Leading Edge
Previews Gut Microbiota: The Link to Your Second Brain Vanessa Ridaura1,2 and Yasmine Belkaid1,2,* 1Program
in Barrier Immunity and Repair Immunology Section, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD 20892, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2015.03.033 2Mucosal
Serotonin is a highly ubiquitous signaling molecule that plays a role in the regulation of various physiological functions. Several lines of evidence, including the present work from Hsiao and colleagues, demonstrate that, in the gut, microbial-derived metabolites affect the production of serotonin that in turn impacts host physiological functions. The body’s epithelial surfaces act as a scaffold to sustain diverse communities of commensals that include bacteria, archaea, fungi, protozoa, and virus. Although the notion that these microbial partners can promote human health is not a recent concept, the extent to which the microbiota controls all physiological systems has only recently begun to be appreciated. Of particular interest are the recent lines of investigation linking the microbiota to both the hormonal and nervous systems. In this context, a set of recent findings, including the work of Hsiao and colleagues, uncovers a role for the microbiota in controlling the production of a major neurotransmitter, serotonin. In 1967, Abrams and Bishop showed that animals devoid of live microbes (germ-free) had decreased gut motility compared to animals harboring a conventional mouse microbiota (Abrams and Bishop, 1967). Decreased serotonin levels in the absence of microbes have been proposed as a potential cause for this defect (Wikoff et al., 2009; Kashyap et al., 2013). Serotonin is a highly ubiquitous signaling molecule that plays a fundamental role in the regulation of various physiological functions via its action as both a neurotransmitter and a hormone. The vast majority of serotonin is produced in the gut by enterochromaffin cells, a specialized subset of cells strategically positioned to respond to chemical and mechanical stimuli (Figure 1). As a single molecule, serotonin has a remarkably wide range of effects on host physiology, ranging from the control of gut motility, secretory reflexes, platelet ag-
gregation, bone development, and cardiac function to the regulation of immune responses (Mawe and Hoffman, 2013). Germ-free mice display depressed levels of this neurotransmitter compared to conventionally raised animals (Wikoff et al., 2009). Colonization of germ-free animals with the gut microbiota from humans or mice can significantly accelerate gut transit time, an effect that can be partially blocked using a pharmacologic antagonist of a serotonin receptor (Kashyap et al., 2013). In the present issue of Cell, the work of Yano et al. (2015), together with previous lines of evidence, proposes a model in which microbial-derived metabolites, such as short-chain fatty acids (i.e., butyrate and acetate) or secondary bile acids (specifically deoxycolate), directly act upon enterochromaffin cells (ECs), inducing transcription of the rate-limiting serotonin biosynthetic enzyme thp1 (Yano et al., 2015; Fukumoto et al., 2003; Reigstad et al., 2014; Figure 1). A link between microbiota-derived metabolic products and enterochromaffin cell function has been previously reported by Reigstad et al., where they propose that short-chain fatty acids can modulate transcription of Chga gene, which encodes the neuroendocrine secretory protein chromogranin A, released together with serotonin (Figure 1). These results were corroborated by Yano et al. and correlated, in treated mice, with decreased transit time. Further, via increase in serotonin production, the presence of the microbiota was associated with increased platelet activation and aggregation, find-
ings that help to explain the improved coagulation at the site of injury in animals harboring a gut microbiota compared to germ-free mice. Of interest is the diversity of microbial-derived metabolites that can increase serotonin production, supporting the idea that the mechanisms controlling this brain-gut interaction are redundant and are unlikely to be affected by subtle microbial shifts. Because of the fundamental importance of serotonin in mediating central body functions, such redundancy may have been maintained as a means to sustain the production of this neurotransmitter in the face of constitutive microbial fluctuation. Nonetheless, not all microbes are equally efficient at promoting serotonin production. Yano et al. correlated the localized changes of serotonin with the presence of sporeforming bacteria, primarily from the Clostridium genus. Given the diversity of microbially derived metabolites, it is unlikely that a defined microbe will be associated with this effect. The mechanism by which the microbiota promotes serotonin production and, in particular, if and how enterochromaffin cells directly respond to microbiota-derived products and metabolites remain unclear. Furthermore, the systemic effects of this control on distal tissues and peripheral function are still unknown. Of interest, and yet to be studied, is the effect that increased serotonin may have on the ecology and metabolism of the gut microbiota (Figure 1). Serotonin can act directly or indirectly on the immune system, which in turn can shape the microbiota composition and localization.
