Crosstalk between microbiota, pathogens and the innate immune responses

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Abstract

Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis.

Section snippets

Microbiota and innate immune recognition

Research in the last 10 years has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence multiple developmental, metabolic and even neurological parameters of the host. This process starts shortly after birth (Lotz et al., 2006; Koenig et al., 2011; Fulde and Hornef, 2014) and is achieved by multiple, frequently redundant signals from transiently colonizing and residential microbial communities.

Impact of the microbiota on host cell death pathways during intestinal inflammation and microbial infection

The abundance of trillions of beneficial commensal microorganisms in the gastrointestinal tract that reside together with cells of the gut-associated immune system requires epithelial surfaces as an effective barrier in order to define host–microbial interaction and to conserve tissue homeostasis. This physical and biochemical barrier is established by the tight contact of intestinal epithelial cells through tight junctions and the mucus layer. Highly specialized intestinal epithelial cells

Antimicrobial peptides—Modulated by and regulators of the microbiota

Important components of the intestinal barrier include AMPs. On one hand, this barrier component is important to prevent commensals and pathogens from crossing the epithelium, and on the other hand, these host peptides shape the microbiota, while the microbiota can also shape AMP populations (Salzman, 2010). Thus, AMPs, in concert with mucus (Dupont et al., 2014; Cobo et al., 2015), are a well-controlled multi-level barrier and a major factor in keeping the balance between host and microbiota.

Crosstalk between the microbiota and the intestinal immune system—Signals, pathways, and innate immune cells

Pathogens and commensals can use various molecules, including TLR and NLR ligands, other factors, e.g. glycans (Stowell et al., 2014) and diverse metabolites, for instance short chain fatty acids (SCFA) (Castro et al., 2015), in order to influence host immunity and resident microbiota (Gronbach et al., 2014; Winter et al., 2010; Faber et al., 2015). The cellular signaling hubs Myd88 and TRAF6, which are harnessed, among others, by Toll-like receptors and cytokine receptors, are strongly engaged

How intestinal dysbiosis and pathogens act in concert to disturb the innate immune balance

It is well known by now that the disturbance of the intestinal microbiota, can, for instance by depletion of beneficial species, compromise immune cell maturation, migration and proliferation (Gaboriau-Routhiau et al., 2009), and also the resistance toward pathogen infection [termed “colonization resistance” (Stecher, 2015, Schubert et al., 2015)]. The underlying mechanisms are determined both by the protectivity of niche occupancy and by immunological influences in the intestinal tract (

Carcinogenic mechanisms linked to the immune environment provided by the intestinal microbiota

Concerning the intestinal milieu, evidence is fast accumulating that individuals with colorectal adenomas and carcinomas harbor a distinct microbiota (Ericsson et al., 2015, Dejea et al., 2014) and that the microbiota or intestinal dysbiosis contribute to colon cancer (Hold and Garrett, 2015, Louis et al., 2014, Gao et al., 2015, Sheflin et al., 2014, Irrazabal et al., 2014). It is a highly likely scenario that alterations to the gut microbiota may allow the outgrowth of bacterial populations

Conclusions and future perspectives

Microbiome research can build upon the above-mentioned modeling approaches and refined animal models as generators of testable hypotheses to find out more about its connection to immune response and pathology. The rich microbiota will hopefully be a future source of defined beneficial microbes that can also modulate the immune system (Ahern et al., 2014). In the same line of approaches, interventional strategies in humans to modulate the host immune system by addressing or reconstituting the

Acknowledgements

The German Research Foundation (DFG) is acknowledged for financial support of CG and JW (priority program SPP1656 “Intestinal Microbiota—a Microbial Ecosystem at the Edge between Immune Homeostasis and Inflammation”). CJ acknowledges funding from the DFG (SFB900 center grant) and German Center for Infection Research (DZIF). CG acknowledges funding by the Interdisciplinary Center for Clinical Research (IZKF) of the University Erlangen-Nuremberg. We thank all members of the consortium SPP1656 for

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