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The octapeptide NAP is well known for its neuroprotective properties. We here investigated whether NAP treatment could alleviate pro-inflammatory immune responses during experimental subacute ileitis. To address this, mice with a human gut microbiota were perorally infected with one cyst of Toxoplasma gondii (day 0) and subjected to intraperitoneal synthetic NAP treatment from day 1 until day 8 postinfection (p.i.). Whereas placebo (PLC) control animals displayed subacute ileitis at day 9 p.i., NAP-treated mice exhibited less pronounced pro-inflammatory immune responses as indicated by lower numbers of intestinal mucosal T and B lymphocytes and lower interferon (IFN)-γ concentrations in mesenteric lymph nodes. The NAP-induced anti-inflammatory effects were not restricted to the intestinal tract but could also be observed in extra-intestinal including systemic compartments, given that pro-inflammatory cytokines were lower in liver, kidney, and lung following NAP as compared to PLC application, whereas at day 9 p.i., colonic and serum interleukin (IL)-10 concentrations were higher in the former as compared to the latter. Remarkably, probiotic commensal bifidobacterial loads were higher in the ileal lumen of NAP as compared to PLC-treated mice with ileitis. Our findings thus further support that NAP might be regarded as future treatment option directed against intestinal inflammation.

Open access

Human immunodeficiency virus (HIV) infections cause severe CD4+ T cell depletion leading to chronic inflammation and immune activation, impaired barrier function, and microbial translocation. Even under effective antiretroviral therapy, these processes persist, leading to gut microbiome dysbiosis and disturbance of microbiome–host homeostasis. This systematic review aims at analyzing how gut microbiome and host immune system influence each other during HIV pathogenesis. An online search applying the PubMed database was conducted. The number of total results (n = 35) was narrowed down to 5 relevant studies focusing on the interaction between the host and gut microbiome, whereas strict exclusion criteria were applied, thereby assuring that no other comorbidities impacted study results. Our analyses revealed that gut microbiome diversity correlated positively with CD4+ T cell counts and negatively with microbial translocation markers. However, quantitative changes in bacterial richness did not consistently correlate with the numbers of metabolically active bacterial populations. Despite the reported increase in potentially pathogenic bacteria and, conversely, decrease in protective populations, the gut microbiota exhibited immune-modulating qualities given that mucosal inflammatory sequelae were dampened by decreasing pro-inflammatory and accelerating anti-inflammatory cytokine responses. Future research is needed to further elucidate these findings, to gain a deeper insight into host–microbiota interactions and to develop novel therapeutic strategies.

Open access

Abstract

As antimicrobial resistance poses a globally rising health problem, the identification of alternative antimicrobial agents is urgently required. The short chain fatty acid propionate which is physiologically produced by the gut microbiota constitutes a promising molecule given that it has been widely used as a cosmetics and food preservative due to its antimicrobial effects. This literature survey aims to determine the most recent state of knowledge about the antimicrobial and immune-modulatory properties of propionate. Both in vitro and in vivo studies published between 2011 and 2020 confirmed the ability of propionate to inhibit the growth of several cellular pathogens, including Gram-positive and Gram-negative multi-drug resistant bacteria and fungi. In addition, heterogenous immune-modulatory and in particular, anti-inflammatory effects of propionate could be assessed involving a diverse signaling network that needs further comprehension. In conclusion, our literature survey provides evidence that propionate displays a plethora of health-beneficial including antimicrobial and immune-modulatory effects. Future research is required to further unravel the underlying molecular mechanisms and to set the basis for in vivo infection and clinical studies to broaden the path of propionate as a promising adjunct antibiotics-independent option in the combat of infections caused by multi-drug resistant bacteria.

