Tattooing deposits ink into the dermis comprising an immunologically highly active organ that filters foreign antigens via lymphatic drainage towards regional lymph nodes. Given chronic antigenic stimulation upon dermal tattoo pigment deposition, lymphadenopathies might manifest both locally and even generalized as granulomatous inflammatory morbidities including sarcoidosis but might not be considered as tattoo-related differential diagnosis. This prompted us to summarize recent evidence on tattoo-associated lymphadenopathies by analyzing clinical presentation, localization, diagnostic workup including histopathology, treatment, and outcomes in a systemic literature survey. The included publications revealed that local lymphadenopathies consistently showed pigment-laden macrophages in draining lymph nodes without granuloma formation, supporting passive lymphatic transport. Conversely, generalized tattoo-associated lymphadenopathy cases predominantly involved hilar or mediastinal lymph nodes particularly observed in sarcoidosis patients, often with granulomatous changes in lymph nodes and/or tattooed skin. In several reports, the disease onset followed immune-modulating events such as laser tattoo removal, immune checkpoint inhibitor therapy, or vaccination. Importantly, affected lymph nodes frequently demonstrated avidity in scintigraphy, often leading to invasive procedures and psychological distress due to suspected malignancy. Hence, dermal tattoo pigments act as chronic triggers for distinct immunological host responses emphasizing the importance of thorough tattooing anamnesis when evaluating unexplained local or generalized lymphadenopathies including sarcoidosis.

Abstract Infected pancreatic fluid collections (PFC) are among the most challenging entities in therapeutic endoscopy, requiring multiple interventions. In this multicenter study, we investigated whether microbiological profiles and antimicrobial resistance are associated with outcomes after endoscopic ultrasound-guided drainage. The primary endpoint was time to clinical success, defined as radiographic resolution of the PFC to < 30 mm, no need for additional intervention, and clinical improvement. Secondary outcomes included surgery-free survival, number of interventions, and ICU stay. Among 398 included patients (median age: 56.5 years; 70.6% male), 232 (58.3%) had microbiologically confirmed infection. Complete resolution was achieved in 89.2% of infected PFCs (median: 70 days; IQR 37–118) versus 95.2% of sterile PFCs (57 days; IQR 33–91). Resolution was significantly delayed in Enterococcus ( n = 107; 26.9%) and polymicrobial resistant infections ( n = 38; 9.5%): 87 days ( p = 0.003) and 120 days ( p < 0.001), respectively. Enterococcus species remained an independent predictor in multivariable Cox regression, and in a sensitivity analysis restricted to the necrosectomy group (aHR 2.50; p = 0.002). Vancomycin-resistant Enterococcus (VRE) infection ( n = 26; 6.5%) was associated with the highest number of interventions (median: 6), longest ICU stays (median: 72 days), and highest mortality (23%). In summary, this study identifies an association of Enterococcus species and antimicrobial resistance with poor outcomes after EUS-guided therapy, emphasizing the importance of microbiology-informed treatment strategies.

C57BL/6 mice serve as in vivo-model mimicking acute enteritis caused by Salmonella Typhimurium (S. Tm) but succumb to infection within a week. CBA mice, however, were shown to be clinically resistant to S. Tm-infection, survive the acute phase and are hence suitable to study chronic infection. We performed a comprehensive survey of enteropathogenic loads and immunopathological responses in intestinal compartments during the early and late phase of S. Tm-infection. Upon oral challenge of CBA mice, the enteropathogens colonized the intestines with highest loads in the cecum and colon. Whereas all mice survived the 4-week observation period and did not display any symptoms, marked inflammatory cell damage became overt in the cecum as early as 24 h post-infection (p.i.) that was accompanied by increased numbers of large intestinal innate immune cells including neutrophils, macrophages, and monocytes on days 1 and 14 p.i., whereas recruitment of adaptive immune cells such as T and B lymphocytes and regulatory T cells to the cecum and colon was pronounced on days 14 and 28 p.i. Depending on the time point S. Tm-infection resulted in differential cytokine secretion alongside the intestinal tract. Collectively, our results underscore CBA mice as a model to study chronic S. Tm-infection including long-term fecal pathogen shedding.

