New cross-kingdom communication mechanism found in gut bacteria

Dr Regis Stentz

Dr Regis Stentz

Researchers from the Institute of Food Research and the University of East Anglia have discovered how the beneficial bacteria in our guts communicate with our own cells. Here, Dr Regis Stentz of the GHFS programme talks about uncovering a novel signalling mechanism from commensal bacteria with potential to influence host epithelial cells and how this signal is protected from degradation in the gut.

Over the past few decades, it became clear to gut physiologists and microbiologists that the establishment of complex symbiotic relationships between the gut microbiome and the host intestinal cells is essential for health. It is known that commensal bacteria from the gut use diffusible small molecules such as hormones and nutrients to interact at a distance with the host. In this article, we describe a new crosstalk mechanism involving an enzyme packaged into outer membrane vesicles (OMVs) produced by the prevalent symbiotic gut bacterium, Bacteroides thetaiotaomicron.

First of all, our study has identified and characterised for the first time a homolog of a eukaryotic inositolphosphate signaling phosphatase, MINPP, in major species of human gut bacterial genomes. This is novel, as bacteria have not previously been thought to use the inositol phosphate signaling cascade (Michell, 2008).

Electron micrograph of Outer Membrane Vesicles (OMVs) - Kathryn Cross, IFR

Electron micrograph of Outer Membrane Vesicles (OMVs) – Kathryn Cross, IFR

One of the key questions we address in this manuscript is how MINPP expressed by B. thetaiotaomicron (BtMinpp) in the gut survives a hostile protease-containing environment and yet accesses extracellular InsP6 (phytate). We show that substantial InsP6 phosphatase activity is detected in OMVs and demonstrate the capacity of intact vesicles containing BtMinpp to degrade InsP6 in the external milieu including caecal contents of mice. These findings demonstrated that BtMinpp is retained inside the OMVs, which InsP6 must enter in order to access the BtMinpp phosphatase. 

It is well established that OMVs produced by some bacterial pathogens are capable of interacting with host cells to deliver virulence factors such as proteases and toxins (Ellis & Kuehn, 2010). We hypothesised therefore that a similar mechanism might be used by B. thetaiotaomicron OMVs to deliver BtMinpp into host intestinal epithelial cells. We demonstrated for the first time that BtMinpp interacts with the inositol polyphosphate signaling pathways of cultivated human epithelial cells and triggers the release of calcium from intracellular stores such as the endoplasmic reticulum, into the cytosol.

Graphical Abstract from Stentz et al, Cell Reports (2014) A Bacterial Homolog of a Eukaryotic Inositol Phosphate-Signaling Enzyme Mediates Cross-kingdom Dialog in the Mammalian Gut, Regis Stentz et al. will be published in the journal Cell Reports on 13th February 2014. doi: 10.1016/j.celrep.2014.01.021

Graphical Abstract from Stentz et al, Cell Reports (2014)  doi: 10.1016/j.celrep.2014.01.021

The physiological significance of InsP6 phosphatase activity in the human gut is multifactorial. First, there is nutritional benefit to both the host and the bacterial community from the inorganic phosphate and the inositol moiety that are both released by the phosphatase. Additionally, the hydrolysis of InsP6 eliminates its anti-nutritive properties, such as divalent ion chelation and inhibition of polysaccharide digestibility. High concentrations of InsP6 have been considered to have anti-carcinogenic properties in the human colon (Fox & Eberl, 2002; Vucenik & Shamsuddin, 2003). Our data reveal that commensal gut bacteria utilize OMVs in a manner that is beneficial to the host, by contributing to InsP6 homeostasis.

Furthermore, the ability of BtMinpp-containing OMVs to stimulate intracellular Ca2+ release in human colonic epithelial cells suggests a further biological significance to bacterial Minpps. The possibility for an enzyme to mediate dialog between gut bacteria and the human host is a novel addition to a field of research that has previously focused on the roles of diffusible, small-molecule hormones and nutrients.

Reference: A Bacterial Homolog of a Eukaryotic Inositol Phosphate-Signaling Enzyme Mediates Cross-kingdom Dialog in the Mammalian Gut, Regis Stentz et al. will be published in the journal Cell Reports on 13th February 2014. doi: 10.1016/j.celrep.2014.01.021

Ellis TN, Kuehn MJ (2010) Virulence and Immunomodulatory Roles of Bacterial Outer Membrane Vesicles. Microbiol Mol Biol R 74: 81-94

Fox CH, Eberl M (2002) Phytic acid (IP6), novel broad spectrum anti-neoplastic agent: a systematic review. Complement Ther Med 10: 229-234

Michell RH (2008) Inositol derivatives: evolution and functions. Nature reviews Molecular cell biology 9: 151-161

Vucenik I, Shamsuddin AM (2003) Cancer inhibition by inositol hexaphosphate (IP6) and inositol: From laboratory to clinic. J Nutr 133: 3778S-3784S

 

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The programme receives funding from the BBSRC - Biotechnology and Biological Sciences Research Council and involves leading researchers from the Institute of Food Research, Imperial College, University of East Anglia and St. Mark's Hospital and Academic Institute

Institute of Food ResearchImperial College LondonUniversity of East AngliaSt. Mark's Hospital and Academic InstituteBBSRC - Biotechnology and Biological Sciences Research Council