Vitamin D in Acute Campylobacteriosis–Results From an Intervention Study Applying a Clinical Campylobacter jejuni Induced Enterocolitis Model

Mousavi, Soraya; Sá, Fábia Daniela Lobo de; Schulzke, Jörg–Dieter; Bücker, Roland; Bereswill, Stefan; Heimesaat, Markus M.

doi:10.3389/fimmu.2019.02094

Cited by 29 publications

(37 citation statements)

References 77 publications

(82 reference statements)

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“…The importance of epithelial cell death suggests the use of antiapoptotic substances for prevention or treatment of the C. jejuni enteritis. Although medical use of caspase-inhibitors like Q-VD-OPh is unreasonable, substances with pronounced anti-apoptotic and immune-modulatory effect, e.g., vitamin D, curcumin and myrrh, have already been proven to their effectiveness in cellculture or mouse models (Rosenthal et al, 2017;Bücker et al, 2018;Lobo de Sá et al, 2019;Mousavi et al, 2019). These compounds represent a potent alternative to the antibiotic treatment of C. jejuni infection.…”

Section: Apoptosis As a Limiting Mechanism Of C Jejuni Translocationmentioning

confidence: 99%

Contribution of Epithelial Apoptosis and Subepithelial Immune Responses in Campylobacter jejuni-Induced Barrier Disruption

et al. 2020

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Campylobacter jejuni is a widespread zoonotic pathogen and the leading bacterial cause of foodborne gastroenteritis in humans. Previous infection studies showed disruption of intercellular contacts, induction of epithelial apoptosis, and immune activation, all three contributing to intestinal barrier dysfunction leading to diarrhea. The present study aims to determine the impact of subepithelial immune cells on intestinal barrier dysfunction during Campylobacter jejuni infection and the underlying pathological mechanisms. Infection was performed in a co-culture of confluent monolayers of the human colon cell line HT-29/B6-GR/MR and THP-1 immune cells. Twenty-two hours after infection, transepithelial electrical resistance (TER) was decreased by 58 ± 6% compared to controls. The infection resulted in an increase in permeability for fluorescein (332 Da; 4.5-fold) and for FITC-dextran (4 kDa; 3.5-fold), respectively. In contrast, incubation of the co-culture with the pan-caspase inhibitor Q-VD-OPh during the infection resulted in a complete recovery of the decrease in TER and a normalization of flux values. Fluorescence microscopy showed apoptotic fragmentation in infected cell monolayers resulting in a 5-fold increase of the apoptotic ratio, accompanied by an increased caspase-3 cleavage and caspase-3/7 activity, which both were not present after Q-VD-OPh treatment. Western blot analysis revealed increased claudin-1 and claudin-2 protein expression. Inhibition of apoptosis induction did not normalize these tight junction changes. TNFα concentration was increased during the infection in the co-culture. In conclusion, Campylobacter jejuni infection and the consequent subepithelial immune activation cause intestinal barrier dysfunction mainly through caspase-3-dependent epithelial apoptosis. Concomitant tight junction changes were caspase-independent. Anti-apoptotic and immune-modulatory substances appear to be promising agents for treatment of campylobacteriosis.

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Section: Apoptosis As a Limiting Mechanism Of C Jejuni Translocationmentioning

confidence: 99%

Contribution of Epithelial Apoptosis and Subepithelial Immune Responses in Campylobacter jejuni-Induced Barrier Disruption

et al. 2020

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“…vitamin D treated mice displayed an uncompromised colonic epithelial barrier function which was accompanied by (viii.) less distinct bacterial translocation from the inflamed gut to extra-intestinal compartments in the latter as compared to the former 74 .…”

