[Modulation of the intestinal microbiota by nutritional interventions]. / Modulation der intestinalen Mikrobiota durch Ernährungsinterventionen.

Humans live in symbiosis with billions of commensal bacteria. The so-called microbiota live on different biological interfaces such as the skin, the urogenital tract and the gastrointestinal tract. Commensal bacteria replace potentially pathogenic microbes, synthesize vitamins and ferment dietary fibre. An imbalance in the bacterial composition of the intestinal microbiota has been associated with various diseases including gut-associated disorders such as inflammatory bowel diseases, colorectal cancer and nonalcoholic fatty liver disease. Furthermore, a shift in the microbiota composition appears to be of pathophysiological relevance which renders the specific modulation of the intestinal microbiota a promising approach in the treatment of the above mentioned diseases. Our intestinal microbiota composition is mainly modulated by dietary macro- and micronutrients but also by secondary plant compounds and synthetic food additives such as emulsifiers and artificial sweeteners. Nutritional interventions with the purpose to modulate the intestinal microbiota show only limited therapeutic potential in the treatment of gut-associated disorders, which may be due to individual differences in the intestinal microbiota composition and a lack of specificity. A combination of newly established technical analytic approaches involving a machine-learning algorithm may bridge the currently existing limitations by providing a personalized, highly-specific and consequently therapeutically effective microbiota modulation.

Human kappa light chain targeted Pseudomonas exotoxin A--identifying human antibodies and Fab fragments with favorable characteristics for antibody-drug conjugate development.

Antibody-drug conjugates (ADC) represent promising agents for targeted cancer therapy. To allow rational selection of human antibodies with favorable characteristics for ADC development a screening tool was designed obviating the need of preparing individual covalently linked conjugates. Therefore, α-kappa-ETA' was designed as a fusion protein consisting of a human kappa light chain binding antibody fragment and a truncated version of Pseudomonas exotoxin A. α-kappa-ETA' specifically bound to human kappa light chains of human or human-mouse chimeric antibodies and Fab fragments. Antibody-redirected α-kappa-ETA' specifically inhibited proliferation of antigen-expressing cell lines at low toxin and antibody concentrations. Selected antibodies that efficiently delivered α-kappa-ETA' in the novel assay system were used to generate scFv-based covalently linked immunotoxins. These molecules efficiently triggered apoptosis of target cells, indicating that antibodies identified in our assay system can be converted to functional immunoconjugates. Finally, a panel of human epidermal growth factor receptor (EGFR) antibodies was screened--demonstrating favorable characteristics with antibody 2F8. These data suggest that antibodies with potential for Pseudomonas exotoxin A-based ADC development can be identified using the novel α-kappa-ETA' conjugate.

Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes.

Immunosenescence is characterized by a quantitative decline of adequate immune responses, which renders the elderly individual particularly susceptible to bacterial, viral and fungal pathogens. Whereas changes of the aging adaptive immune system (for example, reduced immunoglobulin secretion) have been extensively characterized, alterations of the innate immune system are still poorly understood. The aim of the present study was to systematically examine mRNA expression levels of innate immune genes and proinflammatory cytokines in peripheral and intestinal leukocytes of subjects of different ages. In both, whole blood samples and in colonic biopsies most of the Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain-like receptors (NLRs) transcript levels were significantly downregulated in elderly subjects (90-99 years). Older individuals, when compared to the younger, exhibited an increased expression and/or secretion of proinflammatory cytokines by peripheral and intestinal leukocytes as well as an increased level of nuclear factor-kappaB activation in colonic biopsies. The observed downregulation of TLRs and NLRs during the aging process may contribute to the lack of effective recognition of invading pathogens or the commensal flora. This effect results in aberrant secondary immune cell activation and could significantly contribute to morbidity and mortality at advanced age.