Open access

Abstract

The excessive prescription of antibiotics has led to an increasing number of antimicrobial resistances, posing a major public health concern. Therefore, the pharmacological research has shifted its focus to the identification of natural compounds that exhibit anti-pathogenic properties without triggering antibiotic resistance. Butyrate has received increasing attention as a promising candidate for the treatment of bacterial infections in the gastrointestinal tract, particularly when antibiotic treatment is contraindicated. This literature survey summarizes recently investigated antibacterial and immune-modulatory effects of butyrate. This survey revealed that butyrate exerts direct antimicrobial effects against distinct strains of Acinetobacter baumannii, Escherichia coli, Bacillus, and Staphylococcus species. In addition, in vitro and in vivo studies confirmed indirect antimicrobial effects of butyrate, which were exhibited via induction of host defensin production as well as by activation of innate and adaptive immune responses. Finally, the synergistic action of butyrate in combination with other antimicrobial compounds results in a striking clearance of bacterial pathogens. In conclusion, butyrate and its derivatives might be considered as promising antibacterial and immune-modulatory agents in order to tackle bacterial infections without antibiotics.

Open access

Abstract

The use of antibiotics has provoked an emergence of various multidrug-resistant (MDR) bacteria. Infectious diseases that cannot be treated sufficiently with conventional antibiotic intervention strategies anymore constitue serious threats to human health. Therefore, current research focus has shifted to alternative, antibiotic-independent therapeutic approaches. In this context, vitamin E constitutes a promising candidate molecule due to its multi-faceted modes of action. Therefore, we used the PubMed database to perform a comprehensive literature survey reviewing studies addressing the antimicrobial properties of vitamin E against bacterial pathogens including MDR bacteria. The included studies published between 2010 and 2020 revealed that given its potent synergistic antimicrobial effects in combination with distinct antibiotic compounds, vitamin E constitutes a promising adjunct antibiotic treatment option directed against infectious diseases caused by MDR bacteria such as Pseudomonas aeruginosa, Burkholderia cenocepacia and methicillin-resistant Staphylococcus aureus (MRSA). In conclusion, the therapeutic value of vitamin E for the treatment of bacterial infections should therefore be investigated in future clinical studies.

Open access

Abstract

Infections with multi-drug resistant (MDR) bacteria including carbapenem-resistant Klebsiella pneumoniae are emerging worldwide but are difficult to treat with the currently available antibiotic compounds and therefore constitute serious threats to human health. This prompted us to perform a literature survey applying the MEDLINE database and Cochrane Register of Controlled Trials including clinical trials comparing different treatment regimens for infections caused by carbapenem-resistant K. pneumoniae. Our survey revealed that a combined application of antibiotic compounds such as meropenem plus vaborbactam, meropenem plus colistin and carbapenem plus carbapenem, resulted in significantly increased clinical cure and decreased mortality rates as compared to respective control treatment. However, further research on novel antibiotic compounds, but also on antibiotic-independent molecules providing synergistic or at least resistance-modifying properties needs to be undertaken in vitro as well as in large clinical trials to provide future options in the combat of emerging life-threatening infections caused by MDR bacteria.

Open access

Abstract

The physiological colonization resistance exerted by the murine gut microbiota prevents conventional mice from Campylobacter jejuni infection. In the present study we addressed whether this also held true for Campylobacter coli. Following peroral application, C. coli as opposed to C. jejuni could stably establish within the gastrointestinal tract of conventionally colonized mice until 3 weeks post-challenge. Neither before nor after either Campylobacter application any changes in the gut microbiota composition could be observed. C. coli, but not C. jejuni challenge was associated with pronounced regenerative, but not apoptotic responses in colonic epithelia. At day 21 following C. coli versus C. jejuni application mice exhibited higher numbers of adaptive immune cells including T-lymphocytes and regulatory T-cells in the colonic mucosa and lamina propria that were accompanied by higher large intestinal interferon-γ (IFN-γ) concentrations in the former versus the latter but comparable to naive levels. Campylobacter application resulted in decreased splenic IFN-γ, tumor necrosis factor-α (TNF-α), and IL-6 concentrations, whereas IL-12p70 secretion was increased in the spleens at day 21 following C. coli application only. In either Campylobacter cohort decreased IL-10 concentrations could be measured in splenic and serum samples. In conclusion, the commensal gut microbiota prevents mice from C. jejuni, but not C. coli infection.

