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Innate leukocyte responses during early stages of campylobacteriosis. During infection, neutrophils are recruited to the site of infection as a result of IEC IL-8 secretion, leading to elaboration of NETs and degranulation. Macrophages and dendritic cells are then recruited to the site of infection and perform both inflammatory and anti-inflammatory signaling. Within these first days of infection, macrophages, dendritic cells, neutrophils, and colonocyte antimicrobial proteins reduce C. jejuni levels within the infected host. These innate immune responses classically peak on day 3 postinfection, the heightened day of infection in hosts.
Source publication
Campylobacter spp. are the leading cause of bacterial-derived gastroenteritis worldwide, impacting ninety-six million individuals annually. Unlike other bacterial pathogens of the gastrointestinal tract, Campylobacter spp. lack many of the classical virulence factors that are often associated with the ability to induce disease in humans, including...
Citations
... Bacterial infiltration of wounded enteric vasculature, mediated by chemotaxis and the chemoreceptor Tsr, suggests serum attraction plays a role in the bloodstream entry of these bacterial species. In a broader context, the attraction of Enterobacteriaceae to serum aligns with an emerging understanding of how bacterial chemotaxis can drive tropism for sites of damaged tissue, injury, and inflammation (Figure 1; Zhou et al., 2023;Scales and Huffnagle, 2013;Aihara et al., 2014;Callahan et al., 2021;Croxen and Finlay, 2010;Hanyu et al., 2019;Rivera-Chávez et al., 2013). This phenomenon of bacterial attraction to serum through chemotaxis to access serum nutrients represents a novel pathogenesis strategy, which we term 'bacterial vampirism' (Figure 9). ...
Bacteria of the family Enterobacteriaceae are associated with gastrointestinal (GI) bleeding and bacteremia and are a leading cause of death, from sepsis, for individuals with inflammatory bowel diseases. The bacterial behaviors and mechanisms underlying why these bacteria are prone to bloodstream entry remain poorly understood. Herein, we report that clinical isolates of non-typhoidal Salmonella enterica serovars, Escherichia coli , and Citrobacter koseri are rapidly attracted toward sources of human serum. To simulate GI bleeding, we utilized an injection-based microfluidics device and found that femtoliter volumes of human serum are sufficient to induce bacterial attraction to the serum source. This response is orchestrated through chemotaxis and the chemoattractant L-serine, an amino acid abundant in serum that is recognized through direct binding by the chemoreceptor Tsr. We report the first crystal structures of Salmonella Typhimurium Tsr in complex with L-serine and identify a conserved amino acid recognition motif for L-serine shared among Tsr orthologues. We find Tsr to be widely conserved among Enterobacteriaceae and numerous World Health Organization priority pathogens associated with bloodstream infections. Lastly, we find that Enterobacteriaceae use human serum as a source of nutrients for growth and that chemotaxis and the chemoreceptor Tsr provide a competitive advantage for migration into enterohemorrhagic lesions. We define this bacterial behavior of taxis toward serum, colonization of hemorrhagic lesions, and the consumption of serum nutrients as ‘bacterial vampirism’, which may relate to the proclivity of Enterobacteriaceae for bloodstream infections.
... However, food chain transmission via contaminated undercooked meat from poultry or other livestock, unpasteurized milk, and its byproducts, as well as surface water may all be considered as potential infectious sources upon ingestion by humans (5). After a successful gastro-duodenal passage, the highly motile C. jejuni bacteria invade the distal intestinal tissues, and specific bacterial cell wall components, such as the endotoxin lipo-oligosaccharide (LOS), induce the Toll-like receptor-4 (TLR-4)-dependent hyperactivation of the host immune system (6)(7)(8)(9). In this proinflammatory immune cascade, both innate and adaptive immune cell subsets, including neutrophils and T cells, respectively, are recruited to the infection site, and pro-inflammatory mediators including interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), interleukin (IL)-6, and nitric oxide (NO) are released to restrict the infection, but by the expenses of exerting oxidative stress and damage to the intestinal tissues (10). ...
