Beyond Digestion: The Pancreas Shapes Intestinal Microbiota and Immunity

Our understanding of the regulatory mechanisms that shape the gut microbiota is rapidly emerging. The intestinal microbial landscape is modulated by a plethora of host-extrinsic and host-intrinsic factors. In this issue of Cell Metabolism, Ahuja et al., 2017Ahuja M. Schwartz D.M. Tandon M. Son A. Zeng M. Swaim M. Eckhaus M. Hoffmann V. Cui Y. Xiao B. et al.Cell Metab. 2017; 25 (this issue): 635-646Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar demonstrate that mediators secreted by pancreatic acini shape the intestinal microbiota and intestinal immunity. Our understanding of the regulatory mechanisms that shape the gut microbiota is rapidly emerging. The intestinal microbial landscape is modulated by a plethora of host-extrinsic and host-intrinsic factors. In this issue of Cell Metabolism, Ahuja et al., 2017Ahuja M. Schwartz D.M. Tandon M. Son A. Zeng M. Swaim M. Eckhaus M. Hoffmann V. Cui Y. Xiao B. et al.Cell Metab. 2017; 25 (this issue): 635-646Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar demonstrate that mediators secreted by pancreatic acini shape the intestinal microbiota and intestinal immunity. The gut microbiota has recently evolved as an important player in the pathophysiology of intestinal and extraintestinal diseases (Marchesi et al., 2016Marchesi J.R. Adams D.H. Fava F. Hermes G.D. Hirschfield G.M. Hold G. Quraishi M.N. Kinross J. Smidt H. Tuohy K.M. et al.Gut. 2016; 65: 330-339Crossref PubMed Scopus (1357) Google Scholar). Development of culture-independent technologies and evolution of bioinformatics revealed the microbial complexity and overwhelming genetic information in this tissue over the last decade. A plethora of excellent studies demonstrated that a healthy microbiome is characterized by an enormous diversity and functional capacity. In contrast, an imbalance in the microbial composition and functionality, commonly termed dysbiosis, might be involved in disease processes of gastrointestinal and extraintestinal disorders. However, the regulation of the intestinal microbiota is incompletely understood. Recent studies suggest that exogenous and endogenous factors modulate the human microbiome. Probably one of the most critical influences on the microbial landscape is exerted by the human diet, with short- and long-term effects (David et al., 2014David L.A. Maurice C.F. Carmody R.N. Gootenberg D.B. Button J.E. Wolfe B.E. Ling A.V. Devlin A.S. Varma Y. Fischbach M.A. et al.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5616) Google Scholar). Other extrinsic microbial modulators are antibiotics and drugs (e.g., proton pump inhibitors [Imhann et al., 2016Imhann F. Bonder M.J. Vich Vila A. Fu J. Mujagic Z. Vork L. Tigchelaar E.F. Jankipersadsing S.A. Cenit M.C. Harmsen H.J. et al.Gut. 2016; 65: 740-748Crossref PubMed Scopus (646) Google Scholar]), environmental stressors, and exercise. Host-intrinsic factors such as age, gender, and genetics have been implicated in shaping the gut microbiota, in part by affecting host immune responses. Furthermore, bile acids appear to critically modulate the intestinal microbiota (Staley et al., 2017Staley C. Weingarden A.R. Khoruts A. Sadowsky M.J. Appl. Microbiol. Biotechnol. 2017; 101: 47-64Crossref PubMed Scopus (289) Google Scholar), which is licensed by the upper gastrointestinal tract (Ryan et al., 2014Ryan K.K. Tremaroli V. Clemmensen C. Kovatcheva-Datchary P. Myronovych A. Karns R. Wilson-Pérez H.E. Sandoval D.A. Kohli R. Bäckhed F. Seeley R.J. Nature. 2014; 509: 183-188Crossref PubMed Scopus (689) Google Scholar). In line with this, gastric surgery (i.e., bariatric surgery) profoundly affects the gut microbiome. The pancreas, however, has not been considered in the regulation of the gut microbiota. Ahuja and colleagues now demonstrate in this issue that peptides secreted by the pancreas critically control microbial communities in the intestine. When this function is compromised by timed genetic deletion of the Ca2+ channel Orai1 specifically in pancreatic acinar cells, detrimental intestinal bacterial overgrowth and inflammation emerges (Ahuja et al., 2017Ahuja M. Schwartz D.M. Tandon M. Son A. Zeng M. Swaim M. Eckhaus M. Hoffmann V. Cui Y. Xiao B. et al.Cell Metab. 2017; 25 (this issue): 635-646Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Pancreatic exocytosis of antimicrobials is mediated by Ca2+ influx from the endoplasmic reticulum which is controlled by Ca2+ channels such as ORAI calcium release-activated calcium modulator 1 (Orai1). Ahuja and colleagues demonstrate that timed deletion of Orai1 specifically in pancreatic acinar cells impaired Ca2+ signaling and exocytosis of cathelicidine-related antimicrobial peptide (CRAMP), which resulted in moderate pancreatic injury. Although genetic deletion of Orai1 was confined to the pancreas epithelium, the authors observed microbial alterations in the intestine and a bacterial overgrowth which could not be explained by defects in intestinal antimicrobial production. Surprisingly, in 65% of mice, Orai1 deletion in the pancreas was sufficient to induce death after 3 weeks in mice fed a standard solid diet which was associated with spontaneous CD3+ T cell infiltration and intestinal inflammation. Death of pancreas-specific Orai1 knockout mice could be rescued by oral supplementation of pancreatic antimicrobials (but not digestive enzymes) or by a comparable (i.e., isocaloric) liquid diet. These data indicate that pancreatic exocytosis of antimicrobial peptides controls intestinal microbial communities and inflammation. Vice versa, a recent study demonstrated that the production of pancreatic antimicrobials by β cells is controlled by microbiota-derived short-chain fatty acids (Sun et al., 2015Sun J. Furio L. Mecheri R. van der Does A.M. Lundeberg E. Saveanu L. Chen Y. van Endert P. Agerberth B. Diana J. Immunity. 