrier disruption, persistent immune activation, and chronic intestinal inflammation [16, 17]. Moreover, alterations in bacteriophage communities, fungal dysbiosis, and mucosal‐associated microbiota have emerged as important modulators of microbial ecology and host immune responses in IBD [18–20].
Among the enteric pathogens associated with IBD, Yersinia enterocolitica and Yersinia pseudotuberculosis deserve particular attention because they provide a unique model for understanding the interaction between microbial infection and host genetic factors in CD. Experimental and clinical studies have demonstrated that these pathogens interact with key NOD2‐ and ATG16L1‐dependent pathways, preferentially target the terminal ileum and mesenteric lymph nodes, and exploit defects in epithelial barrier integrity, autophagy, and innate immune responses [21–24]. Consequently, Yersinia has become an important model for elucidating host–pathogen interactions and the molecular mechanisms underlying CD pathogenesis.
These zoonotic bacteria are transmitted primarily through contaminated food or water, are substantial contributors to worldwide foodborne disease [25]. Y. enterocolitica, the fourth most prevalent foodborne zoonosis in 2023 [26], exhibits significant clinical and pathological parallels with CD, which can lead to misdiagnosis and hinder patients from receiving timely and effective treatment [27]. Although Y. enterocolitica is commonly found in CD lesions, its exact involvement in the etiology of CD—whether as a passive observer or an active contributor—has yet to be clarified [28].
The ability of Yersinia infections to provoke intestinal inflammation, coupled with their detection in the intestinal tissues of patients with CD, suggests a possible role in disease development [29]. However, current evidence is insufficient to distinguish whether these observations reflect transient enteric infection, persistent colonization, or a direct contribution to chronic intestinal inflammation [21, 30].
This review explores the historical development, taxonomy, and bioserotype classification of Y. enterocolitica and Y. pseudotuberculosis, highlighting their ecological traits, host diversity, and zoonotic transmission pathways. This study further investigates the interaction between these pathogens and intestinal immunity, emphasizing their ability to exploit epithelial barrier breakdown and modify innate and adaptive responses relevant to CD and UC. Particular focus is given on host genetic susceptibilities—such as polymorphisms in NOD2 and ATG16L1—that influence the immunological consequences of Yersinia–host interactions in IBD.
Furthermore, we assess existing therapeutic techniques, including antibiotic regimens and microbiome‐modifying methods, and examine how these interventions may reduce Yersinia‐related inflammatory processes in the gastrointestinal tract. This integrative strategy aims to reclassify Yersinia from random enteric pathogens into potential contributors to the complex and multifaceted nature of IBD pathogenesis.
2. History, Taxonomy and Bioserotypes Determination
The genus Yersinia belongs to the family Enterobacteriaceae and comprises 28 species [31], of which Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis are pathogenic to humans. Y. pestis is classified as a Category A priority disease via the National Institute of Allergy and Infectious Diseases (NIAID) because of its potential for bioterrorism abuse and its past involvement in three significant pandemics [32]. The historical development of the Yersinia taxonomy is summarized in Figure 1a.
Y. enterocolitica, a heterogeneous species, and the more homogenous Y. pseudotuberculosis are often classified using biotyping (based on biochemical activity) and serotyping (based on lipopolysaccharide [LPS] O‐antigens) [33, 34]. Based on metabolic activity, Y. enterocolitica is classified into six biotypes. Highly virulent strains associated with human infection are primarily classified within biotypes 1B, 2, 3, 4, and 5 [35].
Among 70 distinct serotypes, O:3 (biogroup 4), O:8 (biogroup 1B, which causes a more severe disease), O:9 (biogroup 2), and O:5 (especially 5,27, biogroups 2 and 3) often infect humans [36, 37]. Researchers widely acknowledge that bioserotype 1B/O:8 is the most highly pathogenic, responsible for four out of the six food poisoning epidemics in the United States [38]. Studies have identified serotypes 4/O:3, 2/O:9, and 2/O:5.27 as the main agents causing human cases of yersiniosis in Europe [39–41].
In 2021, the European Food Safety Authority recorded 25 outbreaks of yersiniosis, with Denmark and Finland reporting the highest notification rates (Figure 1b) [42]. Annually, yersiniosis occurs at an average rate of 7.2 cases per 100,000 people in Germany, with children under five experiencing the highest incidence. Approximately 90% of infections originated from domestic sources, and bioserotype O:3 emerged as the predominant serotype [43].
Although the global burden of IBD has increased substantially over recent decades, particularly in newly industrialized regions, whether this trend parallels the epidemiology of yersiniosis remains unclear. These observations suggest that Yersinia is more likely to represent one of several environmental contributors to IBD rather than a primary determinant of its global epidemiological patterns.
3. Ecological Characteristics, Host Diversity, and Transmission Pathways
Enteropathogenic Yersinia species are facultatively anaerobic, non‐spore‐forming bacilli responsible for gastrointestinal diseases in humans [44]. These organisms are predominantly spread via contaminated food or water, frequently leading to clinical manifestations such as diarrhea, stomach discomfort, and fever [45]. Y. enterocolitica is widely found in the environment and among animals, with pigs as the principal reservoir, in addition to other domestic and wild species that may enable zoonotic transmission [46].
