A Germ of Understanding in the Gut Microbiome

Bacteria haven’t had much luck with the press.  Since the advent of germ theory in the 1800s, pathogenic bacteria – the disease-causing “bad apples” of the bacterial barrel – have hogged the spotlight in both science and popular imagination. This trend has started shifting over the last decade, as researchers have turned their attention toward the human microbiome: the trillions of bacteria, archaea, and other microbes which reside inside the human body (primarily the gastrointestinal tract) and are now known to contribute to host immunity, metabolism, and even behavior.

But how? By what mechanisms do these microscopic guests communicate with their host to exert such profound effects?  In contrast to well-characterized host-pathogen interactions, interactions between hosts and commensal (i.e., “friendly”) microbes have remained largely unexplored. In a recent collaborative study, Mark Ladinsky of the California Institute of Technology and Dr. Leandro Araujo of Columbia University sought to change that.

Ladinsky and Araujo focused their investigation on one class of microbes in particular: segmented filamentous bacteria (SFB), which make their home inside the small intestine of humans and other animals. Though these bacteria do not cause tissue damage or overt inflammation, they do stimulate an immune response in the host, resulting in the induction of immune cells that specifically recognize SFB and help control the population of these bacteria. This specificity relies on access of host cells to SFB antigens: foreign proteins or other distinctive components on bacterial targets that make them recognizable to immune cells. In the case of harmful bacteria, antigens arise in abundance as pathogens attack host cells and vice versa, but SFB don’t possess the machinery for invasion of host cells and show no hallmarks of destructive mechanisms. So how does the immune system come to recognize these peaceful residents? The answer, the scientists found, lies in a previously unknown communication pathway between commensal bacteria and host intestinal epithelial cells (IECs).

Using electron tomography, a technique that allows three-dimensional reconstruction of cellular and subcellular structures at high resolution, the authors found that IEC plasma membranes were forming small cavities exclusively where they interfaced with bacteria.  These cavities eventually bud off into bubble-like vesicles inside the host cell. This series of events at the host-bacteria interface was characteristic of normal cellular processes for bringing external substances into cells, known as endocytosis. Upon discovering that the observed vesicles contained a bacterial cell wall protein and common SFB antigen, the researchers confirmed that this pathway – which they termed “microbial adhesion-triggered endocytosis,” or “MATE” – served as a means by which SFB make their presence known to their host. Thus, host IECs can sample their commensal bacterial population without consuming and destroying whole microbial cells.  This peaceful transfer is likely advantageous in allowing the host to mount a mild immune response for SFB population control without triggering dramatic inflammation, though the mechanistic links between MATE and downstream immune effects remain unclear as of yet.

The authors, asking whether this unknown and surprisingly harmonious communication mechanism might be common among “healthy” microbes, next looked for signs of MATE among other classes of commensal intestinal bacteria, including those that are known to activate host immune responses similar to SFB responses. Though MATE communication was absent in all of the other species observed, the researchers noted that none of these microbes associated directly with IECs, as they observed in the case of SFB. Indeed, apart from SFB, the only microbes known to interact closely with IECs are bacterial pathogens, which themselves showed no signs of MATE signaling. These findings might indicate that MATE is a unique communication method specifically between host IECs and SFB (or other, as-yet-unidentified bacterial species), but they also suggest that strategies for crosstalk between microbes and hosts may be as diverse as the microbes themselves. 

Like MATE, many new pathways of host-commensal interaction might be awaiting discovery. Such pathways could someday open doors for alternative vaccine or drug-delivery strategies, reducing the necessity for much-dreaded needle shots. They may even facilitate therapies for regulating microbial populations as a revolutionary treatment for metabolic diseases like irritable bowel syndrome or obesity. If so, perhaps “germs” might get a little credit as heroes in the story of human health. Some good press at last.

 

Mark Ladinsky is an Electron Microscopy Scientist at the California Institute of Technology.  Dr. Leandro Araujo is a Postdoctoral Research Scientist in the Department of Microbiology & Immunology at Columbia University.

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