Abstract
Compelling evidence demonstrates the pivotal role of the commensal intestinal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. Aim of this study was to investigate the impact of antibiotics induced depletion and subsequent restoration of the intestinal microbiota composition on the murine mucosal and systemic immunity. To address this, conventional C57BL/6j mice were subjected to broad-spectrum antibiotic treatment for 8 weeks. Restoration of the intestinal microbiota by peroral fecal microbiota transplantation (FMT) led to reestablishment of small intestinal CD4+, CD8+, and B220+ as well as of colonic CD4+ cell numbers as early as 7 days post-FMT. However, at d28 following FMT, colonic CD4+ and B220+ cell numbers were comparable to those in secondary abiotic (ABx) mice. Remarkably, CD8+ cell numbers were reduced in the colon upon antibiotic treatment, and FMT was not sufficient to restore this immune cell subset. Furthermore, absence of gut microbial stimuli resulted in decreased percentages of memory/effector T cells, regulatory T cells, and activated dendritic cells in the small intestine, colon, mesenteric lymph nodes (MLN), and spleen. Concurrent antibiotic treatment caused decreased cytokine production (IFN-γ, IL-17, IL-22, and IL-10) of CD4+ cells in respective compartments. These effects were, however, completely restored upon FMT. In summary, broad-spectrum antibiotic treatment resulted in profound local (i.e., small and large intestinal), peripheral (i.e., MLN), and systemic (i.e., splenic) changes in the immune cell repertoire that could, at least in part, be restored upon FMT. Further studies need to unravel the distinct molecular mechanisms underlying microbiota-driven changes in immune homeostasis subsequently providing novel therapeutic or even preventive approaches in human immunopathologies.
Highlights
The human gastrointestinal tract harbors a plethora of microorganisms, including bacteria, viruses, fungi, helminths, and protozoa that are referred to as commensal microbiota
We have focused on the effects of a complex murine microbiota on the immune system following antibiotics induced impairments of the intestinal ecosystem and of peripheral as well as systemic immune functions
Whether the here displayed beneficial restoring effects exerted by reintroduced microbial antigens are due to the large bacterial loads, complexity and/or diversity of the introduced complex microbiota, or whether distinct species in concert with each other play a more important role in an orchestrated fashion, with the host immune system as the conductor, should be unraveled in more detail, but appears literally rather as a search for the needle in the hay stack
Summary
The human gastrointestinal tract harbors a plethora of microorganisms, including bacteria, viruses, fungi, helminths, and protozoa that are referred to as commensal microbiota. Constitute the vast majority of the intestinal microbiota [1]. A recent study revealed that the ratio of human cells and bacteria is close to 1:1 with absolute numbers approximating 1013 each [2]. A more detailed examination of distinct hostmicrobiota interactions remains of utmost interest. Under steadystate conditions, this interaction is largely defined by mutual benefits. The host provides the microbiota with a physiological niche in a nutrient rich environment, while the microbiota exerts various beneficial functions for the host such as vitamin production [3], digestion of dietary compounds [4], and protection from pathogens [5]
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