Y. pseudotuberculosis was initially linked to a significant outbreak in 1998 related to contaminated iceberg lettuce [47]. Subsequent outbreaks involve fresh produce—especially carrots—along with milk and water (Figure 2a) [48]. Foodborne exposure may include elevated bacterial concentrations (107–109 CFU/mL), above the estimated human infectious dosage of 104–106 CFU/mL.
Moreover, companion animals like dogs and cats can excrete pathogenic Y. enterocolitica in their feces, posing a transmission risk to humans, especially to small children in close proximity to domestic pets [49].
Familial aggregation and environmental factors may influence the emergence of CD and Y. enterocolitica infections in individuals. These findings correspond with the research conducted by Van Kruiningen et al. [50], who examined familial CD in Belgium and discovered that environmental factors, including the use of unpasteurized dairy products and undercooked meat, particularly pig, are likely to precipitate CD in genetically susceptible individuals. The findings support the hypothesis that foods with a high risk of Yersinia contamination could trigger CD.
Epidemiological studies show that infections caused by Y. enterocolitica and Y. pseudotuberculosis exhibit a clear seasonal pattern, with incidence rates peaking during the colder months [51]. This aligns with the organism’s ability to thrive at cooler temperatures and its common reservoir in pigs slaughtered during colder seasons. However, whether this seasonal pattern influences the onset or exacerbation of IBD remains unclear, with no consistent evidence linking seasonal Yersinia infections to IBD disease activity.
4. Interplay Between Yersinia and Mucosal Immunity in IBD
Intraepithelial cells (IECs), integral to the gut barrier, maintain intestinal integrity by facilitating the flow of vital ions, minerals, and water while preventing the passage of bacterial toxins and infections [52, 53]. In IBD, compromise of the gastrointestinal lining results in reduced epithelial integrity, triggering a cascade of pathogenic immune responses [54]. The process includes dysregulated immune cell activation, an imbalance between proinflammatory cytokines—such as integrins, interferons (IFNs), and interleukins (IL‐1, IL‐6, IL‐12, IL‐17, IL‐18, IL‐21, and IL‐23), along with tumor necrosis factor alpha (TNF‐α)—and anti‐inflammatory mediators, including IL‐10, IL‐35, and transforming growth factor‐beta (TGF‐β) [54].
Enhanced intestinal permeability facilitates the translocation of bacteria and their metabolites across the epithelial lining, triggering inappropriate immune responses and sustaining mucosal inflammation [55]. For instance, pathogens such as Y. enterocolitica, Campylobacter jejuni (C. jejuni), and AIEC exploit the compromised epithelial barrier, leading to persistent inflammation and mucosal damage [28, 56, 57]. Moreover, altered immune cell response to a dysbiotic microbial association, along with inappropriate or excessive T‐cell activation, intensifies the chronic inflammation and tissue damage typical of CD and UC [54, 58].
It is noted that prolonged activation of innate responses and dysregulation between IECs and unicellular phagocytes, which secrete critical proinflammatory cytokines, may precipitate chronic inflammation in IBD [59]. Furthermore, CD is frequently associated with an elevated immune response, driven primarily by T helper cell type 1 (Th1) and Th17 cells, characterized by increased secretion of cytokines such as IFN‐γ, IL‐12, IL‐17, and IL‐23 [60]. Conversely, UC is generally associated with a Th2/Th9‐mediated response characterized by increased levels of IL‐5, IL‐9, and IL‐13 [61].
Th1‐ and Th17‐mediated responses promote macrophage activation, neutrophil recruitment, and antibacterial immunity, thereby contributing to host defense against enteric pathogens such as Yersinia [62–64]. In contrast, Th2‐ and Th9‐mediated responses are primarily associated with mucosal repair, epithelial barrier maintenance, and immune regulation [63–65]. Dysregulation of the balance between these effector pathways is thought to contribute to the distinct immunopathological features of CD and UC [64].
Although these distinctions are beneficial, it is crucial to recognize that all these cytokines are present in the inflamed mucosa, albeit in differing quantities (Table S1).
The genus Yersinia has been linked to the onset and progression of IBD, primarily through its interactions with the human immune system and gut microbiome [66]. These interactions may trigger innate immune responses that identify pathogen‐associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) [67]. These PRRs, such as those within the nucleotide‐binding leucine‐rich repeat (NLR) family proteins, including NLR‐containing protein 3 (NLRP3), NLR family CARD domain‐containing protein 4 (NLRC4), and pyrin, form inflammasomes in response to diverse bacterial toxins and components.
Upon stimulation, inflammasomes recruit caspase‐1, which processes proinflammatory cytokines IL‐1β and IL‐18 into their active and functional forms. This event triggers pyroptosis—a destructive, regulated mode of necrotic and inflammatory cell death designed to eliminate pathogens—characterized by caspase activation, cytokine release, and membrane disruption [68]. Furthermore, non‐canonical inflammasomes, like caspase‐4/5/11 inflammasome, can be activated by cytosolic LPS [69].
