Gut T Cells Feast on GLP-1 to Modulate Cardiometabolic Disease

Glucagon-like peptide-1 (GLP-1) is an enteroendocrine hormone that controls insulin secretion, intestinal function, and food intake. Recently in Nature, He et al., 2019He S. Kahles F. Rattik S. Nairz M. McAlpine C.S. Anzai A. Selgrade D. Fenn A.M. Chan C.T. Mindur J.E. et al.Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.Nature. 2019; 566: 115-119Crossref PubMed Scopus (84) Google Scholar reported that gut intraepithelial T cells regulate GLP-1 bioavailability by capturing it on GLP-1 receptors and impacting L-cell numbers. This study delineates a novel endocrine-immune axis through which intestinal immune cells regulate whole-body metabolism. Glucagon-like peptide-1 (GLP-1) is an enteroendocrine hormone that controls insulin secretion, intestinal function, and food intake. Recently in Nature, He et al., 2019He S. Kahles F. Rattik S. Nairz M. McAlpine C.S. Anzai A. Selgrade D. Fenn A.M. Chan C.T. Mindur J.E. et al.Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.Nature. 2019; 566: 115-119Crossref PubMed Scopus (84) Google Scholar reported that gut intraepithelial T cells regulate GLP-1 bioavailability by capturing it on GLP-1 receptors and impacting L-cell numbers. This study delineates a novel endocrine-immune axis through which intestinal immune cells regulate whole-body metabolism. The intestinal immune system is emerging as an important modulator of whole-body metabolism, with the ability to impact aspects of metabolic syndrome. Metabolic syndrome features a cluster of conditions, including abdominal obesity, glucose intolerance, hypertension, and dyslipidemia, and is associated with increased risk of cardiovascular disease and type 2 diabetes. Prior work has shown that the composition of the intestinal immune system changes during obesity in mice and humans. Diet-induced obesity alters the gut microbiome and dietary metabolites, leading to increasing proportions of recruited macrophages and IFNγ-secreting T cells, along with reduced proportions of regulatory T cells, IL-17-secreting T cells (Th17), and IL-22-producing innate lymphoid cells within the gut (Winer et al., 2016Winer D.A. Luck H. Tsai S. Winer S. The intestinal immune system in obesity and insulin resistance.Cell Metab. 2016; 23: 413-426Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). Genetic ablation of the β7-integrin that homes immune cells to the gut can improve obesity-related insulin resistance and atherosclerosis in mouse models (Luck et al., 2015Luck H. Tsai S. Chung J. Clemente-Casares X. Ghazarian M. Revelo X.S. Lei H. Luk C.T. Shi S.Y. Surendra A. et al.Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.Cell Metab. 2015; 21: 527-542Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Zhi et al., 2014Zhi K. Li M. Zhang X. Gao Z. Bai J. Wu Y. Zhou S. Li M. Qu L. α4β7 integrin (LPAM-1) is upregulated at atherosclerotic lesions and is involved in atherosclerosis progression.Cell. Physiol. Biochem. 2014; 33: 1876-1887Crossref PubMed Scopus (16) Google Scholar), suggesting that this integrin, and potentially intestinal immune cells, has the capacity to impact cardiometabolic disease. An important question is how gut immune cells exert control over systemic metabolism and diet-related metabolic disease. Previously proposed mechanisms have centered around crosstalk with the gut microbiome and the immune system's ability to modify intestinal barrier function or maintain tolerance to luminal antigen (Winer et al., 2016Winer D.A. Luck H. Tsai S. Winer S. The intestinal immune system in obesity and insulin resistance.Cell Metab. 2016; 23: 413-426Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). However, in a recent Letter published in Nature, He et al. describe an exciting intestinal T cell-incretin axis that provides new insight into gut resident immune cells' capacity to regulate whole-body metabolism with important effects on metabolic syndrome (He et al., 2019He S. Kahles F. Rattik S. Nairz M. McAlpine C.S. Anzai A. Selgrade D. Fenn A.M. Chan C.T. Mindur J.E. et al.Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.Nature. 2019; 566: 115-119Crossref PubMed Scopus (84) Google Scholar). First, He et al. noticed that when β7-integrin-deficient mice, which contain reduced numbers of intraepithelial lymphocytes (IELs), were fed a normal chow diet (NCD), they exhibited heightened basal energy metabolism and improved glucose tolerance (He et al., 2019He S. Kahles F. Rattik S. Nairz M. McAlpine C.S. Anzai A. Selgrade D. Fenn A.M. Chan C.T. Mindur J.E. et al.Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.Nature. 2019; 566: 115-119Crossref PubMed Scopus (84) Google Scholar). When subjected to a high-fat, sugar, and sodium diet (HFSSD), the systemic lack of β7-integrin protected mice from developing features of metabolic syndrome, such as adipocyte hypertrophy, hypertension, and glucose intolerance. Furthermore, β7-integrin deficiency, as well as the administration of anti-β7-integrin blocking antibodies, a strong gut anti-inflammatory agent, protected mice from developing atherosclerosis and led to improved glucose tolerance in a high-cholesterol-diet model. Using mixed bone marrow approaches, the authors next isolated the cell types responsible for mediating protective metabolic effects. Consistent with T cells' reliance on β7-integrin to home to the gut, the authors showed that the specific absence of β7-integrin on either αβ or γδ T cells improved glucose tolerance. These findings point to an overall pathogenic role of gut-homing IELs, especially gut resident T cells, in mediating aspects of metabolic syndrome (He et al., 2019He S. Kahles F. Rattik S. Nairz M. McAlpine C.S. Anzai A. Selgrade D. Fenn A.M. Chan C.T. Mindur J.E. et al.Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.Nature. 2019; 566: 115-119Crossref PubMed Scopus (84) Google Scholar). Mechanistically, the authors observed that β7-integrin deficiency was associated with increased circulating levels of the incretin glucagon-like peptide-1 (GLP-1), coupled with an induction of gut proglucagon mRNA expression. The authors then confirmed that gut intraepithelial T cells express the GLP-1R, which can sequester GLP-1. Accordingly, loss of GLP-1R on β7-integrin-expressing cells led to increased numbers of GLP-1-producing L-cells, elevated total GLP-1 levels, and athero-protective effects (He et al., 2019He S. Kahles F. Rattik S. Nairz M. McAlpine C.S. Anzai A. Selgrade D. Fenn A.M. Chan C.T. Mindur J.E. et al.Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.Nature. 2019; 566: 115-119Crossref PubMed Scopus (84) Google Scholar). The study by He et al. thus delineates a novel immune-endocrine axis whereby intestinal immune cells regulate dietary metabolism and nutrient sensing through modulating intestinal L-cell numbers and GLP-1 bioavailability. This study raises several additional questions regarding immune-endocrine interactions surrounding GLP-1 and IELs. Specifically, are there additional means by which intraepithelial T cells modify GLP-1 levels in the body? How do the findings described by He et al. fit into the current literature on intestinal immunity and diet-induced metabolic disease? How necessary is GLP-1 in mediating the metabolic effects of gut T cells? Aside from sequestering GLP-1, IELs might regulate GLP-1 levels through further means (Figure 1). For instance, in addition to the GLP-1R, gut T cells potentially express dipeptidyl peptidase-4 (DPP4, CD26), which could function to inactivate GLP-1 (Klemann et al., 2016Klemann C. Wagner L. Stephan M. von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system.Clin. Exp. Immunol. 2016; 185: 1-21Crossref PubMed Scopus (262) Google Scholar). An immune stimulatory environment, such as during an HFSSD, could promote T cell activation and CD26 upregulation to facilitate this process. Moreover, during an HFSSD, T cells dictate the production of key inflammatory cytokines that could further impact L-cell GLP-1 secretion. For example, chronic exposure of intestinal L-cells to TNFα has been shown to reduce GLP-1 production (Gagnon et al., 2015Gagnon J. Sauvé M. Zhao W. Stacey H.M. Wiber S.C. Bolz S.S. Brubaker P.L. Chronic exposure to TNFα impairs secretion of glucagon-like peptide-1.Endocrinology. 2015; 156: 3950-3960Crossref PubMed Scopus (34) Google Scholar). Furthermore, during obesity, gut intraepithelial CD8αβ T cell-derived inflammatory cytokines can induce local insulin resistance in the gut epithelium (Monteiro-Sepulveda et al., 2015Monteiro-Sepulveda M. Touch S. Mendes-Sá C. André S. Poitou C. Allatif O. Cotillard A. Fohrer-Ting H. Hubert E.L. Remark R. et al.Jejunal T cell inflammation in human obesity correlates with decreased enterocyte insulin signaling.Cell Metab. 