Introduction
Human infections with the food-borne enteropathogen Campylobacter jejuni are responsible for increasing incidences of acute campylobacteriosis cases worldwide. Since antibiotic treatment is usually not indicated and the severity of the enteritis directly correlates with the risk of developing serious autoimmune disease later-on, novel antibiotics-independent intervention strategies with non-toxic compounds to ameliorate and even prevent campylobacteriosis are utmost wanted. Given its known pleiotropic health-promoting properties, curcumin constitutes such a promising candidate molecule. In our actual preclinical placebo-controlled intervention trial, we tested the anti-microbial and anti-inflammatory effects of oral curcumin pretreatment during acute experimental campylobacteriosis.
Methods
Therefore, secondary abiotic IL-10-/- mice were challenged with synthetic curcumin via the drinking water starting a week prior oral C. jejuni infection. To assess anti-pathogenic, clinical, immune-modulatory, and functional effects of curcumin prophylaxis, gastrointestinal C. jejuni bacteria were cultured, clinical signs and colonic histopathological changes quantitated, pro-inflammatory immune cell responses determined by in situ immunohistochemistry and intestinal, extra-intestinal and systemic pro-inflammatory mediator measurements, and finally, intestinal epithelial barrier function tested by electrophysiological resistance analysis of colonic ex vivo biopsies in the Ussing chamber.
Results and discussion
Whereas placebo counterparts were suffering from severe enterocolitis characterized by wasting symptoms and bloody diarrhea on day 6 post-infection, curcumin pretreated mice, however, were clinically far less compromised and displayed less severe microscopic inflammatory sequelae such as histopathological changes and epithelial cell apoptosis in the colon. In addition, curcumin pretreatment could mitigate pro-inflammatory innate and adaptive immune responses in the intestinal tract and importantly, rescue colonic epithelial barrier integrity upon C. jejuni infection. Remarkably, the disease-mitigating effects of exogenous curcumin was also observed in organs beyond the infected intestines and strikingly, even systemically given basal hepatic, renal, and serum concentrations of pro-inflammatory mediators measured in curcumin pretreated mice on day 6 post-infection. In conclusion, the anti-Campylobacter and disease-mitigating including anti-inflammatory effects upon oral curcumin application observed here highlight the polyphenolic compound as a promising antibiotics-independent option for the prevention from severe acute campylobacteriosis and its potential post-infectious complications.
... Specifically, the increase in immune cells, including mast cells, macrophages, monocytes, T lymphocytes and intraepithelial lymphocytes, has been recorded for up to five years, tracking infection [10]. Starting from day 11 of human post-infection, B lymphocytes significantly increase the production of circulating antibodies, predominantly targeting the flagellin of C. jejuni as their epitope [40]. These antibodies remain detectable in circulation for up to one year following the initial infection [40]. ...
... Starting from day 11 of human post-infection, B lymphocytes significantly increase the production of circulating antibodies, predominantly targeting the flagellin of C. jejuni as their epitope [40]. These antibodies remain detectable in circulation for up to one year following the initial infection [40]. Furthermore, colonic supernatants from PI-IBS patients hold the capacity to activate mast cells, which are recognized as key mediators of visceral hypersensitivity in IBS [10]. ...
This comprehensive review investigates the specific impact of the foodborne pathogen Campylobacter jejuni (C. jejuni) on gastrointestinal health, focusing on its connection to post-infectious irritable bowel syndrome (PI-IBS). This review examines the pathogen’s pathophysiology, clinical implications and epidemiological trends using recent research and data to highlight its prevalence and association with PI-IBS. A detailed literature analysis synthesizes current research to illuminate Campylobacter’s long-lasting effects on gut microbiota and intestinal function. It provides a detailed analysis of the literature to shed light on C. jejuni’s long-term impact on gut microbiota and intestinal function. The findings suggest the need for multifaceted prevention and treatment approaches considering individual, microbial and epidemiological factors, thus contributing to a more nuanced understanding of PI-IBS following C. jejuni infection.