Persistent inflammasome activation promotes excessive maturation of IL‐1β and IL‐18, thereby amplifying intestinal inflammation through enhanced leukocyte recruitment, epithelial barrier dysfunction, and sustained immune activation. Consequently, dysregulated inflammasome signaling is increasingly recognized as a key driver of chronic mucosal inflammation in IBD [70–72].
Enteropathogenic Yersinia species, in contrast to internal infections such as Salmonella Typhi and Brucella, employ various strategies to evade host immune responses and establish infection [73]. Yersinia regulates the expression of its virulence components to avoid immune detection and adapt to environmental fluctuations in temperature [74]. Héchard et al. [75] demonstrated that Yersinia modulating protein A (YmoA) serves as a pivotal stress sensor, regulating virulence and metabolism in response to variations in temperature, and osmolarity.
At reduced temperatures, they produce flagellin and hexa‐acylated LPS, both of which are powerful toll‐like receptor (TLR) agonists [76]. However, at elevated temperatures within the mammalian host, they downregulate the flagellin expression and generate a less immunogenic variant of LPS. This temperature‐sensitive control enables it to evade early detection by the host immune system [77].
Once the bacteria penetrate the small intestine, they adhere to and infiltrate the specialized microfold (M) cells of the epithelium. Y. enterocolitica and Y. pseudotuberculosis exhibit various adhesins and virulence factors that may lead to dissemination to the mesenteric lymph nodes or other extraintestinal tissues, such as the spleen, liver, and/or lungs, contingent upon the infected individual’s underlying health (Figure 2b–d). To successfully disseminate and survive in the harsh host environment, such as the acidic stomach, Yersinia produces urease [78].
Yersinia initiates an infection by invading the gut epithelium through the production of three primary virulence factors: Inv, attachment invasion locus (Ail), and Yersinia adhesin A (YadA) (Figure 3a) [79]. Following its invasion of the small intestine, it penetrates lymphoid follicles, particularly M cells, which facilitate bacterial translocation across the mucosal barrier. In the broader context of IBD, epithelial barrier dysfunction is characterized by disruption of tight junction proteins, depletion of the mucus layer, dysregulated antimicrobial peptide production, and Paneth cell dysfunction, all of which contribute to impaired mucosal defense and chronic intestinal inflammation [80–82].
In addition to facilitating epithelial invasion, Yersinia further compromises intestinal barrier integrity by disrupting tight junction proteins, including occludin, claudins, tricellulin, and ZO‐1, thereby increasing epithelial permeability [83].
In terms of the binding site, Y. pseudotuberculosis demonstrates a superior binding affinity for fibronectin, whereas Y. enterocolitica shows a heightened affinity for collagen and laminin [79]. Besides acid tolerance, Yersinia utilizes immune evasion mechanisms by producing OMPs such as YadA and Ail, which engage with complement system inhibitors, including C4b‐binding protein and factor H, thus hindering the host’s immunological response [79]. Furthermore, bacteria employ strategies to survive within phagocytic cells by producing virulence factors such as OmpR, global stress requirement (GsrA), and superoxide dismutase (SodA), which are crucial for alleviating oxidative stress and other antimicrobial defenses within the host cell [74].
4.1. Secretion Systems and Their Multifaceted Roles in the Pathogenicity of Yersinia
The bacteria utilize a common type III secretion system (T3SS) to translocate chromosomal and plasmid‐encoded effector proteins, known as Yersinia outer proteins (Yops), into host cells, where they subvert immune signaling and promote bacterial survival [84]. The principal molecular targets and immunomodulatory functions of T3SS effector proteins are summarized in Table S2. Among these effectors, YopE and YopT inactivate Rho GTPases, disrupting cytoskeletal organization, impairing phagocytosis, and attenuating host immune responses (Figure 3a) [85, 86].
YopO (YpkA in Y. pseudotuberculosis), a serine/threonine kinase, contributes to Yersinia virulence by disrupting Rho GTPase signaling, leading to cytoskeletal rearrangement, impaired phagocytosis, and suppression of host immune responses [87–92]. YopH, a protein tyrosine phosphatase, further subverts host immunity by dephosphorylating key signaling molecules involved in phagocytosis and leukocyte activation, thereby inhibiting calcium signaling, reactive oxygen species (ROS) production, and neutrophil antimicrobial functions (Figure 3a–c) [93, 94]. In addition, YopH limits bacterial uptake by M cells, facilitating immune evasion and bacterial persistence [95].
In Y. pseudotuberculosis, additional virulence factors, including cytotoxic necrotizing factor (CNF‐γ), disrupt Rho GTPase activity, thereby affecting cellular signaling pathways such as phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)/NF‐κβ and signal transducer and activator of transcription 3 (STAT3) (Figure 3a) [96, 97]. Furthermore, Y. pseudotuberculosis‐derived mitogen (YPM) directly binds to class II major histocompatibility complex (MHC II) molecules, effectively activating T cells, including hepatotoxic CD4+ T cells (Figure 3c) [98]. Also, Y. pseudotuberculosis synthesizes InvD, a virulence component that selectively binds to host IgG/IgA antibodies with VH3/VK1 domains, likely targeting specific B‐cell subsets and modifying antibody function and disease development (Figure 3d) [99].
