Authors:Minnja S. Hartmann, Soraya Mousavi, Stefan Bereswill, and Markus M. Heimesaat
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.
Authors:Luis Q. Langfeld, Ke Du, Stefan Bereswill, and Markus M. Heimesaat
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.
Authors:Rasmus G. Bandick, Soraya Mousavi, Stefan Bereswill, and Markus M. Heimesaat
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.
Authors:Ke Du, Stefan Bereswill, and Markus M. Heimesaat
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.
Authors:Markus M. Heimesaat, Marie E. Alutis, Ursula Grundmann, André Fischer, Ulf B. Göbel, and Stefan Bereswill
We have recently shown that, within 1 week following peroral Campylobacter jejuni infection, conventional infant mice develop self-limiting enteritis. We here investigated the role of IL-23, IL-22, and IL-18 during C. jejuni strain 81-176 infection of infant mice. The pathogen efficiently colonized the intestines of IL-18−/− mice only, but did not translocate to extra-intestinal compartments. At day 13 postinfection (p.i.), IL-22−/− mice displayed lower colonic epithelial apoptotic cell numbers as compared to wildtype mice, whereas, conversely, colonic proliferating cells increased in infected IL-22−/− and IL-18−/− mice. At day 6 p.i., increases in neutrophils, T and B lymphocytes were less pronounced in gene-deficient mice, whereas regulatory T cell numbers were lower in IL-23p19−/− and IL-22−/− as compared to wildtype mice, which was accompanied by increased colonic IL-10 levels in the latter. Until then, colonic pro-inflammatory cytokines including TNF, IFN-γ, IL-6, and MCP-1 increased in IL-23p19−/− mice, whereas IL-18−/− mice exhibited decreased cytokine levels and lower colonic numbers of T and B cell as well as of neutrophils, macrophages, and monocytes as compared to wildtype controls. In conclusion, IL-23, IL-22, and IL-18 are differentially involved in mediating C. jejuni-induced immunopathology of conventional infant mice.
Authors:Ana Beatriz Dein Terra Mota Ribeiro, Markus M. Heimesaat, and Stefan Bereswill
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.
Authors:Markus M. Heimesaat, Ulrike Escher, Anne Grunau, Ulrike Fiebiger, and Stefan Bereswill
Within 1 week following high-dose Toxoplasma gondii infection, mice develop lethal necrotizing ileitis. However, data from a subacute T. gondii-induced ileitis model are scarce. Therefore, mice harboring a human gut microbiota were perorally infected with one cyst of T. gondii. Within 9 days post-infection, the intestinal microbiota composition shifted towards higher loads of commensal enterobacteria and enterococci. Following T. gondii infection, mice were clinically only mildly affected, whereas ≈60% of mice displayed fecal blood and mild-to-moderate ileal histopathological changes. Intestinal inflammation was further characterized by increased apoptotic intestinal epithelial cells, which were accompanied by elevated proliferating gut epithelial cell numbers. As compared to naive controls, infected mice displayed elevated numbers of intestinal T lymphocytes and regulatory T-cells and increased pro-inflammatory mediator secretion. Remarkably, T. gondii-induced apoptotic and pro-inflammatory immune responses were not restricted to the gut, but could also be observed in extra-intestinal compartments including kidney, liver, and lung. Strikingly, low-dose T. gondii infection resulted in increased serum levels of pro- and anti-inflammatory cytokines. In conclusion, the here presented subacute ileitis model following peroral low-dose T. gondii infection of humanized mice allows for detailed investigations of the molecular mechanism underlying the “ménage à trois” of pathogens, human gut microbiota, and immunity.
Authors:Claudia Genger, Sigri Kløve, Soraya Mousavi, Stefan Bereswill, and Markus M. Heimesaat
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.
Authors:Samuel Füchtbauer, Soraya Mousavi, Stefan Bereswill, and Markus M. Heimesaat
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.
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.