... ; https://doi.org/10.1101/2024.04.10.588895 doi: bioRxiv preprint disseminate to other organs [79][80][81][82] . C. jejuni is reported to use paracellular transmigration to translocate into the host mucosal tissue and invade gut epithelial cells in basolateral fibronectin & integrin-dependent manner 83,84 . ...
The interactions between Campylobacter jejuni , a critical foodborne cause of gastroenteritis, and the intestinal microbiota during infection are not completely understood. The crosstalk between C. jejuni and its host is impacted by the gut microbiota through mechanisms of competitive exclusion, microbial metabolites, or immune response. To investigate the role of gut microbiota on C. jejuni pathogenesis, we examined campylobacteriosis in the IL10KO mouse model, which was characterized by an increase in the relative abundance of intestinal proteobacteria, E. coli , and inflammatory cytokines during C. jejuni infection. We also found a significantly increased abundance of microbial metabolite Trimethylamine N-Oxide (TMAO) in the colonic lumens of IL10KO mice. We further investigated the effects of TMAO on C. jejuni pathogenesis. We determined that C. jejuni senses TMAO as a chemoattractant and the administration of TMAO promotes C. jejuni invasion into Caco-2 monolayers. TMAO also increased the transmigration of C. jejuni across polarized monolayers of Caco-2 cells, decreased TEER, and increased C. jejuni -mediated intestinal barrier damage. Interestingly, TMAO treatment and presence during C. jejuni infection of Caco-2 cells synergistically caused an increased inflammatory cytokine expression, specifically IL-1β and IL-8. These results establish that C. jejuni utilizes microbial metabolite TMAO for increased virulence during infection.
... During the acute phase of infection, the very motile enteropathogens successfully pass through the gastro-duodenum and invade the distal intestinal tissues [7,8]. Distinct bacterial cell wall molecules, such as lipo-oligosaccharide (LOS) induce the recruitment of innate immune cells including macrophages, monocytes, and neutrophils but also of adaptive T and B lymphocytes to the inflamed sites of intestinal infection [9,10]. The subsequently induced pro-inflammatory mediator storm damages the intestinal tissues as indicated by enhanced oxidative stress and apoptotic cell responses, ulcerations, and crypt abscesses mounting in a malabsorptive disease [9,[11][12][13]. ...
... Distinct bacterial cell wall molecules, such as lipo-oligosaccharide (LOS) induce the recruitment of innate immune cells including macrophages, monocytes, and neutrophils but also of adaptive T and B lymphocytes to the inflamed sites of intestinal infection [9,10]. The subsequently induced pro-inflammatory mediator storm damages the intestinal tissues as indicated by enhanced oxidative stress and apoptotic cell responses, ulcerations, and crypt abscesses mounting in a malabsorptive disease [9,[11][12][13]. After an incubation period of two to five days, the balance between enteropathogen's arsenal of virulence factors and the human host's immunological fitness determines the severity of symptoms that infected individuals display [14][15][16]. ...
Incidence rates of human Campylobacter jejuni infections are progressively increasing globally. Since the risk for the development of post-infectious autoimmune diseases correlates with the severity of the preceding enteritis and campylobacteriosis treatment usually involves symptomatic measures, it is desirable to apply antibiotic-independent compounds to treat or even prevent disease. Given its health-promoting including anti-inflammatory properties carvacrol constitutes a promising candidate. This prompted us to test the disease-alleviating including immune-modulatory effects of carvacrol prophylaxis in acute murine campylobacteriosis. Therefore, human gut microbiota-associated IL-10−/− mice were orally challenged with synthetic carvacrol starting a week before C. jejuni infection and followed up until day 6 post-infection. Whereas carvacrol prophylaxis did neither affect gastrointestinal pathogen loads, nor the human commensal gut microbiota composition, it improved the clinical outcome of mice, attenuated colonic epithelial cell apoptosis, and dampened pro-inflammatory immune responses not only in the intestinal tract but also in extra-intestinal organs including the liver and the spleen. In conclusion, our preclinical placebo-controlled intervention study provides convincing evidence that oral carvacrol pretreatment constitutes a promising option to mitigate acute campylobacteriosis and in turn, to reduce the risk for post-infectious complications.
