Am J Physiol Gastrointest Liver Physiol 306: G824–G825, 2014; doi:10.1152/ajpgi.00435.2013.
Editorial Focus
Luminal ATP: the missing link between intestinal alkaline phosphatase, the gut microbiota, and inflammation? Jean-Paul Lallès INRA-ADNC, Saint-Gilles, France
feature to many inflammatory diseases but the cause-and-effect relationships between the gut microbiota and host inflammation are poorly understood. For metabolic disorders and obesity, however, bacterial lipopolysaccharide (LPS), an emblematic member of pathogen-associated molecular patterns (PAMPs), has been shown to promote metabolic inflammation and diet-induced obesity (DIO) in mice, e.g., after fat intake (2). Recently, Kaliannan et al. (6) demonstrated the ability of exogenous intestinal alkaline phosphatase (IAP) to prevent and reverse metabolic syndrome in mice. This important finding demonstrates IAP as a potent endogenous anti-inflammatory component. One major function of gut IAP is the detoxification of LPS by dephosphorylation, thus leading to repression of TLR4-dependent inflammatory cascade (4). Differences in IAP activities and inflammation between DIO-prone and DIO-resistant rats have been documented (3). Inflammation was suggested to cause microbiota disturbances but evidence was lacking. A role for IAP in shaping the microbiota has been proposed recently but the mechanisms were not elucidated (8). Free IAP detoxified PAMPs from dead but not live bacteria in vitro. By contrast, IAP bound to intestinal epithelial cell (IEC) could downregulate inflammatory cytokine (IL-8) production by IEC in presence of various gram-negative but not gram-positive bacteria. Last, cultured IEC expressing IAP could delay the growth of Escherichia coli, but not that of gram-positive bacteria. In this issue of American Journal of Physiology-Gastrointestinal and Liver Physiology, Hodin’s group from Harvard (9) provides the “missing link,” demonstrating how IAP shapes the gut microbiota indirectly by acting on luminal ATP and other nucleotide triphosphates (9). IAP by itself favors bacterial growth in the lumen whereas luminal ATP inhibits it dose dependently. This inhibition is reversed by exogenous IAP, which dephosphorylates, thus inactivating free ATP. Importantly, ATP differentially inhibits bacterial growth, targeting specifically gram-positive but not gram-negative bacteria. Extracellular ATP is normally inactivated by IEC ecto-ATPases but IAP seems more potent to do so. This major discovery links luminal ATP, gut microbiota, and inflammation (Fig. 1). Indeed, luminal ATP drives intestinal lamina propria differentiation of Th17 T lymphocytes (1). These cells are low in healthy intestine, but they increase dramatically during inflammation and infection. Importantly, intestinal level of Th17 cells depends on bacteria and TLR signaling, and luminal administration of ATP increases Th17 cell density and exacerbates colitis (1). Th17 cells secrete various cytokines, including IL-17 and IL-22. IL-17 induces neutrophil recruitment while both cytokines stimulate the production of antibacterial peptides, which in turn influence gut microbiota composition. IEC ecto-ATPases
GUT DYSBIOSIS IS A COMMON
Address for reprint requests and other correspondence: J.-P. Lallès, INRAADNC, F-35590 Saint-Gilles, France (e-mail: [email protected]). G824
Fig. 1. Luminal ATP, intestinal alkaline phosphatase, microbiota, and inflammation.