In addition to the T3SS, the type II secretion system (T2SS) is a crucial component for the maintenance and pathogenicity of Yersinia (Figure 4a,b) [100]. In Y. enterocolitica, the Yts1 T2SS is essential for virulence, facilitating dispersion throughout the host and survival in critical organs such as the mesenteric lymph nodes, liver, and spleen [101]. Furthermore, the T6SS has been recognized as a significant pathogenicity factor in numerous Yersinia species (Figure 4c) [102].
This intricate apparatus is an essential mechanism in bacterial pathogenesis, enhancing cytotoxicity, facilitating intracellular persistence, and contributing to effective host spread [103].
4.2. Dysregulation of Host Immune Responses by Virulence Factors of Yersinia
Apart from the aforementioned factors, Yersinia spp. employs other virulence factors to subvert host immunity, the principal molecular targets and immunomodulatory functions of which are summarized in Table S2. YopE and YopT significantly modulate inflammation via regulating the release of caspase‐1 and IL‐1β, in addition to inflammasome activation (Figure 4d) [104]. YopE plays a complex function in Yersinia infections by provoking an immune response while concurrently obstructing bacterial absorption by specific M cells [95].
YopP (YopJ in Y. pseudotuberculosis) is an acetyltransferase effector that suppresses host immune responses by targeting MAPK and NF‐κB signaling pathways, thereby reducing proinflammatory cytokine production and promoting macrophage apoptosis [93, 105]. In addition to its anti‐inflammatory activity, YopP/J modulates cell death pathways by influencing apoptosis and pyroptosis through caspase‐dependent mechanisms, including RIPK1–caspase‐8‐mediated GSDME activation and IL‐1β release [106–110]. Additionally, YopJ has been demonstrated to inhibit prostaglandin E2 (PGE2) production, hence further influencing host immunity [111].
Despite these findings, the molecular factors that regulate the transition between apoptotic and pyroptotic pathways in response to YopP/J activity remain a subject of current research (Figure 4d). YopM contributes to immune evasion by disrupting inflammasome activation through interactions with host kinases, thereby limiting inflammatory responses and promoting bacterial persistence [112]. YopQ (YopK in Y. pseudotuberculosis), a unique virulence factor shared throughout pathogenic Yersinia species, is essential for inhibiting inflammasome activation and evading innate immune responses [113], specifically neutrophil‐mediated phagocytosis, by targeting antiphagocytic effector proteins (Figure 4d) [114].
In Y. pseudotuberculosis, TsTYp exerts diverse effects on immune cells via cyclic adenosine monophosphate (cAMP)‐dependent activation of protein kinase A and downstream targets such as extracellular signal‐regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) [113, 115]. It modulates phagocytic activity in both neutrophils and monocytes, impacting ROS production and apoptosis. TsTYp regulates cAMP concentrations in a dose‐dependent manner, inhibiting ROS formation in monocytes at low doses—potentially facilitating immune evasion—while augmenting ROS creation in neutrophils [116].
Furthermore, TcpYI possesses a C‐terminal hydrophobic domain characteristic of the transport inhibitor response 1 (TIR1) domain family, which promotes intracellular survival of Y. pseudotuberculosis within macrophages and in mouse spleens [117]. Previous studies have shown that toxin‐coregulated pili (TCP)‐containing bacteria often suppress host defenses by targeting TLR4 signaling, a key pathway in pyroptosis induction [118, 119]. Particularly, TcpYI directly binds to TIR, suggesting a mechanism to block TLR4 signaling and potentially protect host cells from nicotinamide adenine dinucleotide (NAD+) depletion via its NAD+‐hydrolase activity.
Moreover, Y. pseudotuberculosis can also exploit host cell receptors, such as CD209, to facilitate dissemination to systemic organs. This interaction promotes bacterial spread to lymph nodes, the kidney, the spleen, and the liver [120], resulting in consequences such as septic shock, acute organ damage, abscess development, and splenic infarction, especially in individuals with liver disease or compromised immunity [121, 122].
The aforementioned genetic factors, encompassing specific mutations and the dysregulation of cytokines such as IL‐1, TNF‐α, IL‐6, monocyte chemoattractant protein‐1 (MCP‐1), IL‐10, IFN‐γ, and TGF‐β1, alongside the absence of TLR1 and TLR5 and the presence of the immunomodulatory protein galectin‐1 [123–125], which hinders bacterial clearance, collectively foster chronic inflammation in the abdominal cavity of individuals with IBD. While bacterial invasion is deemed significant in the pathophysiology of IBD (Table 1), the molecular specifics regarding the subsequent weakening of the intestinal barrier remain mostly unknown.
5. Classification Methods and Genetic Attributes in IBD
In 2003, a dedicated group of researchers established a classification system for IBD that integrates clinical, genetic, and serological information. The Vienna and Montreal classification systems describe CD based on age of onset, geographic distribution, and disease behavior. The Montreal classification system for CD has introduced a new category for early‐onset disease, defined as diagnosis at 16 years of age or younger.