Lentinan, a β-(1,3)-glucan derived from the mushroom Lentinus edodes, is known for its health-beneficial including anti-oxidant, anti-inflammatory, and anti-tumor effects particularly in the gastrointestinal tract, and even regarded as adjuvant in cancer treatment in Asia. There is, however, a knowledge gap regarding lentinan's clinical application and the underlying mechanisms of its pleiotropic effects. This prompted us to perform a scoping review summarizing current knowledge of lentinan's health-promoting and disease-alleviating properties in the gastrointestinal tract and beyond. Preclinical and clinical studies revealed protective and therapeutic effects of the compound in distinct gastrointestinal pathologies, including colitis, chemotherapy- and immunosuppression-induced intestinal injury, infection models as well as in colorectal carcinogenesis by modulating intestinal epithelial barrier integrity, immune signaling, and microbiota composition. Lentinan was reported to exert its anti-tumor effects by interfering with apoptosis, autophagy, stemness, and angiogenesis. Notably, lentinan enhanced the effectiveness of chemotherapy and chimeric antigen receptor T-cell (CAR-T) therapy, reduced treatment-related adverse events, improved survival and quality of life. The observed effects were dependent on lentinan's molecular weight, dose, and route of administration. In conclusion, lentinan application constitutes a promising intervention strategy in gastrointestinal and extra-intestinal including systemic morbidities that should be further investigated in preclinical and clinical studies.

The commensal yeast Candida albicans is a major inducer of human mucosal Th17 cells. How C. albicans drives Th17 cell responses at homeostasis, and whether such responses contribute to inflammatory diseases, remains poorly understood. Here, we showed that C. albicans-reactive Th17 cells targeted a limited set of proteins enriched in fungal extracellular vesicles. At homeostasis, these cells predominantly resided in the oral mucosa. However, T cell receptor profiling revealed shared clonotypes across oral and gut tissues, with C. albicans being a major driver of this repertoire overlap. In patients with Crohn’s disease, C. albicans-specific Th17 cells with features of oral priming were enriched in intestinal tissues, where they retained their focused antigen specificity but acquired pathogenic Th17 cell traits. Together, our results reveal a stable, antigen-restricted C. albicans Th17 subset that is shared across mucosal sites and undergoes functional adaptation in the inflamed intestine. These cells represent a potential target for immune modulation in Crohn’s disease.

Aronia melanocarpa, a main constituent of black chokeberry, provides a rich source of bioactive molecules including polyphenols, flavonoids, and anthocyanins and has been used for long in traditional medicine due to its various health-promoting and disease-alleviating properties. The aim of our literature survey was to provide an actual update of evidence regarding the antibacterial activities exerted by Aronia melanocarpa and its potential application for the treatment of human bacterial pathogenic including food-borne infections. Our survey revealed that distinct ingredients in Aronia melanocarpa do not only inhibit growth of Gram-positive and to a lesser extent of Gram-negative bacteria, but also biofilm formation that is even more pronounced upon combined application. Furthermore, the anti-microbial effects against food-spoiling bacteria underscores the application of defined Aronia-derived molecules in food preservation decreasing the risk for transmission of food-borne pathogens and thereby, improving food safety. Notably, in vivo studies revealed that prophylactic Aronia juice application alleviated murine Listeria monocytogenes-induced enteritis, dampened growth of streptococci involved in dental caries development, and decreased the incidence of urinary tract infections in nursing home residents. In conclusion, Aronia-derived bioactive molecules exhibit promising anti-bacterial and disease-alleviating effects that should be further elucidated in clinical studies.

Besides its live-saving properties, antibiotic treatment affects the commensal microbiota facilitating colonization with potentially harmful microorganisms. Here we tested how commonly applied antibiotics induced gut microbiota changes and predisposed to intestinal carriage of multi-drug resistant Pseudomonas aeruginosa (MDR Psae) upon exposure. Therefore, mice received either vancomycin, ciprofloxacin, ampicillin plus sulbactam (A/S) or no antibiotics via the drinking water and were perorally challenged with a clinical MDR Psae isolate after antibiotic withdrawal. Whereas 100% of A/S and 55% of ciprofloxacin pretreated mice harbored Psae in their feces seven days post-challenge, intestinal Psae carriage rates were 20.0% and 26.3% in vancomycin pretreated and untreated mice, respectively. Microbiota analyses revealed that immediately before MDR Psae challenge, A/S pretreated mice displayed the lowest total bacterial, lactobacilli and Clostridium leptum fecal loads compared to other cohorts. Seven days following Psae exposure, however, higher numbers of apoptotic colonic epithelial cells were observed in A/S pretreated versus untreated mice that were accompanied by more enhanced innate and adaptive immune cell responses and nitric oxide secretion in colonic and ileal biopsies in the former versus the latter. In conclusion, distinct gut microbiota shifts following A/S pretreatment facilitate pronounced intestinal MDR Psae colonization and pro-inflammatory immune responses upon oral exposure.