contribute to control luminal ATP and Th17 cell responses (7). However, amounts and roles of ATP secretion by bacteria and IECs are largely unknown. Exogenous IAP is effective in reducing inflammation in various models of colitis, peritonitis, sepsis, and metabolic syndrome (8). In humans, studies with exogenous IAP support its anti-inflammatory action in ulcerative colitis, coronary surgery, and sepsis-associated renal failure (8). The novel discovery of Malo et al. (9) opens new perspectives in microbiology, physiology, and nutrition. First, the mechanisms of secretion and roles of extracellular ATP in bacteria are poorly understood (5). Second, more is to be discovered on ATP secretion and hydrolysis at the IEC level (7) as well as in distant organs (10). Third, dietary modulation of gut pools of PAMPs, free ATP, and IAP activity deserves research as sustainable approach for minimizing (metabolic) inflammation (8). REFERENCES 1. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K. ATP drives lamina propria TH17 cell differentiation. Nature 455: 808 –812, 2008. 2. Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 15: 1546 –1558, 2009. 3. de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 299: G440 –G448, 2010. 4. Goldberg RF, Austen WG Jr, Zhang X, Munene G, Mostafa G, Biswas S, McCormack M, Eberlin KR, Nguyen JT, Tatlidede HS, Warren HS, Narisawa S, Millán JL, Hodin RA. Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc Natl Acad Sci USA 105: 3551–3556, 2008. 5. Hironaka I, Iwase T, Sugimoto S, Okuda K, Tajima A, Yanaga K, Mizunoe Y. Glucose triggers ATP secretion from bacteria in a growthphase-dependent manner. Appl Environ Microbiol 79: 2328 –2335, 2013. 6. Kaliannan K, Hamarneh SR, Economopoulos KP, Nasrin Alam S, Moaven O, Patel P, Malo NS, Ray M, Abtahi SM, Muhammad N, Raychowdhury A, Teshager A, Mohamed MM, Moss AK, Ahmed R,
0193-1857/14 Copyright © 2014 the American Physiological Society
http://www.ajpgi.org
Editorial Focus G825 Hakimian S, Narisawa S, Millán JL, Hohmann E, Warren HS, Bhan AK, Malo MS, Hodin RA. Intestinal alkaline phosphatase prevents metabolic syndrome in mice. Proc Natl Acad Sci USA 110: 7003–7008, 2013. 7. Kusu T, Kayama H, Kinoshita M, Jeon SG, Ueda Y, Goto Y, Okumura R, Saiga H, Kurakawa T, Ikeda K, Maeda Y, Nishimura J, Arima Y, Atarashi K, Honda K, Murakami M, Kunisawa J, Kiyono H, Okumura M, Yamamoto M, Takeda K. Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. J Immunol 190: 774 –783, 2013. 8. Lallès JP. Intestinal alkaline phosphatase: novel functions and protective effects. Nutr Rev 72: 82–94, 2014.
9. Malo MS, Muhammad N, Moaven O, Biswas B, Alam SN, Economopoulos KP, Gul SS, Hamarneh SR, Malo NS, Teshager A, Rafat Mohamed MM, Tao Q, Narisawa S, Millán JL, Hohmann EL, Warren HS, Robson SC, Hodin RA. Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotides. Am J Physiol Gastrointest Liver Physiol. First published April 10, 2014; doi:10.1152/ajpgi.00357.2013. 10. Pike AF, Kramer NI, Blaauboer BJ, Seinen W, Brands R. A novel hypothesis for an alkaline phosphatase ‘rescue’ mechanism in the hepatic acute phase immune response. Biochim Biophys Acta 1832: 2044 –2056, 2013.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00435.2013 • www.ajpgi.org
Editorial Focus
Luminal ATP: the missing link between intestinal alkaline phosphatase, the gut microbiota, and inflammation? Jean-Paul Lallès INRA-ADNC, Saint-Gilles, France
feature to many inflammatory diseases but the cause-and-effect relationships between the gut microbiota and host inflammation are poorly understood. For metabolic disorders and obesity, however, bacterial lipopolysaccharide (LPS), an emblematic member of pathogen-associated molecular patterns (PAMPs), has been shown to promote metabolic inflammation and diet-induced obesity (DIO) in mice, e.g., after fat intake (2). Recently, Kaliannan et al. (6) demonstrated the ability of exogenous intestinal alkaline phosphatase (IAP) to prevent and reverse metabolic syndrome in mice. This important finding demonstrates IAP as a potent endogenous anti-inflammatory component. One major function of gut IAP is the detoxification of LPS by dephosphorylation, thus leading to repression of TLR4-dependent inflammatory cascade (4). Differences in IAP activities and inflammation between DIO-prone and DIO-resistant rats have been documented (3). Inflammation was suggested to cause microbiota disturbances but evidence was lacking. A role for IAP in shaping the microbiota has been proposed recently but the mechanisms were not elucidated (8). Free IAP detoxified PAMPs from dead but not live bacteria in vitro. By contrast, IAP bound to intestinal epithelial cell (IEC) could downregulate inflammatory cytokine (IL-8) production by IEC in presence of various gram-negative but not gram-positive bacteria. Last, cultured IEC expressing IAP could delay the growth of Escherichia coli, but not that of gram-positive bacteria. In this issue of American Journal of Physiology-Gastrointestinal and Liver Physiology, Hodin’s group from Harvard (9) provides the “missing link,” demonstrating how IAP shapes the gut microbiota indirectly by acting on luminal ATP and other nucleotide triphosphates (9). IAP by itself favors bacterial growth in the lumen whereas luminal ATP inhibits it dose dependently. This inhibition is reversed by exogenous IAP, which dephosphorylates, thus inactivating free ATP. Importantly, ATP differentially inhibits bacterial growth, targeting specifically gram-positive but not gram-negative bacteria. Extracellular ATP is normally inactivated by IEC ecto-ATPases but IAP seems more potent to do so. This major discovery links luminal ATP, gut microbiota, and inflammation (Fig. 1). Indeed, luminal ATP drives intestinal lamina propria differentiation of Th17 T lymphocytes (1). These cells are low in healthy intestine, but they increase dramatically during inflammation and infection. Importantly, intestinal level of Th17 cells depends on bacteria and TLR signaling, and luminal administration of ATP increases Th17 cell density and exacerbates colitis (1). Th17 cells secrete various cytokines, including IL-17 and IL-22. IL-17 induces neutrophil recruitment while both cytokines stimulate the production of antibacterial peptides, which in turn influence gut microbiota composition. IEC ecto-ATPases
GUT DYSBIOSIS IS A COMMON
Address for reprint requests and other correspondence: J.-P. Lallès, INRAADNC, F-35590 Saint-Gilles, France (e-mail: [email protected]). G824
Fig. 1. Luminal ATP, intestinal alkaline phosphatase, microbiota, and inflammation.