Cell 161, April 9, 2015 ª2015 Elsevier Inc. 193
intestinal disorders (Manocha and Khan, 2012). Based on the present findings, further understanding of the mechanism by which the microbiota regulates host’s serotonin levels may be a first step toward developing pro- and/or prebiotic strategies to complement or potentially replace existing clinical treatments. ACKNOWLEDGMENTS This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health.
REFERENCES Abrams, G.D., and Bishop, J.E. (1967). Proc. Soc. Exp. Biol. Med. 126, 301–304.
Figure 1. Role of the Microbiota in Serotonin Production The gut microbiota influences the number and function of enterochromaffin cells, thereby promoting the release of serotonin (5-HT). The microbiota promotes serotonin production via various metabolites, including short-chain fatty acid (SCFA). Serotonin can act on various physiological systems promoting gut motility, secretory reflexes, and platelet function. The action of serotonin can be local as well as distal (on bone development and cardiac function) via platelet-mediated transport. Serotonin can also influence the immune system, an effect that could feed back on enterochromaffin cells and the microbiota itself. Defined microbes have also been shown to produce serotonin, a pathway that may further link the microbiota and host serotonin levels.
Fukumoto, S., Tatewaki, M., Yamada, T., Fujimiya, M., Mantyh, C., Voss, M., Eubanks, S., Harris, M., Pappas, T.N., and Takahashi, T. (2003). Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1269–R1276. Kashyap, P.C., Marcobal, A., Ursell, L.K., Larauche, M., Duboc, H., Earle, K.A., Sonnenburg, E.D., Ferreyra, J.A., Higginbottom, S.K., Million, M., et al. (2013). Gastroenterology 144, 967–977. Manocha, M., and Khan, W.I. (2012). Clin. Transl. Gastroenterol. 3, e13. Mawe, G.M., and Hoffman, J.M. (2013). Nature Rev. Gastroenterol. Hepatol. 10, 473–486.
The feedback loop associated with this control remains to be explored. Microbially induced changes in serotonin concentrations may regulate the host’s immune response and may subsequently influence how the host deals with pathogens or commensals. Of interest, defined microbes themselves can produce serotonin (O’Mahony et al., 2015); this raises the question of whether serotonin can play a direct role in microbial metabolism or in the maintenance of the ecological niche of certain phylogenetic groups (i.e., spore-forming bacteria).
An important line of future investigation will be to explore how microbiota control of serotonin levels contributes to mucosal disorders, a question of particular importance because of the known role of serotonin in promoting immunity and inflammation. Of interest, in various models of mucosal inflammation or infections, as well as in Celiac disease patients, serotonin levels are significantly increased (Mawe and Hoffman, 2013). Further, both antagonists and agonists to the serotonin receptor have been used to clinically treat a variety of gastro-
194 Cell 161, April 9, 2015 ª2015 Elsevier Inc.
O’Mahony, S.M., Clarke, G., Borre, Y.E., Dinan, T.G., and Cryan, J.F. (2015). Behav. Brain Res. 277, 32–48. Reigstad, C.S., Salmonson, C.E., Rainey, J.F., 3rd, Szurszewski, J.H., Linden, D.R., Sonnenburg, J.L., Farrugia, G., and Kashyap, P.C. (2014). FASEB J. Published online December 30, 2014. http://dx. doi.org/10.1096/fj.14-259598. Wikoff, W.R., Anfora, A.T., Liu, J., Schultz, P.G., Lesley, S.A., Peters, E.C., and Siuzdak, G. (2009). Proc. Natl. Acad. Sci. USA 106, 3698–3703. Yano, J.M., Yu, K., Donaldson, G.P., Shastri, G.G., Ann, P., Ma, L., Nagler, C.R., Ismagilov, R.F., Mazmanian, S.K., and Hsiao, E.Y. (2015). Cell 161, this issue, 264–276.
