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Dissecting the interplay between intestinal microbiota and host immunity in health and disease: Lessons learned from germfree and gnotobiotic animal models
Authors: Ulrike Fiebiger, Stefan Bereswill and Markus M. Heimesaat

This review elaborates the development of germfree and gnotobiotic animal models and their application in the scientific field to unravel mechanisms underlying host—microbe interactions and distinct diseases. Strictly germfree animals are raised in isolators and not colonized by any organism at all. The germfree state is continuously maintained by birth, raising, housing and breeding under strict sterile conditions. However, isolator raised germfree mice are exposed to a stressful environment and exert an underdeveloped immune system. To circumvent these physiological disadvantages depletion of the bacterial microbiota in conventionally raised and housed mice by antibiotic treatment has become an alternative approach. While fungi and parasites are not affected by antibiosis, the bacterial microbiota in these “secondary abiotic mice” have been shown to be virtually eradicated. Recolonization of isolator raised germfree animals or secondary abiotic mice results in a gnotobiotic state. Both, germfree and gnotobiotic mice have been successfully used to investigate biological functions of the conventional microbiota in health and disease. Particularly for the development of novel clinical applications germfree mice are widely used tools, as summarized in this review further focusing on the modulation of bacterial microbiota in laboratory mice to better mimic conditions in the human host.

Open access
Immunomodulatory and antimicrobial effects of vitamin C
Authors: Soraya Mousavi, Stefan Bereswill and Markus M. Heimesaat

Humans have lost their vitamin C-synthesizing capacities during evolution. Therefore, the uptake of this essential compound from external sources is mandatory in order to prevent vitamin C-deficient conditions resulting in severe morbidities such as scurvy. The potent antioxidant, immunomodulatory, and antiinfectious effects of vitamin C are known since the 1930s. We here (i) review the impact of vitamin C on innate and adaptive immune functions, (ii) provide an overview of its antimicrobial, antibacterial, antiviral, antiparasitic, and antifungal properties, and finally, (iii) discuss vitamin C as an adjunct treatment option for the combat of human infections by bacteria, particularly by emerging multidrug-resistant species.

Open access

Antimicrobial multidrug-resistance (MDR) constitutes an emerging threat to global health and makes the effective prevention and treatment of many, particularly severe infections challenging, if not impossible. Many antibiotic classes have lost antimicrobial efficacy against a plethora of infectious agents including bacterial species due to microbial acquisition of distinct resistance genes. Hence, the development of novel anti-infectious intervention strategies including antibiotic-independent approaches is urgently needed. Vitamins such as vitamin D and vitamin D derivates might be such promising molecular candidates to combat infections caused by bacteria including MDR strains. Using the Pubmed database, we therefore performed an in-depth literature survey, searching for publications on the antimicrobial effect of vitamin D directed against bacteria including MDR strains. In vitro and clinical studies between 2009 and 2019 revealed that vitamin D does, in fact, possess antimicrobial properties against both Gram-positive and Gram-negative bacterial species, whereas conflicting results could be obtained from in vivo studies. Taken together, the potential anti-infectious effects for the antibiotic-independent application of vitamin D and/or an adjunct therapy in combination with antibiotic compounds directed against infectious diseases such as tuberculosis, H. pylori infections, or skin diseases, for instance, should be considered and further investigated in more detail.

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Fecal microbiota transplantation decreases intestinal loads of multi-drug resistant Pseudomonas aeruginosa in murine carriers
Authors: Katharina Mrazek, Stefan Bereswill and Markus M. Heimesaat

Intestinal carriage of multi-drug resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (Psae) constitutes a pivotal prerequisite for subsequent fatal endogenous infections in patients at risk. We here addressed whether fecal microbiota transplantation (FMT) could effectively combat MDR-Psae carriage. Therefore, secondary abiotic mice were challenged with MDR-Psae by gavage. One week later, mice were subjected to peroral FMT from either murine or human donors on 3 consecutive days. Irrespective of murine or human origin of fecal transplant, intestinal MDR-Psae loads decreased as early as 24 h after the initial FMT. Remarkably, the murine FMT could lower intestinal MDR-Psae burdens by approximately 4 log orders of magnitude within 1 week. In another intervention study, mice harboring a human gut microbiota were perorally challenged with MDR-Psae and subjected to murine FMT on 3 consecutive days, 1 week later. Strikingly, within 5 days, murine FMT resulted in lower loads and carrier rates of MDR-Psae in mice with a human gut microbiota. In conclusion, FMT might be a promising antibiotics-independent option to combat intestinal MDR-Psae carriage and thus prevent from future endogenous infections of patients at risk.