Antibiotics have revolutionized medicine and drastically reduced mortality from bacterial infections. However, the widespread misuse of antibiotics in human and veterinary medicine, but also farming has greatly accelerated the emergence of multidrug-resistant (MDR) pathogens hampering treatment of infectious diseases. Therefore, novel anti-infectious treatment concepts applying antibiotic-independent natural compounds are highly appreciated. Ginger ( Zingiber officinale Roscoe) has been proposed as such promising candidate given its health-beneficial including anti-microbial effects. Therefore, our systematic literature review summarizes current evidence for anti-bacterial effects of ginger and derived molecules to elaborate perspectives for treatment options of infectious diseases caused by bacterial pathogens. The included 22 articles revealed that defined ginger extracts, essential oils, and distinct molecules including gingerol and shogaol i) inhibited growth of Gram-positive and Gram-negative bacteria including MDR isolates and ii) reduced distinct bacterial virulence factors including biofilm formation. Furthermore, iii) application of ginger together added to other plant-derived compounds or synthetic antibiotics markedly enhanced anti-bacterial effects of the latter, whereas iv) ginger could also exert immune-modulatory including anti-inflammatory and anti-oxidant activities in vitro and in vivo . In conclusion, ginger-derived molecules constitute promising alternative or adjunct antibiotics-independent options in the combat of infectious diseases caused by bacterial pathogens including MDR strains.

Critical illness often leads to the development of intestinal dysbiosis, which can have a significant impact on disease outcome. Intestinal barrier dysfunction is a common problem in intensive care unit patients, particularly those with sepsis. Despite its importance, early and reliable diagnosis of barrier dysfunction and evaluation of therapeutic options remain lacking in clinical practice. Given that intestinal hyperpermeability is associated with increased translocation of luminal antigens and subsequent priming of naïve T cells, we hypothesized that analysis of circulating peripheral antigen-reactive T cells could provide insight into the functionality of the intestinal barrier. To test this hypothesis, 70 ICU patients were enrolled, including those with sepsis, those not meeting sepsis criteria, and COVID-19 patients, as well as 20 healthy volunteers. We identified a sepsis-specific T-helper cell signature in peripheral blood using the antigen-reactive T-cell enrichment (ARTE) technique followed by flow cytometric analysis. This signature was characterized by an expansion of gut trophic Bifidobacterium longum-reactive T-helper cells, indicating significant intestinal barrier dysfunction during sepsis. This approach allows the study of intestinal barrier functionality and provides a means to monitor the effects of potential therapeutic interventions over time using blood samples.

Bacterial pathogens, particularly antibiotic-resistant strains may constitute major challenges for the successful treatment of infected patients. Therefore, novel antibiotics or alternative, antibiotics-independent compounds with antimicrobial properties such as phytonutrients are needed. Our systematic literature review summarizes current knowledge on antibacterial effects of sulforaphane (SFN) in vitro and in vivo, including human studies. The isothiocyanate SFN is abundant in plants from the Brassicaceae family including broccoli. The 28 reports reviewed herein revealed that SFN i.) exerted antimicrobial effects against a variety of Gram-positive and Gram-negative bacteria; ii.) counteracted distinct virulence factors such as biofilm formation and toxin production (e.g. Shiga toxin); iii.) enhanced antibacterial immune cell responses mounting in anti-oxidant and anti-inflammatory actions thereby supporting bacterial killing and dampening inflammatory cell and tissue damage; iv.) prevented from aspirin-induced small intestinal cell injury; and v.) alleviated Helicobacter pylori-induced gastritis. In conclusion, given its antibacterial, immune-modulatory, and disease-alleviating effects, SFN constitutes a promising alternative antibiotic-independent candidate for the treatment of bacterial infections, warranting further consideration in clinical trials.