Section: Discussionmentioning

confidence: 84%

Vitamin C alleviates acute enterocolitis in Campylobacter jejuni infected mice

Mousavi

Escher

Thunhorst

et al. 2020

Sci Rep

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Human foodborne infections with the zoonotic pathogen Campylobacter jejuni are on the rise and constitute a significant socioeconomic burden worldwide. The health-beneficial, particularly antiinflammatory effects of vitamin C (ascorbate) are well known. In our preclinical intervention study, we assessed potential anti-pathogenic and immunomodulatory effects of ascorbate in C. jejuni-infected secondary abiotic IL-10 −/− mice developing acute campylobacteriosis similar to humans. Starting 4 days prior peroral C. jejuni-infection, mice received synthetic ascorbate via the drinking water until the end of the experiment. At day 6 post-infection, ascorbate-treated mice harbored slightly lower colonic pathogen loads and suffered from less severe C. jejuni-induced enterocolitis as compared to placebo control animals. Ascorbate treatment did not only alleviate macroscopic sequelae of infection, but also dampened apoptotic and inflammatory immune cell responses in the intestines that were accompanied by less pronounced pro-inflammatory cytokine secretion. Remarkably, the anti-inflammatory effects of ascorbate pretreatment in C. jejuni-infected mice were not restricted to the intestinal tract but could also be observed in extra-intestinal compartments including liver, kidneys and lungs. In conclusion, due to the potent anti-inflammatory effects observed in the clinical murine C. jejuniinfection model, ascorbate constitutes a promising novel option for prophylaxis and treatment of acute campylobacteriosis. Campylobacter jejuni are the most common cause of food-borne gastroenteritis with increasing prevalence worldwide 1,2. In fact, human campylobacteriosis represents a socioeconomic burden given estimated disease-associated costs of approximately 2.4 billion Euro 3. Most commonly, C. jejuni transfer via consumption of contaminated raw or undercooked meat and milk or the ingestion of contaminated surface water to humans 4-8. The intestinal colonization of C. jejuni induces a strong inflammatory response of the innate immune system affecting both, absorptive and secretory functions of the gastrointestinal tract 1. In fact, campylobacteriosis constitutes a classical sodium malabsorption syndrome 9 , which depending on the bacterial strain and the host immune status, results in illness of varying degree 10. Whereas some patients remain asymptomatic or display mild symptoms, others develop fever, abdominal pain and watery diarrhea, or suffer from acute campylobacteriosis characterized by severe enterocolitis with inflammatory, bloody diarrhea 1,11. In the majority of events, the disease is self-limited and treated symptomatically, whereas patients with immunosuppressive comorbidities require antibiotic treatment 11,12. However, in few instances, post-infectious sequelae including Guillain-Barré syndrome, Miller Fisher syndrome, reactive arthritis and chronic inflammatory conditions of the intestinal tract might develop with a latent period of weeks or longer 1,13. Even though human campylobacteriosis is becoming increasingly impo...

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“…Since then, abiotic IL-10 −/− mouse model has been successfully employed in many studies [48][49][50][51]. In recent studies, the abiotic IL-10 −/− mouse model was also used to determine the barrier protective and anti-inflammatory effects on C. jejuni infection using curcumin or vitamin D [52,53].…”

Section: Discussionmentioning

confidence: 99%

Campylobacter concisus Impairs Sodium Absorption in Colonic Epithelium via ENaC Dysfunction and Claudin-8 Disruption

Nattramilarasu

Bücker

Sá

et al. 2020

IJMS

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The epithelial sodium channel (ENaC) can increase the colonic absorptive capacity for salt and water. Campylobacter concisus is a common pathogenic epsilonproteobacterium, causing enteritis and diarrhea. It can induce barrier dysfunction in the intestine, but its influence on intestinal transport function is still unknown. Therefore, our study aimed to characterize C. concisus effects on ENaC using the HT-29/B6-GR/MR (epithelial cell line HT-29/B6 transfected with glucocorticoid and mineralocorticoid receptors) cell model and mouse colon. In Ussing chambers, C. concisus infection inhibited ENaC-dependent Na+ transport as indicated by a reduction in amiloride-sensitive short circuit current (−55%, n = 15, p < 0.001). This occurred via down-regulation of β- and γ-ENaC mRNA expression and ENaC ubiquitination due to extracellular signal-regulated kinase (ERK)1/2 activation, predicted by Ingenuity Pathway Analysis (IPA). In parallel, C. concisus reduced the expression of the sealing tight junction (TJ) protein claudin-8 and induced claudin-8 redistribution off the TJ domain of the enterocytes, which facilitates the back leakage of Na+ ions into the intestinal lumen. In conclusion, C. concisus caused ENaC dysfunction via interleukin-32-regulated ERK1/2, as well as claudin-8-dependent barrier dysfunction—both of which contribute to Na+ malabsorption and diarrhea.

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Vitamin D in Acute Campylobacteriosis–Results From an Intervention Study Applying a Clinical Campylobacter jejuni Induced Enterocolitis Model

Cited by 29 publications

References 77 publications

Contribution of Epithelial Apoptosis and Subepithelial Immune Responses in Campylobacter jejuni-Induced Barrier Disruption

Contribution of Epithelial Apoptosis and Subepithelial Immune Responses in Campylobacter jejuni-Induced Barrier Disruption

Vitamin C alleviates acute enterocolitis in Campylobacter jejuni infected mice

Campylobacter concisus Impairs Sodium Absorption in Colonic Epithelium via ENaC Dysfunction and Claudin-8 Disruption

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