Open access
Multidrug-resistant Pseudomonas aeruginosa induce systemic pro-inflammatory immune responses in colonized mice
Authors: Eliane von Klitzing, Stefan Bereswill and Markus M. Heimesaat

The World Health Organization has rated multidrug-resistant (MDR) Pseudomonas aeruginosa as a critical threat to human health. In the present study, we performed a survey of intestinal colonization, and local and systemic immune responses following peroral association of secondary abiotic mice with either a clinical MDR P. aeruginosa or a commensal murine Escherichia coli isolate. Depletion of the intestinal microbiota following antibiotic treatment facilitated stable intestinal colonization of both P. aeruginosa and E. coli that were neither associated with relevant clinical nor histopathological sequelae. Either stable bacterial colonization, however, resulted in distinct innate and adaptive immune cell responses in the intestines, whereas a pronounced increase in macrophages and monocytes could be observed in the small as well as large intestines upon P. aeruginosa challenge only, which also applied to colonic T lymphocytes. In addition, TNF secretion was exclusively elevated in large intestines of P. aeruginosa-colonized mice. Strikingly, association of secondary abiotic mice with MDR P. aeruginosa, but not commensal E. coli, resulted in pronounced systemic pro-inflammatory responses, whereas anti-inflammatory responses were dampened. Hence, intestinal carriage of MDR P. aeruginosa as compared to a mere commensal Gram-negative strain in otherwise healthy individuals results in distinct local and systemic pro-inflammatory sequelae.

Open access
Toll-like receptor-4 dependent inflammatory responses following intestinal colonization of secondary abiotic IL10-deficient mice with multidrug-resistant Pseudomonas aeruginosa
Authors: Anne Grunau, Ulrike Escher, Stefan Bereswill and Markus M. Heimesaat

The rising incidences of infections with multidrug-resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have gained increasing attention in medicine, but also in the general public and global health politics. The mechanisms underlying opportunistic pathogen—host interactions are unclear, however. To address this, we challenged secondary abiotic IL10−/− mice deficient for Toll-like receptor-4 (TLR4−/− × IL10−/−), the main receptor of the Gram-negative cell wall constituent lipopolysaccharide, with a clinical MDR PA isolate. Despite higher intestinal colonization densities, apoptotic colonic epithelial cell numbers were lower in TLR4−/− × IL10−/− mice as compared to IL10−/− controls at day 14 postinfection (p.i.), whereas proliferating/regenerating cells had increased in the latter only. Furthermore, PA-colonized TLR4−/− × IL10−/− mice displayed less distinct innate and adaptive immune cell responses in the colon as compared to IL10−/− counterparts that were accompanied by lower nitric oxide concentrations in mesenteric lymph nodes in the former at day 14 p.i. Conversely, splenic NO levels were higher in both naive and PA-colonized TLR4-deficient IL10−/− mice versus IL10−/− controls. Remarkably, intestinal MDR PA was able to translocate to extra-intestinal including systemic compartments of TLR4−/− × IL10−/− mice only. Hence, MDR PA-induced intestinal and systemic immune responses observed in secondary abiotic IL10−/− mice are TLR4-dependent.

Open access
Intestinal expression of genes encoding inflammatory mediators and gelatinases during Arcobacter butzleri infection of gnotobiotic IL-10 deficient mice
Authors: Markus M. Heimesaat, Thomas Alter, Stefan Bereswill and Greta Gölz

We have previously shown that Arcobacter butzleri induces intestinal, extra-intestinal, and systemic immune responses in perorally infected gnotobiotic IL-10−/− mice in a strain-dependent fashion. Here, we present a comprehensive survey of small and large intestinal expression profiles of inflammatory and regulatory mediators as well as of the matrix-degrading gelatinases MMP-2 and MMP-9 following murine A. butzleri infection. Gnotobiotic IL-10−/− mice were infected with A. butzleri strains CCUG 30485 or C1 of human and chicken origin, respectively. At day 6 following A. butzleri infection, mucin-2 mRNA, an integral part of the intestinal mucus layer, was downregulated in the colon, whereas TNF and IL-23p19 mRNA were upregulated in the ileum. Furthermore, IFN-γ, IL-17A, IL-1β, and IL-22 mRNA were upregulated in both colonic and ileal ex vivo biopsies at day 6 post strain CCUG 30485 infection. These changes were accompanied by downregulated colonic MMP-9 levels, whereas both MMP-2 and MMP-9 mRNA were upregulated in the ileum. In conclusion, these data indicate that A. butzleri infection induces changes in the expression of genes involved in pro-inflammatory and regulatory immune responses as well as in tissue degradation.