2015; 43: 304-317Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). This appears to be of particular note, as pancreatic antimicrobials control pancreatic immune responses that regulate susceptibility to autoimmune diabetes in non-obese diabetic mice (Sun et al., 2015Sun J. Furio L. Mecheri R. van der Does A.M. Lundeberg E. Saveanu L. Chen Y. van Endert P. Agerberth B. Diana J. Immunity. 2015; 43: 304-317Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). CRAMP supplementation rescued the detrimental phenotype of pancreas-specific Orai1-deficient mice (Ahuja et al., 2017Ahuja M. Schwartz D.M. Tandon M. Son A. Zeng M. Swaim M. Eckhaus M. Hoffmann V. Cui Y. Xiao B. et al.Cell Metab. 2017; 25 (this issue): 635-646Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) and auto-immune diabetes (Sun et al., 2015Sun J. Furio L. Mecheri R. van der Does A.M. Lundeberg E. Saveanu L. Chen Y. van Endert P. Agerberth B. Diana J. Immunity. 2015; 43: 304-317Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). A similar protective effect of CRAMPs is documented for skin-related diseases (Reinholz et al., 2012Reinholz M. Ruzicka T. Schauber J. Ann. Dermatol. 2012; 24: 126-135Crossref PubMed Scopus (159) Google Scholar). In line with these observations, a recent study linked pancreatic antimicrobials with islet function (glucoregulation) and alterations in the gut microbiota (Pound et al., 2015Pound L.D. Patrick C. Eberhard C.E. Mottawea W. Wang G.S. Abujamel T. Vandenbeek R. Stintzi A. Scott F.W. Diabetes. 2015; 64: 4135-4147Crossref PubMed Scopus (41) Google Scholar). Collectively, these studies provide evidence for a close communication loop between the pancreas and the intestine. Disturbances in this loop may cause predisposition to pancreatic and intestinal disease, respectively (Figure 1). The study by Ahuja and colleagues (Ahuja et al., 2017Ahuja M. Schwartz D.M. Tandon M. Son A. Zeng M. Swaim M. Eckhaus M. Hoffmann V. Cui Y. Xiao B. et al.Cell Metab. 2017; 25 (this issue): 635-646Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) provides a prime example that the pancreas may protect against intestinal disease processes and dysbiosis. Several issues, however, remain poorly understood. For example, why do 35% of Orai1-knockout mice survive, and is the intestinal pathology indeed causing this detrimental phenotype? Do Cathelicidine-related peptides exhibit a protective effect(s) by modulation of the microbiota and/or through direct immuno-modulation? And, most importantly, how can these findings be translated into human physiology? More specifically, the report by Ahuja and colleagues poses this question: does the human pancreas regulate the intestinal microbiota? Pancreatectomy in humans may represent a valid clinical model to investigate postoperative changes and subsequent effects on the gut microbiota, although such studies are also limited by the fact that this surgical procedure is commonly performed in pancreatic cancers with often limited life expectancy. A first report assessed microbial alterations in fecal samples, pancreatic fluid, bile, and jejunal content of humans undergoing pancreaticoduodenectomy (Rogers et al., 2017Rogers M.B. Aveson V. Firek B. Yeh A. Brooks B. Brower-Sinning R. Steve J. Banfield J.F. Zureikat A. Hogg M. et al.Pancreas. 2017; 46: 260-267Crossref PubMed Scopus (38) Google Scholar). This study describes microbiota alterations with an enrichment of Klebsiella spp. and a decrease in benefical and potentially anti-inflammatory strains such as Faecalibacterium prausnitzii and Roseburia spp. (Rogers et al., 2017Rogers M.B. Aveson V. Firek B. Yeh A. Brooks B. Brower-Sinning R. Steve J. Banfield J.F. Zureikat A. Hogg M. et al.Pancreas. 2017; 46: 260-267Crossref PubMed Scopus (38) Google Scholar). Another interesting clinical entity may be chronic pancreatitis/pancreatic insufficiency, although it is currently unknown if this condition is also associated with impaired production of pancreatic antimicrobial peptides. If so, do patients with pancreatic insufficiency exhibit microbial alterations, and do these changes render individuals susceptible to intestinal disease? Similarly, the study of the human microbiota after pancreas transplantation may be of help to translate the observations by Ahuja and colleagues. Notably, clinicians have not linked pancreatic derrangements with intestinal inflammation until today. Collectively, this work sheds light on a novel link between pancreatic function and intestinal colonization which may impact on intestinal disease processes. The importance of these findings deserves further clinical investigations. Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate ImmunityAhuja et al.Cell MetabolismMarch 07, 2017In BriefWhile gut innate immunity is thought to be primarily maintained by intestinal epithelial cells, Ahuja et al. show that secretion of antimicrobials from pancreatic acinar cells regulates gut microbiota composition and innate immunity. Blocking acinar cell exocytosis in mice leads to gut dysbiosis, inflammation, systemic bacterial translocation, and ultimately death. Full-Text PDF Open Archive