A surprising role for enteroendocrine cells and GLP-1 in regulating intestinal inflammation.
14 June 2023
Based on: Lebrun LJ, Lenaerts K, Kiers D, Pais de Barros JP, Le Guern N, Plesnik J, et al. Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion. Cell Rep. 2017;21(5):1160-8.
One of the most vexing issues in the field of inflammation research pertains to how the very bacteria and cells in the intestine that are required for host survival can also induce life-threatening inflammation. In its mildest form, inflammation in the gut may induce only brief discomfort or food intolerance, whereas in the extreme, gut inflammation can manifest as Crohn’s disease or ulcerative colitis, with life threatening implications. The precise factors that either accelerate or stop the development of inflammation in the intestine remain incompletely understood. The work of Lebrun et al now adds an important piece to this puzzle by describing a critical and previously unrecognized role for the gut-derived hormone glucagon-like-peptide 1 (GLP-1) in the regulation of intestinal inflammation.
Enteroendocrine cells (EECs) are specialized epithelial cells that are responsible for the release of a variety of gut hormones. Chief amongst the various hormones that are secreted from the EECs is GLP-1, a peptide whose actions result in the regulation of circulating glucose, the control of appetite, and the motivation for food intake. Agonists of the GLP-1 receptor have been developed to treat type 2 diabetes, and recent studies suggest that such agonists may also have important effects in the control of obesity1, 2. In foundational studies leading up to the current work, other authors have focused on the fact that enteric bacteria produce lipopolysaccharide (LPS) that can influence gut hormone release3, 4. LPS mainly acts through the activation of toll-like receptor 4 (TLR4), a membrane bound receptor that serves as a convergence point for both infectious and non-infectious stimuli, triggering a proinflammatory response5. Under normal physiological conditions, several mechanisms restrict LPS signaling within the gut lumen; however, in inflammatory disease states, particularly when intestinal barrier integrity and function may be compromised, LPS can enter the circulation, where it can activate TLR4 on inflammatory cells and trigger a systemic inflammatory response.
Lebrun et al. set out to determine whether enteroendocrine cells (EECs) could sense circulating LPS and thus release GLP-1 in order to modulate the pro-inflammatory response6. Starting with a murine ileum explant model, the authors showed that intraluminal LPS could stimulate GLP-1 secretion and that GLP-1 secretion was rapidly increased after direct LPS stimulation of an EEC cell line (STC-1 cells). Plasma levels of pro- and anti-inflammatory cytokines were increased in wild-type (WT) but not in TLR4-deficient (Tlr4−/−) mice, while GLP-1 secretion could be abolished when STC-1 cells were exposed to LPS in the presence of a TLR4 antagonist (TAK-242). These findings point to the critical role of TLR4 in coupling LPS to GLP-1 secretion.
Next, the authors used animal models to investigate the effect of LPS on GLP-1 secretion in the setting of compromised gut barrier function. They found that LPS administration either intravenously or intraperitoneally induced GLP-1 secretion, while no effects were observed when LPS was administered orally to mice with an intact intestinal barrier. In contrast, in models of compromised gut barrier function (DSS-induced colitis and mesenteric ischaemia/reperfusion injury models), oral administration of LPS increased GLP-1 secretion. This increase could be blunted by treatment with an antibiotic that binds to LPS (polymyxin B) or by a TLR4 antagonist (TAK-242). The authors also found that IL-6 was linked to the stimulation of GLP-1 secretion, as injection of LPS into IL-6 deficient mice led to an attenuated increase in GLP-1 release. Finally, the authors performed experiments on human subjects to evaluate the impact of LPS injection on plasma GLP-1 levels. Three hours after LPS injection, there was an observed increase in GLP-1 levels that was not seen after saline injection. The authors point out that other studies have shown heightened levels of circulating GLP-1 in critically ill patients7, who would presumably have some degree of impaired intestinal barrier function. In summary, these studies reveal that enteroendocrine cells and GLP-1 have roles that extend well beyond their known metabolic functions, suggesting they may be crucial sensors of gut injury.
There are several important implications of the current work. First, and most obviously, GLP-1 may emerge as a promising candidate biomarker for the early detection of gut injury in humans, while also representing a novel therapeutic target for the control of inflammation in the gut. Second, the canonical TLR4 pathway is now shown to be a crucial driver of the signals linking LPS to the stimulation of GLP-1 secretion. The ensuing negative feedback loop may involve not only EECs but also Paneth cells and intestinal intraepithelial lymphocytes, as these cells have been reported to express the receptor for GLP-1 (namely GLP-1R), and loss of GLP-1R increases the severity of DSS-induced intestinal injury8, 9. These results are also consistent with previous studies showing that GLP-1 analogues improve gut permeability and protect the gut against oxidative damage10, 11, strengthening the current work.
While the studies by Lebrun et al have exciting implications for the treatment of gut injury and critical illness, the precise cell types (i.e. immune vs. epithelial cells) that are responsible for recognizing LPS in order to induce the release of GLP-1 from EECs remain unknown. Moreover, the various steps by which GLP-1 can act to limit inflammation still remain unresolved. That said, the current work greatly advances our understanding of how bacterial signalling in the gut can both induce and also curtail intestinal inflammation, and reveals an exciting role for the gut hormone GLP-1 as a potential therapeutic target in the regulation of inflammatory diseases of the intestine.
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