Campylobacter jejuni, non-typhoidal Salmonella spp., Listeria monocytogenes and enteropathogenic/enterohemorrhagic Escherichia coli (EPEC/EHEC) are leading causes of food-borne illness worldwide. Citrobacter rodentium has been used to model EPEC and EHEC infection in mice. The gut microbiome is well-known to affect gut colonization and host responses to many food-borne pathogens. Recent progress has established gnotobiotic mice as valuable models to study how microbiota affect the enteric infections by S. Typhimurium, C. rodentium and L. monocytogenes. However, for C. jejuni, we are still lacking a suitable gnotobiotic mouse model. Moreover, the limited comparability of data across laboratories is often negatively affected by variations between different research facilities or murine microbiotas. In this study, we applied the standardized gnotobiotic OligoMM12 microbiota mouse model and compared the infections in the same facility. We provide evidence of robust colonization and significant pathological changes in OligoMM12 mice following infection with these pathogens. Moreover, we offer insights into pathogen-specific host responses and metabolite signatures, highlighting the advantages of a standardized mouse model for direct comparisons of factors influencing the pathogenesis of major food-borne pathogens. Notably, we reveal for the first time that C. jejuni stably colonizes OligoMM12 mice, triggering inflammation. Additionally, our comparative approach successfully identifies pathogen-specific responses, including the detection of genes uniquely associated with C. jejuni infection in humans. These findings underscore the potential of the OligoMM12 model as a versatile tool for advancing our understanding of food-borne pathogen interactions.

Conventional laboratory mice are protected from oral Campylobacter jejuni infection due to colonization resistance (CR) mediated by their host-specific gut microbiota. Here, we used differential effects of distinct antibiotics on gut microbiota composition to identify microbial groups associated with CR against C. jejuni . Therefore, specific pathogen-free (SPF) mice were subjected to ampicillin plus sulbactam (A/S), ciprofloxacin (CIP), or vancomycin (VAN) via the drinking water for 28 days or left untreated before peroral C. jejuni challenge. Cultural analyses revealed that CR displayed by untreated mice was abrogated by A/S treatment, but only reduced in mice treated with CIP or VAN. Notably, differential analysis of antibiotic-induced microbiota changes and C. jejuni colonization dynamics identified lactobacilli and Clostridium leptum as key microbial groups that were associated with CR. Notably, the complete eradication of intestinal bacteria in A/S treated mice supported high intestinal C. jejuni colonization levels which triggered apoptosis and inflammatory responses accompanied by enhanced expression of matrix-degrading gelatinases in the colon. In conclusion, A/S treated mice represent a valuable infection model for the study of campylobacteriosis and the treatment of mice with specific antibiotics support the investigation of molecular mechanisms involved in CR against enteropathogens.

Cocoa that is abundant in dark chocolate is known for its anti-inflammatory effects that are mainly due to biologically active ingredients like polyphenols and methylxanthines. We here provide a comprehensive literature survey of both, in vitro and in vivo studies including clinical trials summarizing recent evidence on the immune-modulatory effects exerted by application of cocoa-rich dark chocolate or distinct cocoa-derived molecules. The survey revealed that dark chocolate and its derivatives could effectively dampen pro-inflammatory including oxidative stress responses in vascular diseases including atherosclerosis, hypertension, and decompression sickness, metabolic morbidities such as obesity and type 2 diabetes mellitus, celiac disease, chronic kidney diseases, and polycystic ovary syndrome, enhance gut epithelial barrier function, and modulate pain sensations. On the other hand, dark chocolate consumption intake was found to worsen acne symptoms. In conclusion, dietary supplementation with dark chocolate with high contents of biologically active polyphenols and methylxanthines might be promising adjunct immune-modulatory treatment options of distinct acute as well as chronic inflammatory morbidities that need to be evaluated in more detail in future in vivo including clinical studies.

Long-chain fatty acyl solamines, recently identified in the leaves of Solanum bulbocastanum Dun., have been shown to confer resistance against plant pests such as the Colorado potato beetle and the phytopathogenic oomycete Phytophthora infestans (Mont.) de Bary. Owing to their structural resemblance to the antiseptic cetylpyridinium chloride, this study aimed to evaluate a fraction of a methanolic S. bulbucastanum leaf extract mainly containing long-chain fatty acyl solamines for potential antiseptic applications. Minimal inhibitory concentrations (MICs) were determined against eight clinically relevant human pathogens, and minimal bactericidal concentrations (MBCs) were assessed for two model bacteria. Atomic force microscopy and lactate dehydrogenase (LDH) release assays were employed to investigate the mechanism of action. Cytotoxicity was evaluated on normal human dermal fibroblasts and Vero E6 cells using MTT and LDH assays, as well as real-time cell analysis and live-cell imaging. The fraction exhibited antimicrobial activity against all tested pathogens (MICs of 128-256 μg/mL for the majority of the pathogens) and demonstrated bactericidal properties (MBCs of 256 μg/mL), likely mediated by nonspecific membrane disruption. In mammalian cell assays, the fraction mirrored the cytotoxic effect of cetylpyridinium chloride in MTT assay (Fibroblasts: IC50 = 1.2 μg/mL, Vero E6: IC50 = 2.2 μg/mL) and the profile in real time cell analysis, suggesting a comparable mode of action. These findings highlight long-chain fatty acyl solamines as promising candidates for the development as bio-based antiseptics, offering a potential green alternative to conventional agents.