Serological markers, including anti‐neutrophil cytoplasmic autoantibody (p‐ANCA) and anti‐Saccharomyces cerevisiae antibody (ASCA), have been thoroughly investigated in IBD. Although they may be beneficial in some situations, their restricted sensitivity and inconsistent prevalence among patients with IBD limit their diagnostic effectiveness.
As of now, more than 150 genetic loci have been associated with susceptibility to CD. Genome‐wide association studies (GWAS) across many populations have consistently identified single‐nucleotide polymorphisms (SNPs) in genes such as caspase recruitment domain‐containing protein 15/nucleotide‐binding oligomerization domain‐containing protein 2 (Card15/Nod2), immunity‐related GTPase M (Irgm), interleukin 23 receptor (Il23r), autophagy‐related 16‐like 1 (Atg16l1), and leucine‐rich repeat kinase 2 (Lrrk2) as significant risk factors for the condition [137, 138]. Genetic polymorphisms in the NOD2 gene (rs2066843 and rs2076756), located on chromosome 16, impair the recognition of the bacterial component muramyl dipeptide (MDP) (Figure 5a) [139].
NOD2 is crucial for maintaining intestinal health by regulating immune responses to beneficial gut microorganisms. Beyond its role in sensing invading pathogens, NOD2‐mediated recognition of MDP is critical for maintaining immune tolerance to the commensal gut microbiota. Under homeostatic conditions, NOD2 fine‐tunes innate immune signaling, restrains excessive NF‐κB activation, promotes Paneth cell antimicrobial peptide secretion, and preserves host–microbiota mutualism.
Consequently, loss of NOD2 function disrupts these regulatory mechanisms, leading to impaired tolerance to commensal bacteria, microbial dysbiosis, and aberrant mucosal immune activation, thereby fostering the chronic intestinal inflammation that characterizes CD [24, 140, 141]. NOD2 is also implicated in autophagy, a cellular mechanism that eliminates intracellular pathogens. Inadequacies in NOD2‐mediated autophagy may lead to bacterial buildup in the gut epithelium, hence intensifying inflammation [142].
Moreover, extensive research has been conducted on the T300A polymorphism in the ATG16L1 autophagy gene (A > G SNP; chr2; rs2241880), which is associated with CD (Figure 5b) [23, 143]. Cadwell et al. (2008) demonstrated that Paneth cells lacking ATG16L1 exhibit deficiencies in granule exocytosis and gene expression, particularly concerning genes that are upregulated in the contexts of lipid metabolism and inflammation.
Individuals possessing the ATG16L1 risk allele exhibit cellular abnormalities similar to those observed in patients with CD [144]. GWAS have repeatedly identified ATG16L1 T300A as a principal susceptibility gene for CD, particularly in Caucasian populations [145]. Researchers also recognize the G allele of this SNP as a low‐penetrance risk factor, suggesting a complex interaction between genetic and environmental influences in the onset of CD [146].
The frequency rate of ATG16L1 and NOD2 among various populations aligns with the global distribution of yersiniosis, as illustrated in Figures 2 and 5. This genetic diversity in North America, Asian nations, including China and India, and northern Europe highlights the intricate interaction between genetic and environmental influences in the onset of IBD.
6. Relationship Between Yersinia Infection and IBD
Individuals with IBD commonly develop enteric infections that typically induce gut microbiota dysbiosis. Although the precise etiology of IBD remains uncertain, genetic and environmental factors play key roles in the disease pathophysiology and progression [5]. An impaired intestinal environment characterized by inflammation facilitates the proliferation of detrimental microbes and functionally modified commensal bacteria, referred to as pathobionts, which may exhibit pathogenic activity under adverse conditions.
In addition to microbial variation, IBD demonstrates differences in illness distribution. In East Asia, 50%–70% of individuals exhibit ileocolonic engagement, while studies in Western cultures indicate similar participation across the ileal, colonic, and ileocolonic regions.
The etiology of UC is multifaceted, with increasing evidence emphasizing the significance of microbial dysbiosis—specifically, Y. enterocolitica infection—due to its immunomodulatory effects and tissue‐invasive capabilities [147]. Moreover, infection with Y. enterocolitica O:3 has been identified as a potential initiating component in the pathogenesis of UC, highlighting the importance of microbial triggers in the disease’s origin and progression [66]. Several case reports have detected Yersinia spp. in the intestinal tissues of individuals with CD, indicating a potential association (Table 2).
Furthermore, Kallinowski et al. [170] demonstrated the presence of Yersinia species in 63% of patients with CD and 46% of patients with UC using culture and polymerase chain reaction (PCR), compared with the control group. Lamps et al. [21] detected pathogenic Y. enterocolitica DNA in 31% of bowel resection specimens from patients with CD, whereas all controls were PCR negative. Saebo et al. [66] reported higher serological reactivity to enteropathogenic Yersinia among patients with CD than among controls.
