Abstract
Gut barrier function is key in maintaining a balanced response between the host and its microbiome. The microbiota can modulate changes in gut barrier as well as metabolic and inflammatory responses. This highly complex system involves numerous microbiota-derived factors. The gut symbiont Akkermansia muciniphila is positively correlated with a lean phenotype, reduced body weight gain, amelioration of metabolic responses and restoration of gut barrier function by modulation of mucus layer thickness. However, the molecular mechanisms behind its metabolic and immunological regulatory properties are unexplored. Herein, we identify a highly abundant outer membrane pili-like protein of A. muciniphila MucT that is directly involved in immune regulation and enhancement of trans-epithelial resistance. The purified Amuc_1100 protein and enrichments containing all its associated proteins induced production of specific cytokines through activation of Toll-like receptor (TLR) 2 and TLR4. This mainly leads to high levels of IL-10 similar to those induced by the other beneficial immune suppressive microorganisms such as Faecalibacterium prausnitzii A2-165 and Lactobacillus plantarum WCFS1. Together these results indicate that outer membrane protein composition and particularly the newly identified highly abundant pili-like protein Amuc_1100 of A. muciniphila are involved in host immunological homeostasis at the gut mucosa, and improvement of gut barrier function.
Highlights
The human gastrointestinal (GI) tract provides a living environment for the complex and diverse microbiota, which is involved in many metabolic, nutritional, physiological and immunological interactions with the host [1].The host immune system plays an important role in distinguishing between commensal and pathogenic bacteria
Stimulation of peripheral blood mononuclear cells (PBMCs) with A. muciniphila MucT resulted in induction of both anti- and pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10 and TNF-α)
PBMCs were stimulated with the supernatants of these bacteria leading to a markedly different cytokine response for IL-10 and TNF-α, whereas IL-8 and IL-6 showed more similar patterns compared to live bacteria (Fig 2E–2H)
Summary
The human gastrointestinal (GI) tract provides a living environment for the complex and diverse microbiota, which is involved in many metabolic, nutritional, physiological and immunological interactions with the host [1].The host immune system plays an important role in distinguishing between commensal and pathogenic bacteria. The immune system needs to stay alert to recognize potential pathogens, and on the other hand, it has to tolerate the commensal bacteria inhabiting the gut [2]. This homeostasis is achieved through pattern recognition receptor (PRR) families expressed in immune cells. MAMPs are molecules associated with both commensal and pathogenic microorganisms Another important component of the mucosal immune system are the secretory immunoglobulins, such as IgA and IgG, which are secreted by plasma cells and function by excluding bacteria from the epithelium [3, 4]. There is growing evidence about the influence of the gut microbiota on the systemic immune system, and the development of autoimmune diseases [5]
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