Chronic degenerative diseases including osteoarthritis are on the rise leading to a growing demand for joint replacement surgery in elderly and often multimorbid patients. Periprosthetic joint infections (PJIs) constitute serious complications following endoprosthetic surgery. Increasing prevalences of PJIs by multi-drug resistant and/or biofilm-producing bacteria hinder sufficient anti-infectious treatment especially in vulnerable patients. Hence, alternative and/or adjunct therapeutic approaches appear crucial in the combat of difficult-to-treat PJIs. In our review we summarize recent evidence for changes in the spectrum of PJI-associated pathogens over time and elucidate treatment concepts beyond established standard therapies. Our literature search revealed that the spectrum of bacterial pathogens can vary considerably depending on the time course post-surgery, the geographical region, and the patient population. While standard antibiotic therapy besides surgical revision remains the corner stone of treatment, alternative/adjunct antibiotics-independent methods are increasingly coming to the fore. These include the targeted dissolution of bacterial biofilms, enzyme-based approaches, and enhanced infection prevention measures upon risk assessment of the patient. Despite promising methodological approaches clinical evidence of their therapeutic value in everyday care is scarce. Hence, optimized early pathogen detection measures, individually tailored treatment concepts and their application in interdisciplinary settings will be important in the combat of difficult-to-treat PJIs.

Multi-drug resistant bacterial infections are of global concern, leading to staggering health care costs and loss of lives. Hence, novel therapeutic options are highly required. Garcinia mangostana, a plant known as mangosteen (also termed "queen of the fruits"), is said to possess a multitude of favorable features like anti-microbial capacity. Accordingly, we compiled a literature review addressing the potential of the mangosteen and its compounds for the treatment of bacterial infections. The included 23 publications consistently reported the inhibition or elimination of bacteria following the administration of mangosteen extracts and compounds such as the xanthone α-mangostin, both in vitro and in vivo. Even pathogens like methicillin-resistant Staphylococcus aureus as well as vancomycin-resistant Enterococcus species were tackled. While the effect of mangosteen extracts and compounds appeared to be dose-dependent, they exhibited also anti-biofilm activity and strong stability under varying conditions, suggesting suitability for a versatile approach to combat infectious diseases. Moreover, the combination of α-mangostin with other phytotherapeutic agents and especially antibiotics revealed enhanced anti-bacterial results, at low or no toxicity. In light of this review, we conclude that mangosteen extracts and compounds are promising candidates for the anti-bacterial therapy of human infections, warranting further consideration in clinical trials.

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.

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.

Prosthetic joint infections (PJIs) are dreaded arthroplasty complications often caused by Staphylococcus aureus. Due to methicillin-resistant S. aureus (MRSA) strains or biofilm formation, successful treatment remains difficult. Currently, two-stage revision surgery constitutes the gold standard therapy of PJIs, sometimes replaced or supplemented by debridement, antibiotics, and implant retention (DAIR). Given the dire consequences of therapeutic failure, bacteriophage therapy might be another treatment option. Here we provide a comprehensive literature review addressing the efficacy of phages applied against S. aureus as causative agent of PJIs. The included 17 publications had in common that the applied phages proved to be effective against various S. aureus isolates including MRSA even in biofilms. Experiments with mice, rats, rabbits, and moth larvae confirmed favorable features of phage preparations in PJI treatment in vivo; including its synergistic with antibiotics. Case reports of PJI patients unanimously described the bacterial eradication following, alongside other measures, intravenous and intra-articular phage administration. Generally, no major side effects occurred, but in some cases elevated liver transaminases were observed. To conclude, our review compiled promising evidence suggesting the safety and suitability of phage therapy as an adjuvant to DAIR in S. aureus PJIs, and thus, underscores the significance of further research.