Open access
Toll-like receptor-4 dependent intestinal gene expression during Arcobacter butzleri infection of gnotobiotic IL-10 deficient mice
Authors: Greta Gölz, Thomas Alter, Stefan Bereswill and Markus M. Heimesaat

We have previously shown that Arcobacter butzleri infection induces Toll-like receptor (TLR) -4 dependent immune responses in perorally infected gnotobiotic IL-10−/− mice. Here, we analyzed TLR-4-dependent expression of genes encoding inflammatory mediators and matrix-degrading gelatinases MMP-2 and -9 in the small and large intestines of gnotobiotic TLR-4-deficient IL-10−/− mice that were perorally infected with A. butzleri strains CCUG 30485 or C1, of human and chicken origin, respectively. At day 6 following A. butzleri infection, colonic mucin-2 mRNA, as integral part of the intestinal mucus layer, was downregulated in the colon, but not ileum, of IL-10−/− but not TLR-4−/− IL-10−/− mice. CCUG 30485 strain-infected TLR-4-deficient IL-10−/− mice displayed less distinctly upregulated IFN-γ, IL-17A, and IL-1β mRNA levels in ileum and colon, which was also true for colonic IL-22. These changes were accompanied by upregulated colonic MMP-2 and ileal MMP-9 mRNA exclusively in IL-10−/− mice. In conclusion, TLR-4 is essentially involved in A. butzleri mediated modulation of gene expression in the intestines of gnotobiotic IL-10−/− mice.

Open access
Finding novel antibiotic substances from medicinal plants — Antimicrobial properties of Nigella sativa directed against multidrug resistant bacteria
Authors: Seher Nancy Bakal, Stefan Bereswill and Markus M. Heimesaat

The progressive rise in multidrug-resistant (MDR) bacterial strains poses serious problems in the treatment of infectious diseases. While the number of newly developed antimicrobial compounds has greatly fallen, the resistance of pathogens against commonly prescribed drugs is further increasing. This rise in resistance illustrates the need for developing novel therapeutic and preventive antimicrobial options. The medicinal herb Nigella sativa and its derivatives constitute promising candidates. In a comprehensive literature survey (using the PubMed data base), we searched for publications on the antimicrobial effects of N. sativa particularly directed against MDR bacterial strains. In vitro studies published between 2000 and 2015 revealed that N. sativa exerted potent antibacterial effects against both Gram-positive and Gram-negative species including resistant strains. For instance, N. sativa inhibited the growth of bacteria causing significant gastrointestinal morbidity such as Salmonella, Helicobacter pylori, and Escherichia coli. However, Listeria monocytogenes and Pseudomonas aeruginosa displayed resistance against black cumin seed extracts. In conclusion, our literature survey revealed potent antimicrobial properties of N. sativa against MDR strains in vitro that should be further investigated in order to develop novel therapeutic perspectives for combating infectious diseases particularly caused by MDR strains.

Open access
Can microbiota transplantation abrogate murine colonization resistance against Campylobacter jejuni?
Authors: Markus M. Heimesaat, R. Plickert, A. Fischer, U. B. Göbel and S. Bereswill


Enterocolitis caused by Campylobacter jejuni represents an important socioeconomic burden worldwide. The host-specific intestinal microbiota is essential for maintaining colonization resistance (CR) against C. jejuni in conventional mice. Notably, CR is abrogated by shifts of the intestinal microbiota towards overgrowth with commensal E. coli during acute ileitis. Thus, we investigated whether oral transplantation (TX) of ileal microbiota derived from C. jejuni susceptible mice with acute ileitis overcomes CR of healthy conventional animals. Four days following ileitis microbiota TX or ileitis induction and right before C. jejuni infection, mice displayed comparable loads of main intestinal bacterial groups as shown by culture. Eight days following ileitis induction, but not ileal microbiota TX, however, C. jejuni could readily colonize the gastrointestinal tract of conventional mice and also translocate to extra-intestinal tissue sites such as mesenteric lymph nodes, spleen, liver, and blood within 4 days following oral infection. Of note, C. jejuni did not further deteriorate histopathology following ileitis induction. Lack of C. jejuni colonization in TX mice was accompanied by a decrease of commensal E. coli loads in the feces 4 days following C. jejuni infection. In summary, oral ileal microbiota TX from susceptible donors is not sufficient to abrogate murine CR against C. jejuni.

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