contribute to control luminal ATP and Th17 cell responses (7). However, amounts and roles of ATP secretion by bacteria and IECs are largely unknown. Exogenous IAP is effective in reducing inflammation in various models of colitis, peritonitis, sepsis, and metabolic syndrome (8). In humans, studies with exogenous IAP support its anti-inflammatory action in ulcerative colitis, coronary surgery, and sepsis-associated renal failure (8). The novel discovery of Malo et al. (9) opens new perspectives in microbiology, physiology, and nutrition. First, the mechanisms of secretion and roles of extracellular ATP in bacteria are poorly understood (5). Second, more is to be discovered on ATP secretion and hydrolysis at the IEC level (7) as well as in distant organs (10). Third, dietary modulation of gut pools of PAMPs, free ATP, and IAP activity deserves research as sustainable approach for minimizing (metabolic) inflammation (8). REFERENCES 1. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K. ATP drives lamina propria TH17 cell differentiation. Nature 455: 808 –812, 2008. 2. Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 15: 1546 –1558, 2009. 3. de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 299: G440 –G448, 2010. 4. Goldberg RF, Austen WG Jr, Zhang X, Munene G, Mostafa G, Biswas S, McCormack M, Eberlin KR, Nguyen JT, Tatlidede HS, Warren HS, Narisawa S, Millán JL, Hodin RA. Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc Natl Acad Sci USA 105: 3551–3556, 2008. 5. Hironaka I, Iwase T, Sugimoto S, Okuda K, Tajima A, Yanaga K, Mizunoe Y. Glucose triggers ATP secretion from bacteria in a growthphase-dependent manner. Appl Environ Microbiol 79: 2328 –2335, 2013. 6. Kaliannan K, Hamarneh SR, Economopoulos KP, Nasrin Alam S, Moaven O, Patel P, Malo NS, Ray M, Abtahi SM, Muhammad N, Raychowdhury A, Teshager A, Mohamed MM, Moss AK, Ahmed R,
0193-1857/14 Copyright © 2014 the American Physiological Society
http://www.ajpgi.org
Editorial Focus G825 Hakimian S, Narisawa S, Millán JL, Hohmann E, Warren HS, Bhan AK, Malo MS, Hodin RA. Intestinal alkaline phosphatase prevents metabolic syndrome in mice. Proc Natl Acad Sci USA 110: 7003–7008, 2013. 7. Kusu T, Kayama H, Kinoshita M, Jeon SG, Ueda Y, Goto Y, Okumura R, Saiga H, Kurakawa T, Ikeda K, Maeda Y, Nishimura J, Arima Y, Atarashi K, Honda K, Murakami M, Kunisawa J, Kiyono H, Okumura M, Yamamoto M, Takeda K. Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. J Immunol 190: 774 –783, 2013. 8. Lallès JP. Intestinal alkaline phosphatase: novel functions and protective effects. Nutr Rev 72: 82–94, 2014.
9. Malo MS, Muhammad N, Moaven O, Biswas B, Alam SN, Economopoulos KP, Gul SS, Hamarneh SR, Malo NS, Teshager A, Rafat Mohamed MM, Tao Q, Narisawa S, Millán JL, Hohmann EL, Warren HS, Robson SC, Hodin RA. Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotides. Am J Physiol Gastrointest Liver Physiol. First published April 10, 2014; doi:10.1152/ajpgi.00357.2013. 10. Pike AF, Kramer NI, Blaauboer BJ, Seinen W, Brands R. A novel hypothesis for an alkaline phosphatase ‘rescue’ mechanism in the hepatic acute phase immune response. Biochim Biophys Acta 1832: 2044 –2056, 2013.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00435.2013 • www.ajpgi.org