Previews Gut Microbiota: The Link to Your Second Brain Vanessa Ridaura1,2 and Yasmine Belkaid1,2,* 1Program
in Barrier Immunity and Repair Immunology Section, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD 20892, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2015.03.033 2Mucosal
Serotonin is a highly ubiquitous signaling molecule that plays a role in the regulation of various physiological functions. Several lines of evidence, including the present work from Hsiao and colleagues, demonstrate that, in the gut, microbial-derived metabolites affect the production of serotonin that in turn impacts host physiological functions. The body’s epithelial surfaces act as a scaffold to sustain diverse communities of commensals that include bacteria, archaea, fungi, protozoa, and virus. Although the notion that these microbial partners can promote human health is not a recent concept, the extent to which the microbiota controls all physiological systems has only recently begun to be appreciated. Of particular interest are the recent lines of investigation linking the microbiota to both the hormonal and nervous systems. In this context, a set of recent findings, including the work of Hsiao and colleagues, uncovers a role for the microbiota in controlling the production of a major neurotransmitter, serotonin. In 1967, Abrams and Bishop showed that animals devoid of live microbes (germ-free) had decreased gut motility compared to animals harboring a conventional mouse microbiota (Abrams and Bishop, 1967). Decreased serotonin levels in the absence of microbes have been proposed as a potential cause for this defect (Wikoff et al., 2009; Kashyap et al., 2013). Serotonin is a highly ubiquitous signaling molecule that plays a fundamental role in the regulation of various physiological functions via its action as both a neurotransmitter and a hormone. The vast majority of serotonin is produced in the gut by enterochromaffin cells, a specialized subset of cells strategically positioned to respond to chemical and mechanical stimuli (Figure 1). As a single molecule, serotonin has a remarkably wide range of effects on host physiology, ranging from the control of gut motility, secretory reflexes, platelet ag-
gregation, bone development, and cardiac function to the regulation of immune responses (Mawe and Hoffman, 2013). Germ-free mice display depressed levels of this neurotransmitter compared to conventionally raised animals (Wikoff et al., 2009). Colonization of germ-free animals with the gut microbiota from humans or mice can significantly accelerate gut transit time, an effect that can be partially blocked using a pharmacologic antagonist of a serotonin receptor (Kashyap et al., 2013). In the present issue of Cell, the work of Yano et al. (2015), together with previous lines of evidence, proposes a model in which microbial-derived metabolites, such as short-chain fatty acids (i.e., butyrate and acetate) or secondary bile acids (specifically deoxycolate), directly act upon enterochromaffin cells (ECs), inducing transcription of the rate-limiting serotonin biosynthetic enzyme thp1 (Yano et al., 2015; Fukumoto et al., 2003; Reigstad et al., 2014; Figure 1). A link between microbiota-derived metabolic products and enterochromaffin cell function has been previously reported by Reigstad et al., where they propose that short-chain fatty acids can modulate transcription of Chga gene, which encodes the neuroendocrine secretory protein chromogranin A, released together with serotonin (Figure 1). These results were corroborated by Yano et al. and correlated, in treated mice, with decreased transit time. Further, via increase in serotonin production, the presence of the microbiota was associated with increased platelet activation and aggregation, find-
ings that help to explain the improved coagulation at the site of injury in animals harboring a gut microbiota compared to germ-free mice. Of interest is the diversity of microbial-derived metabolites that can increase serotonin production, supporting the idea that the mechanisms controlling this brain-gut interaction are redundant and are unlikely to be affected by subtle microbial shifts. Because of the fundamental importance of serotonin in mediating central body functions, such redundancy may have been maintained as a means to sustain the production of this neurotransmitter in the face of constitutive microbial fluctuation. Nonetheless, not all microbes are equally efficient at promoting serotonin production. Yano et al. correlated the localized changes of serotonin with the presence of sporeforming bacteria, primarily from the Clostridium genus. Given the diversity of microbially derived metabolites, it is unlikely that a defined microbe will be associated with this effect. The mechanism by which the microbiota promotes serotonin production and, in particular, if and how enterochromaffin cells directly respond to microbiota-derived products and metabolites remain unclear. Furthermore, the systemic effects of this control on distal tissues and peripheral function are still unknown. Of interest, and yet to be studied, is the effect that increased serotonin may have on the ecology and metabolism of the gut microbiota (Figure 1). Serotonin can act directly or indirectly on the immune system, which in turn can shape the microbiota composition and localization.