Knösel et al. [171] identified Yersinia species in archived intestinal tissues, whereas Khan et al. [2] detected Y. enterocolitica by RT‐PCR in 10.1% of patients with CD, demonstrating a significant association with the disease. Similarly, Le Baut et al. [22] detected Yersinia species, including Y. enterocolitica, Y. pseudotuberculosis, and Y. intermedia, in the ileum of ~10% of patients with CD.
Collectively, these findings should be interpreted with caution. Most studies relied primarily on PCR‐based detection of bacterial DNA or serological assays, whereas culture‐based confirmation of viable organisms was rarely achieved, conventional cultures were frequently negative, and sequencing of PCR amplicons was often not performed to confirm target specificity. Consequently, the available evidence largely reflects the detection of bacterial DNA or previous exposure rather than active or persistent infection.
In addition, considerable methodological heterogeneity—including differences in specimen type, PCR primer design and target genes, molecular assays, tissue preservation, and study populations—likely contributed to the marked variability in detection rates. Therefore, although these studies suggest a possible association between Yersinia and CD, they do not establish a causal relationship or confirm that viable organisms persist within intestinal tissues [21, 30]. Future well‐designed studies integrating standardized molecular techniques with sequencing confirmation and culture‐based detection of viable organisms are required to clarify the pathogenetic role of Yersinia in IBD.
Another study demonstrated that Y. pseudotuberculosis attaches to β1‐integrin receptors on intestinal epithelial cells through invasin (inv), resulting in the formation of large vesicles that encapsulate both the bacteria and the surrounding fluid, including nanoparticles, and facilitate their transport across the epithelial cells via transcytosis. The compromise of the intestinal barrier facilitates the translocation of bacteria and other deleterious substances into the circulation, hence leading to the onset of CD [172]. These observations are consistent with the current ecological model of IBD, in which disease arises from disrupted host–microbiota interactions rather than a single infectious agent [141].
Within this framework, Yersinia may function as a pathobiont whose persistence is favored by microbial dysbiosis, epithelial barrier dysfunction, and impaired immune regulation, thereby contributing to chronic mucosal inflammation in genetically susceptible individuals [141, 173].
7. Therapeutic Strategies and Antimicrobial Resistance
Yersinia gastroenteritis has numerous clinical and pathological similarities with CD, especially in the terminal ileum, where both illnesses frequently affect Peyer’s patches and solitary lymphoid follicles (Table 3).
The management of Y. enterocolitica is reliant on the clinical presentation, which comprises the severity of the infection and the presence of extraintestinal symptoms [174]. Mild manifestations of the disease, characterized by transient diarrhea and abdominal pain, are typically self‐limiting and do not necessitate therapy [174]. Bacteremia accompanied by elevated fever may necessitate the administration of antipyretic agents, fluids, and broad‐spectrum antibiotics.
Considering that Y. enterocolitica produces both A and B β‐lactamases, combination antibiotic therapy (pending antimicrobial susceptibility testing) may be considered (e.g., a fluoroquinolone with an aminoglycoside, a third‐generation cephalosporin with an aminoglycoside, or a fluoroquinolone with a third‐generation cephalosporin) [175]. In contrast, the management of yersiniosis caused by Y. pseudotuberculosis tends to be more straightforward and clinically favorable owing to the absence of β‐lactamase production by this bacterium. As a result, antimicrobial therapy with agents such as ampicillin, fluoroquinolones, tetracyclines, or aminoglycosides is reasonable [148], while surgical intervention is reserved for cases that are severe/complicated.
Antimicrobial resistance in pathogenic Yersinia species comprises both intrinsic and acquired mechanisms. Intrinsic resistance is largely mediated by the chromosomal β‐lactamases BlaA and BlaB, conferring natural resistance to ampicillin and several first‐generation β‐lactam antibiotics [176]. By contrast, acquired resistance results from chromosomal mutations or horizontal acquisition of resistance genes, reducing susceptibility to fluoroquinolones, tetracyclines, and extended‐spectrum cephalosporins [177, 178].
Although acquired resistance remains uncommon, continued surveillance is warranted because resistance determinants can disseminate through mobile genetic elements and the food chain [176]. Resistance to trimethoprim‐sulfamethoxazole, chloramphenicol, and nalidixic acid has been documented, with strains exhibiting multidrug resistance (MDR) characteristics, especially among biotype 1A and 4/O:3 isolates obtained from animal‐derived diets [179, 180]. Genomic studies have highlighted the importance of transposable elements and plasmids in the dissemination of resistance genes [181].
The Tn2670 transposon, integrated into the chromosomes of Swedish outbreak strains of Y. enterocolitica, harbored genes that confer resistance to chloramphenicol (catA1), streptomycin (aadA1), and sulfonamides (sul1), in addition to a mercury resistance module, highlighting the potential for horizontal gene transfer (HGT) and environmental persistence [179]. Likewise, Y. pseudotuberculosis has demonstrated the ability to acquire multidrug‐resistant plasmids, with reports of multidrug‐resistant strains emerging from various geographical regions [182, 183]. Molecular investigation of strains recovered in Russia and France identified the presence of IncN and IncHI2 conjugative plasmids, which harbored resistance genes to six antibiotic classes, including aminoglycosides, β‐lactams, chloramphenicol, and tetracycline [184].