... After a latency of 2 to 5 days, infected individual presents symptoms of varying severity, including general malaise, tenesmus, nausea, vomiting, and fever accompanied by enteritis with watery or bloody diarrhea accompanied by mucous discharge [8,9]. The severity of the C. jejuniinduced disease depends on both the arsenal of virulence factors of the enteropathogen and the immune competence of infected individuals [10,11]. Following successful passage of the stomach and duodenum, the motile C. jejuni traverse the viscous mucous barrier, reach the subepithelial layers by invasion of epithelial cells, and initiate macrophage activation, macroscopic, and microscopic complications of infection, as well as pro-inflammatory immune responses in the intestinal tract and beyond. ...
Human Campylobacter jejuni infections are of worldwide importance and represent the most commonly reported bacterial enteritis cases in middle- and high-income countries. Since antibiotics are usually not indicated and the severity of campylobacteriosis is directly linked to the risk of developing post-infectious complications, non-toxic antibiotic-independent treatment approaches are highly desirable. Given its health-promoting properties, including anti-microbial and anti-inflammatory activities, we tested the disease-alleviating effects of oral menthol in murine campylobacteriosis. Therefore, human gut microbiota-associated IL-10−/− mice were orally subjected to synthetic menthol starting a week before C. jejuni infection and followed up until day 6 post-infection. Whereas menthol pretreatment did not improve campylobacteriosis symptoms, it resulted in reduced colonic C. jejuni numbers and alleviated both macroscopic and microscopic aspects of C. jejuni infection in pretreated mice vs. controls. Menthol pretreatment dampened the recruitment of macrophages, monocytes, and T lymphocytes to colonic sites of infection, which was accompanied by mitigated intestinal nitric oxide secretion. Furthermore, menthol pretreatment had only marginal effects on the human fecal gut microbiota composition during the C. jejuni infection. In conclusion, the results of this preclinical placebo-controlled intervention study provide evidence that menthol application constitutes a promising way to tackle acute campylobacteriosis, thereby reducing the risk for post-infectious complications.
... In contrast to the avian hosts, humans exhibit heightened sensitivity to TLR-4 ligands such as LPS and LOS of Gram-negative bacteria. Consequently, when C. jejuni infects the human intestinal tract, LOS triggers host immune responses and induces hyperactivation of the innate and adaptive immune system via TLR-4 and mammalian target of rapamycin (mTOR) signaling (Sun et al., 2012;Callahan et al., 2021). This cascade results in damage to intestinal cells such as apoptosis and dissolution of the tight junctions (Lobo de Sá et al., 2021). ...
Food-borne Campylobacter jejuni infections constitute serious threats to human health worldwide. Since antibiotic treatment is usually not indicated in infected immune-competent patients, antibiotic-independent treatment approaches are needed to tackle campylobacteriosis. To address this, we orally applied carvacrol, deferoxamine, deoxycholate, and 2-fucosyl-lactose either alone or all in combination to human microbiota-associated IL-10−/− mice from day 2 until day 6 following oral C. jejuni infection. Neither treatment regimen affected C. jejuni loads in the colon, whereas carvacrol lowered the pathogen numbers in the ileum on day 6 post-infection (p.i.). The carvacrol and combination treatment regimens resulted in alleviated diarrheal symptoms, less distinct histopathological and apoptotic epithelial cell responses in the colon, as well as diminished numbers of colonic neutrophils and T lymphocytes on day 6 p.i., whereas the latter cells were also decreased upon deferoxamine, deoxycholate, or 2-fucosyl-lactose application. Remarkably, the carvacrol, deferoxamine, and combination treatment regimens dampened ex-vivo IFN-γ secretion in the colon, the kidneys, and even in the serum to basal concentrations on day 6 p.i. In conclusion, carvacrol alone and its combination with deferoxamine, deoxycholate, and 2-fucosyl-lactose constitute promising antibiotics-independent treatment options to fight acute campylobacteriosis.