Open access

Abstract

Antibiotic resistance is endangering public health globally and gives reason for constant fear of virtually intractable bacterial infections. Given a limitation of novel antibiotic classes brought to market in perspective, it is indispensable to explore novel, antibiotics-independent ways to fight bacterial infections. In consequence, the antibacterial properties of natural compounds have gained increasing attention in pharmacological sciences. We here performed a literature survey regarding the antibacterial effects of capsaicin and its derivatives constituting natural compounds of chili peppers. The studies included revealed that the compounds under investigation exerted i.) both direct and indirect antibacterial properties in vitro depending on the applied concentrations and the bacterial strains under investigation; ii.) synergistic antibacterial effects in combination with defined antibiotics; iii.) resistance-modification via inhibition of bacterial efflux pumps; iv.) attenuation of bacterial virulence factor expression; and v.) dampening of pathogen-induced immunopathological responses. In conclusion, capsaicin and its derivatives comprise promising antimicrobial molecules which could complement or replace antibiotic treatment strategies to fight bacterial infections. However, a solid basis for subsequent clinical trials requires future investigations to explore the underlying molecular mechanisms and in particular pharmaceutical evaluations in animal infection models.

Open access
European Journal of Microbiology and Immunology
Authors: Marie E. Alutis, Ursula Grundmann, Ulrike Hagen, André Fischer, Anja A. Kühl, Ulf B. Göbel, Stefan Bereswill, and Markus M. Heimesaat

Increased levels of the matrix metalloproteinases (MMPs)-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in the inflamed gut. We have recently shown that synthetic gelatinase blockage reduces colonic apoptosis and pro-inflammatory immune responses following murine Campylobacter (C.) jejuni infection. In order to dissect whether MMP-2 and/or MMP-9 is involved in mediating C. jejuni-induced immune responses, infant MMP-2-/-, MMP-9-/-, and wildtype (WT) mice were perorally infected with the C. jejuni strain B2 immediately after weaning. Whereas, at day 2 postinfection (p.i.), fecal C. jejuni B2 loads were comparable in mice of either genotype, mice expelled the pathogen from the intestinal tract until day 4 p.i. Six days p.i., colonic MMP-2 but not MMP-9 mRNA was upregulated in WT mice. Remarkably, infected MMP-2-/- mice exhibited less frequent abundance of blood in feces, less distinct colonic histopathology and apoptosis, lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa, and higher colonic IL-22 mRNA levels as compared to infected WT mice. In conclusion, these results point towards an important role of MMP-2 in mediating C. jejuni-induced intestinal immunopathogenesis.

Open access
European Journal of Microbiology and Immunology
Authors: Markus M. Heimesaat, Gernot Reifenberger, Viktoria Vicena, Anita Illes, Gabriella Horvath, Andrea Tamas, Balazs D. Fulop, Stefan Bereswill, and Dora Reglodi

Pituitary adenylate cyclase activating polypetide (PACAP) constitutes a neuropeptide that is widely distributed in the host exerting essential cytoprotective properties, whereas PACAP−/− mice display increased susceptibility to distinct immunopathological conditions. The orchestrated interplay between the gut microbiota and the host is pivotal in immune homeostasis and resistance to disease. Potential pertubations of the intestinal microbiota in PACAP−/− mice, however, have not been addressed so far. For the first time, we performed a comprehensive survey of the intestinal microbiota composition in PACAP−/− and wildtype (WT) mice starting 2 weeks postpartum until 18 months of age applying quantitative culture-independent techniques. Fecal enterobacteria and enterococci were lower in PACAP−/− than WT mice aged 1 month and ≥6 months, respectively. Whereas Mouse Intestinal Bacteroides were slightly higher in PACAP−/− versus WT mice aged 1 and 6 months, this later in life held true for Bacteroides/Prevotella spp. (≥12 months) and lactobacilli (>15 months of age). Strikingly, health-beneficial bifidobacteria were virtually absent in the intestines of PACAP−/− mice, even when still breastfed. In conclusion, PACAP deficiency is accompanied by distinct changes in fecal microbiota composition with virtually absent bifidobacteria as a major hallmark that might be linked to increased susceptibility to disease.

Open access