Besides conventional resistance, Y. pseudotuberculosis demonstrates antibiotic tolerance, especially toward doxycycline [185]. Research on gene expression has shown that the regulation of porin genes (e.g., ompF) and tRNA‐modifying genes (e.g., tusB) is crucial for bacterial survival under antibiotic pressure. The downregulation of tusB seems to facilitate doxycycline tolerance.
In contrast, its overexpression increases the bacterium’s susceptibility, suggesting a complex interaction among resistance, tolerance, and gene regulation in the presence of bacteriostatic drugs [186]. Also, epidemiological data indicate that resistance patterns in Y. enterocolitica differ geographically and according to farming practices; a comprehensive European study involving over 1000 porcine 4/O:3 isolates revealed that resistance beyond ampicillin was rare in northern and eastern Europe but markedly elevated in areas with more intensive antimicrobial use for livestock, such as southern Europe [187]. These findings underscore the importance of judicious antibiotic use in agriculture to prevent the development of antibiotic resistance.
Overall, growing genetic evidence highlights the adaptability of Yersinia spp. in acquiring resistance, underscoring the need for continuous monitoring to inform treatment and public health policies.
Moreover, dietary therapies such as exclusive enteral nutrition (EEN) and probiotic therapy may eradicate Yersinia and modify the gut microbiota, potentially mitigating CD symptoms [188]. EEN causes remission by initiating beneficial alterations in the gut microbiome. It fosters the proliferation of beneficial bacteria, such as Lachnospiraceae, and elevates short‐chain fatty acids (SCFAs), which confer protection against inflammation [188].
8. Probiotic‐Based Treatments in Yersinia Infection
Recent research suggests that certain probiotic strains can mitigate Y. enterocolitica infections by exhibiting antibacterial effects, modulating host immunological responses, and enhancing intestinal epithelial barrier function [189–191]. For instance, Bosák et al. [189] demonstrated that recombinant E. coli strains (EcH22, EcColinfant, Ec1127, and Ec1145) synthesizing colicin FY significantly suppressed the proliferation of pathogenic Y. enterocolitica in vitro and dysbiotic mice, indicating the potential use of colicin‐producing probiotics for therapeutic interventions. Frick et al. [190] identified many commensal bacteria, including Bifidobacterium adolescentis DSM 20086, that can inhibit Y. enterocolitica‐induced inflammatory signaling, specifically NF‐κB activation and IL‐8 generation, in HT‐29 epithelial cells.
Wittmann et al. [191] confirmed that B. adolescentis Reuter 1963 (ATCC 15705) facilitates protection by stimulating plasmacytoid dendritic cells (pDCs) and regulatory T cells, which are essential for restricting the spread of Y. enterocolitica. In their murine model, mice pretreated with B. adolescentis exhibited less weight loss and reduced splenic bacterial counts post‐infection. The depletion of pDCs abolished this protective effect, highlighting their essential role in mediating the immune response.
Jurado‐Gámez et al. [192, 193] established that both Lactobacillus plantarum ATCC 8014 and Lactococcus lactis ATCC 11454 suppressed the growth of Y. pseudotuberculosis (NCTC 8580) in co‐culture systems. They found bioactive peptides (e.g., VAL‐TIR‐VAL) in probiotic supernatants using HPLC, which are likely responsible for the observed antibacterial activity. These strains exhibited tolerance to low pH, bile salts, and increased temperatures, demonstrating significant survivability in gastrointestinal environments.
Additionally, L. lactis secreting LcrV ameliorated 2,4,6‐trinitrobenzenesulfonic acid (TNBS)‐ and dextran sulfate sodium (DSS)‐induced colitis by promoting IL‐10 production through TLR2 signaling, highlighting its immunomodulatory potential in experimental IBD while retaining activity against Yersinia [194]. Collectively, these studies highlight the therapeutic potential of probiotic‐based strategies to suppress Yersinia spp. while modulating host immune responses relevant to intestinal inflammation. Frick et al. [195] demonstrated that Lactobacillus fermentum DSMZ 20052 alleviates Y. enterocolitica‐induced inflammation in HeLa 229 and HT‐29 cells by inhibiting IL‐8 release through the suppression of the Rac, p38 MAPK, and NF‐κB pathways.
The anti‐inflammatory impact was associated with the released phospholipid, underscoring the immunomodulatory function of bacterial metabolites. In addition, Lavermicocca et al. [196] showed that Lactobacillus paracasei and Lactobacillus plantarum strains suppressed Y. enterocolitica proliferation and markedly diminished its urease activity in vitro. Urease is an essential virulence component that enhances Y. enterocolitica’s acid resistance and mucosal colonization; its inhibition indicates the capacity of these strains to counteract pathogen survival mechanisms while also facilitating gut acidification, which limits Y. enterocolitica persistence.