... However, in humans, Campylobacter can invade the intestinal mucosa and trigger an inflammatory response, leading to tissue damage and fluid loss [11]. In some cases, Campylobacter infection can also result in serious complications, such as reactive arthritis, Guillain-Barré syndrome, and bacteremia [12]. ...
Campylobacter is a leading bacterial cause of gastrointestinal infections in humans and has imposed substantial medical and public health burdens worldwide. Among a total of 39 species in the Campylobacter genus, C. jejuni is the most important species responsible for approx. 90% of human Campylobacter illness. Most cases of the infection were acquired by ingesting undercooked poultry meat due to the high prevalence of Campylobacter in the products. Here, we reported the dataset of raw sequences, de novo assembled and annotated genomes of C. jejuni strains S27, S33, and S36 recently isolated from retail chicken by using PacBio highly accurate long-read sequencing technology combined with bioinformatics tools. Our data revealed several virulence and antibiotic resistance genes in each of the chromosomes, a type IV secretion system in the plasmid (pCjS33) of C. jejuni S33, and a type IV secretion system and a phage in the plasmid (pCjS36) of C. jejuni S36. This study not only provides new sequence data but also extends the knowledge pertaining to the genomic and functional aspects of this important foodborne pathogen, including the genetic determinants of virulence and antibiotic resistance.
... Both Salmonella and Campylobacter can survive intracellularly and extracellularly, and they have multiple immune-evasion strategies. These pathogens can circumvent either the Th1 cell-mediated or Th2 antibodymediated response if a vaccine confers only a polarized Th1 or Th2 immune response (Callahan et al., 2021;Maue et al., 2013;Wang et al., 2020). Therefore, a polarized immune response might not ensure Statistical significance is denoted as *p < 0.05, **p < 0.01, ***p < 0.001, or ****p < 0.0001. ...
... Although epidemiologic evidence suggests an association, the role of Campylobacter spp. in the pathogenesis of CD, UC, and IBS is not fully understood. It is hypothesized that a dysregulated immune response, changes in the gut microbiota, increased intestinal permeability, and (epi)genetic host factors contribute to the development of both postinfectious IBD and IBS [3,[75][76][77]. ...
Introduction
Reactive arthritis (REA) and Guillain–Barré syndrome (GBS) are postinfectious complications of Campylobacter enteritis (CE); associations with inflammatory bowel diseases and irritable bowel syndrome (IBS) are also discussed. The objective of this study was to summarize existing evidence on the probability of sequelae following confirmed CE.
Methods
All studies included in previous reviews and meta‐analyses on this topic were retrieved and assessed for eligibility; a systematic literature search was conducted to collect more recent reports. For each sequela, random effects meta‐analyses were performed; the risk of bias and the quality of evidence were evaluated.
Results
In total, 50 reports of observational studies were included; between 110,765 and 175,839 CE cases were considered for each sequela. The pooled proportion of CE cases that developed a sequela was 1.72% (95% CI 0.81–3.61; prediction interval [PI]: 0.03–47.65) for REA, 0.07% (0.03–0.16; PI: 0.003–1.59) for GBS, 0.22% (0.06–0.73; PI: 0.002–20.69) for Crohn's disease (CD), 0.35% (0.11–1.15; PI: 0.003–28.16) for ulcerative colitis (UC), and 4.48% (1.92–10.08; PI: 0.09–70.62) for IBS. The high between‐study heterogeneity could partially be explained by study size and design, the method of assessing sequelae, and the period between CE and sequelae onset. The quality of evidence was rated as moderate for GBS and UC, and low for REA, CD, and IBS.
Conclusion
Updated estimates of the probability to develop sequelae after CE are provided, for CD and UC for the first time. However, uncertainty regarding the true probabilities remains, which is reflected in the broad PIs.