Cell 161, April 9, 2015 ª2015 Elsevier Inc. 193
intestinal disorders (Manocha and Khan, 2012). Based on the present findings, further understanding of the mechanism by which the microbiota regulates host’s serotonin levels may be a first step toward developing pro- and/or prebiotic strategies to complement or potentially replace existing clinical treatments. ACKNOWLEDGMENTS This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health.
REFERENCES Abrams, G.D., and Bishop, J.E. (1967). Proc. Soc. Exp. Biol. Med. 126, 301–304.
Figure 1. Role of the Microbiota in Serotonin Production The gut microbiota influences the number and function of enterochromaffin cells, thereby promoting the release of serotonin (5-HT). The microbiota promotes serotonin production via various metabolites, including short-chain fatty acid (SCFA). Serotonin can act on various physiological systems promoting gut motility, secretory reflexes, and platelet function. The action of serotonin can be local as well as distal (on bone development and cardiac function) via platelet-mediated transport. Serotonin can also influence the immune system, an effect that could feed back on enterochromaffin cells and the microbiota itself. Defined microbes have also been shown to produce serotonin, a pathway that may further link the microbiota and host serotonin levels.
Fukumoto, S., Tatewaki, M., Yamada, T., Fujimiya, M., Mantyh, C., Voss, M., Eubanks, S., Harris, M., Pappas, T.N., and Takahashi, T. (2003). Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1269–R1276. Kashyap, P.C., Marcobal, A., Ursell, L.K., Larauche, M., Duboc, H., Earle, K.A., Sonnenburg, E.D., Ferreyra, J.A., Higginbottom, S.K., Million, M., et al. (2013). Gastroenterology 144, 967–977. Manocha, M., and Khan, W.I. (2012). Clin. Transl. Gastroenterol. 3, e13. Mawe, G.M., and Hoffman, J.M. (2013). Nature Rev. Gastroenterol. Hepatol. 10, 473–486.
The feedback loop associated with this control remains to be explored. Microbially induced changes in serotonin concentrations may regulate the host’s immune response and may subsequently influence how the host deals with pathogens or commensals. Of interest, defined microbes themselves can produce serotonin (O’Mahony et al., 2015); this raises the question of whether serotonin can play a direct role in microbial metabolism or in the maintenance of the ecological niche of certain phylogenetic groups (i.e., spore-forming bacteria).
An important line of future investigation will be to explore how microbiota control of serotonin levels contributes to mucosal disorders, a question of particular importance because of the known role of serotonin in promoting immunity and inflammation. Of interest, in various models of mucosal inflammation or infections, as well as in Celiac disease patients, serotonin levels are significantly increased (Mawe and Hoffman, 2013). Further, both antagonists and agonists to the serotonin receptor have been used to clinically treat a variety of gastro-
194 Cell 161, April 9, 2015 ª2015 Elsevier Inc.
O’Mahony, S.M., Clarke, G., Borre, Y.E., Dinan, T.G., and Cryan, J.F. (2015). Behav. Brain Res. 277, 32–48. Reigstad, C.S., Salmonson, C.E., Rainey, J.F., 3rd, Szurszewski, J.H., Linden, D.R., Sonnenburg, J.L., Farrugia, G., and Kashyap, P.C. (2014). FASEB J. Published online December 30, 2014. http://dx. doi.org/10.1096/fj.14-259598. Wikoff, W.R., Anfora, A.T., Liu, J., Schultz, P.G., Lesley, S.A., Peters, E.C., and Siuzdak, G. (2009). Proc. Natl. Acad. Sci. USA 106, 3698–3703. Yano, J.M., Yu, K., Donaldson, G.P., Shastri, G.G., Ann, P., Ma, L., Nagler, C.R., Ismagilov, R.F., Mazmanian, S.K., and Hsiao, E.Y. (2015). Cell 161, this issue, 264–276.