The in vivo efficacy of L. plantarum has been confirmed by De Montijo‐Prieto et al. [197], who illustrated that the kefir‐derived strain L. plantarum C4, when administered to mice, enhanced mucosal immune responses, facilitated rapid elimination of Y. enterocolitica from Peyer’s patches, and elevated secretory IgA levels—essential for pathogen neutralization at mucosal surfaces. Moreover, Shi et al. [198] demonstrated that Levilactobacillus brevis 23017 contributes to intestinal protection during Y. enterocolitica infection by preserving epithelial integrity (e.g., via tight junction stabilization), preventing villus destruction, and mitigating oxidative stress. The effects were mechanistically associated with the control of the p38 MAPK and NF‐κB signaling pathways, highlighting the strain’s multifaceted protective role in immune regulation, barrier preservation, and protection against antioxidants.
Zadernowska et al. [199] found that the addition of Lactobacillus acidophilus LA‐5 to blue cheese inhibited the growth of Y. enterocolitica at refrigerated temperatures, indicating an effective strategy to enhance food safety through probiotic‐enriched dairy products. The findings generally demonstrate the therapeutic efficacy of probiotics in managing Y. enterocolitica infections. Various probiotic strains, notably B. adolescentis, L. fermentum, L. plantarum, and L. brevis, have demonstrated efficacy in preclinical models through the production of antimicrobial peptides, modulation of host immunity, inhibition of inflammatory signaling, and preservation of epithelial integrity (Table S3).
Consequently, additional clinical validation is necessary for incorporating these advantages into human medicinal applications.
9. Limitations and Future Perspectives
Despite accumulating evidence linking Yersinia to IBD, several important limitations remain. Most available studies rely on culture, targeted PCR, or serological assays, resulting in considerable methodological heterogeneity and limiting cross‐study comparisons. Furthermore, although shotgun metagenomic sequencing has substantially advanced the characterization of microbial dysbiosis in IBD, it has not reproducibly identified Yersinia spp. as enriched taxa across independent IBD cohorts [200, 201].
This observation suggests that Yersinia is unlikely to represent a consistent microbial signature of IBD and that, if involved, it may persist at low abundance or only under specific ecological or host genetic conditions. Future longitudinal studies integrating culture‐based approaches with targeted molecular detection, shotgun metagenomics, and host multi‐omics analyses are needed to define the contribution of Yersinia to IBD pathogenesis.
10. Concluding Remarks
The intricate relationship between Yersinia spp. and IBD, particularly CD, highlights a multifaceted environment in which microbial, genetic, immunological, and environmental factors converge to influence disease onset, progression, and treatment response. Rather than being regarded solely as incidental findings, Y. enterocolitica and Y. pseudotuberculosis have been investigated for their potential role in intestinal inflammation in genetically susceptible individuals. However, despite compelling epidemiological and mechanistic evidence, their precise contribution to IBD pathogenesis remains incompletely understood, and a definitive causal relationship has yet to be established.
Their ability to break epithelial barriers, alter host immunity via various secretion systems and effector proteins, and exploit microbial dysbiosis supports their potential role within the ecological dysregulation model of IBD rather than establishing them as primary disease‐initiating pathogens. At the molecular level, the interactions between Yersinia‐associated virulence factors and host immunological sensors—particularly via inflammasome activation, pyroptotic cell death, and dysregulated cytokine cascades—demonstrate a complex bacterial strategy for immune control and persistence. In conjunction with host genetic variations in NOD2, ATG16L1, and associated pathways, these interactions may contribute to the chronic mucosal inflammation typical of CD.
The therapeutic management of Yersinia infections varies from supportive care to tailored antibiotic treatments, which are limited by the bacterium’s β‐lactamase profiles. Recent advancements in probiotic research—specifically concerning B. adolescentis, L. fermentum, L. plantarum, and L. brevis—present intriguing supplementary techniques. These commensals exhibit the ability to reduce the pathogen load, restore immune homeostasis, enhance epithelial integrity, and reduce inflammatory signals.
Emerging evidence also suggests that selected engineered probiotic strains may exert immunomodulatory effects in experimental colitis models, although their therapeutic potential in IBD requires further validation. Future longitudinal studies integrating culture‐based approaches with targeted molecular detection, shotgun metagenomics, and host multi‐omics analyses are needed to determine whether Yersinia represents a transient enteric infection, persistent colonizer, or secondary consequence of intestinal inflammation in IBD. Such efforts may facilitate the development of precision diagnostics and microbiome‐informed therapeutic strategies for patients with IBD.
Author Contributions
Fattaneh Sabzehali performed the literature review, carried out the visualization and wrote the initial manuscript draft. Verena Zerbato, Stefano Di Bella, Stefano Morabito, and Mohammad Reza Zali reviewed and edited the manuscript. Abbas Yadegar conceptualized, designed and supervised the study, acquired funding, contributed to visualization, and critically revised the manuscript.
Funding
This study was financially supported by a research grant (no. RIGLD 1331, IR.SBMU.RIGLD.REC.1404.009) from the Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Disclosure
All authors read and approved the final version of the manuscript.
Ethics Statement
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting Information
Additional supporting information can be found online in the Supporting Information section.
Supporting information