in parentheses

What the Gut? We have a schizophrenic cell in our intestines.

Michael Reginald Pitter / @pitterphoto / Michael is a writer, photographer and a PhD student in immunology at the University of Michigan. He co-founded In Parentheses with Phillipe as an undergraduate. His contributions to the magazine range from analog photography to philosophical essays to articles regarding current advancements in biomedical research. Michael is also interested in the experimental synthesis of art and science through his writings and visuals.

The human gut is complex. It contains multiple organ systems intertwined with our microbiota. The symbiosis spanning across species and organ systems baffle us while this knowledge contributes to advancements in the clinic. Out of the virtual infinity of cell types in the gut, the enteric glial cell (EGC) emerges as among the most unique because of its versatility. While it understands the ‘language’ of the nervous and immune systems and the microbiota, is it useful as a target for disease treatment?

The gut or the gastrointestinal (GI) tract is essentially a thoroughfare through which nutrients among other things are processed. It is one of our body’s gateways to the outside world. Within this digestive system microcosm, the nervous and the immune systems as well as the constellations of our microbiota coalesce. A system is composed of an interconnected network of various cell types communicating. Meanwhile, the microbiota consists of about 100 trillion individual bacteria belonging to different species each varying in abundance from human to human[1]. Good fences make good neighbors. Even at this intriguingly polarized intersection in biology, cooperation is still possible.

While it is seldom reported how the nervous system matters to the immune system and the microbiome, we know a great deal about how bacteria and the immune system are connected. Back in 1890s New York City, William Coley developed his ‘Coley’s toxins’, a rudimentary immunotherapeutic consisting of bacterial remnants that had real anticancer properties[2]. Today, there are numerous reports showing that certain gut microbes can enhance the efficacy of modern immunotherapies[3]^,[4]. This effect that bacteria have on immune cell functioning depends on the binding of bacterial chemicals to immune cell receptors that propagates signaling towards homeostasis or fighting disease[5]^,[6],[7]. The cells of the gut nervous system – EGCs and neurons – also carry receptors that can receive influential messages from microbes^7,[8],11-13. Out of the various cell types in the gut, EGCs are definitely among the least popular but arguably one of the most interesting.

EGCs have a dual personality; they are both a nervous and an immune cell. They nurture the growth, development and maintenance of neurons but can also initiate immune responses[9]^,[10]. Interestingly, they can also ‘communicate’ with gut microbes[11]^,[12],[13].

After a large meal, we humans can relate on the importance of neurons in our small intestine, colon and beyond! The gut nervous system or the enteric nervous system (ENS) regulates the mechanical work of peristalsis, stretching and contracting, moving materials along the GI tract⁷. The ENS also responds to chemical stimuli, adapting to changes in pH, molarity and nutrients⁷. These daily processes depend on glial cells because they serve the critical role in producing glial-derived neurotrophic factor (GDNF)⁹. This is food for neurons. GDNF promotes neuronal survival and proliferation and therefore is essential to the mechanical and chemical processes that happen in our guts 24-7⁹.

Beyond their service to neurons, EGCs have agency in coordinating immune responses and even mediating crosstalk between our gut microbes and the immune system^7,10-11. While the former is well-known, the latter needs more clarification. Symbiotic host-microbe interactions transmitted by glia is possible given the biological machinery present but our knowledge remains limited in this area^11,13. Contrarily, we know that under tissue-damaging environmental stressors in the gut, inflammatory processes will follow^10,15. Similar to the astroglia in the brain, the enteric glia will promote the cascade by rapidly dividing and releasing pro-inflammatory compounds such as nitric oxide and interleukin-6^10,[14]. This is all an effort to rebuild the gut walls and recruit immune cells’ help in repairing damage and disposing of dead tissues¹⁰. In chronic inflammatory bowel diseases such as Crohn’s or ulcerative colitis, this glial-immune response continues aberrantly to the detriment of the host^10,[15]. Enteric glial cell regulation of immune responses in the gut consists of balancing between repairing and promoting damage. In addition to taking part in this classic inflammatory response, EGCs can recognize a variety of gut microbes as well as pathogens and coordinate a distinct immune response¹¹. An exciting question for the future is whether glial responses to microbes can be harnessed and used in treatment.

The means by which enteric glial cells communicate with microbes and push signals onto the immune system are toll-like receptors (TLRs)⁴. As aforementioned, cell surface receptors make possible the essential connectedness between cells and tissues. These are major ports into our cellular circuits, necessary for the unison exhibited by organ systems. Fascinatingly, TLRs are ubiquitous in nature. Plants, insects, reptiles, fish and mammals all have TLRs because they all have a basic innate immune system endowed by nature and evolution for protection from harm[16]. Enteric glial cells express TLRs that can receive or bind bacterial components, which sends a signal into the cell, downstream through a circuit of proteins that facilitate the initiation of an immune response to the bacteria. EGCs can actually ‘sense’ whether the bacteria is good or bad and shapes the response accordingly^11,13. Interacting with probiotic bacteria will promote a positive homeostatic response qualifying to be what we say is “good for the immune system”. Contrarily, binding a pathogen will unleash an uncomfortable pro-inflammatory response. Thank you evolution.

A collision of organ systems and organisms happens in the gut making GI studies tricky. Out of this complexity emerge interesting and clinically important interactions between a kaleidoscopic network of entities. EGCs exist at the interface of two organ systems and have a functional relationship with gut microbes. The dynamic range of ways bacteria interact with host welcomes a future of endless possibilities in medicine. EGCs may constitute a target in treating diseases given its impact and modularity between microbes and our immune system.

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[1] Schmidt et al. The human gut microbiome: from association to modulation. Cell 2018. 172.

[2] Karbach et al. Phase I clinical trial of mixed bacterial vaccine (Coley’s Toxins) in patients with NY-ESO-1 expressing cancers: immunological effects and clinical activity. Clincal Cancer Research AACR 2012. 12: 1116.

[3] Routy et al. Gut microbiome influences efficacy of PD-1 – based immunotherapy against epithelial tumors. Science 2018. 359: 91-97.

[4] Vetizou et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015. 350: 1079-1084.

[5] Takeuchi et al. Pattern recognition receptors and inflammation. Cell 2010. 140: 805-820.

[6] Koh et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolities

[7] Yoo et al. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 2017. 46.

[8] Soret et al. Short chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology 2010. 138: 1772-1782.

[9] Anitha et al. Glial-derived neurotrophic factor modulates enteric neuronal survival and proliferation through neuropeptide Y. Gastroenterology 2006. 131: 1164-1178.

[10] Neunlist et al. Enteric glial cells: recent developments and future directions. Gastoenterology 2014. 147: 1230-1237.

[11] Turco et al. Enteroglial-derived S100B protein integrates bacteria-induced toll-like receptor signaling in human enteric glial cells. Gut 2014. 63: 105-115.

[12] Kabouridis et al. The gut microbiota keeps enteric glial cells on the move: prospective roles of the gut epithelium and immune system. Gut Microbes 2015.

[13] Kabouridis et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 2015. 85: 289-295.

[14] Wang et al. Nitric oxide mediates glial-induced neurodegeneration in Alexander disease. Nature Communications 2015. 6: 8966.

[15] von Boyen et al. Distribution of enteric glia and GDNF during gut inflammation. BMC Gastroenterol 2011. 11:3.

[16] Song et al. The evolution and origin of animal toll-like receptor signaling pathway revealed by network-level molecular evolutionary analyses. PLoS One 2012. 7(12): e51657.

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