2015; 22: 113-124Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). As insulin potentiates GLP-1 secretion from L-cells (Lim et al., 2009Lim G.E. Huang G.J. Flora N. LeRoith D. Rhodes C.J. Brubaker P.L. Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell.Endocrinology. 2009; 150: 580-591Crossref PubMed Scopus (132) Google Scholar), it will be interesting to investigate whether L-cells become insulin resistant during HFSSD feeding, leading to reduced GLP-1 levels. Finally, the intestinal immune system produces a number of anti-microbial peptides and proteins with the capacity to alter microbial composition. As microbial products like short-chain fatty acids, secondary bile acids, endotoxins, and tryptophan metabolites can directly regulate L-cell GLP-1 production (Gribble and Reimann, 2019Gribble F.M. Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism.Nat. Rev. Endocrinol. 2019; (Published online February 13, 2019)https://doi.org/10.1038/s41574-019-0168-8Crossref PubMed Scopus (230) Google Scholar), a better understanding of how intestinal immune cells link the microbiome to L-cell biology will be important to advance this field. Indeed, current understanding of intestinal immune control of whole-body metabolism is centered on its role in interfacing with the gut microbiota and modulating intestinal barrier function. The new work by He et al. adds another facet to this story in which gut T cell interaction with local incretin peptides is a critical component. GLP-1R signaling in gut intraepithelial T cells has been shown to reduce inflammatory cytokine production and modulate epithelial repair genes in the gut (Yusta et al., 2015Yusta B. Baggio L.L. Koehler J. Holland D. Cao X. Pinnell L.J. Johnson-Henry K.C. Yeung W. Surette M.G. Bang K.W. et al.GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP-1R.Diabetes. 2015; 64: 2537-2549Crossref PubMed Scopus (136) Google Scholar). Thus, it is conceivable that GLP-1 may represent an important hormone directing gut immune cell composition enriched in barrier function-promoting cytokines like IL-10/17/22 at homeostasis. During diet-induced obesity, the inflammatory environment overcomes such beneficial effects and an increased number of IELs acts as a "sink" to reduce GLP-1 bioavailability. While the authors describe improved cardiometabolic effects in the absence of intestinal barrier alterations in β7-integrin-deficient mice fed an NCD, more work is needed to dissect the role of GLP-1 in modulating immune composition and intestinal barrier function during HFSSD conditions. Finally, while many of the improved cardiometabolic outcomes described in β7-integrin knockout mice may be linked to GLP-1, it will also be important to clarify GLP-1-independent mechanisms. For instance, increased energy expenditure in the β7-integrin knockout mouse was associated with increased food intake, though GLP-1 is typically considered an anorexigenic hormone. Whether this finding may be due to differing contributions of small intestinal versus colonic L-cell activity, including the ability of gut T cells to interact with other L-cell hormones, such as colonic L-cell-derived insulin-like peptide 5 (INSL5), a potentially orexigenic hormone, requires further investigation (Greiner and Bäckhed, 2016Greiner T.U. Bäckhed F. Microbial regulation of GLP-1 and L-cell biology.Mol. Metab. 2016; 5: 753-758Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Thus, understanding how the intestinal immune system might control food intake, heat production, and energy expenditure by means that are independent of GLP-1 would all be exciting avenues of future research derived from this study. Overall, the Letter by He et al. highlights a central role for gut immunity in regulating whole-body metabolism through interaction with the enteroendocrine system. This work opens up numerous studies to further dissect mechanistic actions and potential therapies targeted at the gut immune system to gain a better understanding of its role in governing metabolic homeostasis and cardiometabolic disease. D.A.W. is funded by a Canadian Institutes of Health Research (CIHR) New Investigator Foundation Grant FDN-148385 and a Canadian Liver Foundation operating grant (2017). D.A.W. holds a Canada Research Chair, Tier 2 in Immunometabolism, and an Ontario Ministry of Innovation Early Researcher Award. S.T. is a recipient of the National Research Council H.L. Holmes Postdoctoral Fellowship.