TY - JOUR
T1 - Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance
AU - Suez, Jotham
AU - Cohen, Yotam
AU - Valdés-Mas, Rafael
AU - Mor, Uria
AU - Dori-Bachash, Mally
AU - Federici, Sara
AU - Zmora, Niv
AU - Leshem, Avner
AU - Heinemann, Melina
AU - Linevsky, Raquel
AU - Zur, Maya
AU - Ben-Zeev Brik, Rotem
AU - Bukimer, Aurelie
AU - Eliyahu-Miller, Shimrit
AU - Metz, Alona
AU - Fischbein, Ruthy
AU - Sharov, Olga
AU - Malitsky, Sergey
AU - Itkin, Maxim
AU - Stettner, Noa
AU - Harmelin, Alon
AU - Shapiro, Hagit
AU - Stein-Thoeringer, Christoph K.
AU - Segal, Eran
AU - Elinav, Eran
N1 - Funding Information:
We thank the members of the Elinav lab, Weizmann Institute of Science, and members of the DKFZ microbiome and cancer division for insightful discussions; Carmit Bar-Nathan for dedicated germ-free mouse husbandry; Hadar Ariely, Gili Weinberg, and Dana Regev-Lehavi for coordinating the clinical trial. J.S. is the recipient of the Strauss Institute research fellowship. M.H. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation , 438122637 ). S.M. and M.I. work was supported by Vera and John Schwartz Family Center for Metabolic Biology . H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. E.E. is supported by The Leona M. and Harry B. Helmsley Charitable Trust ; Adelis Foundation ; Ben B. and Joyce E. Eisenberg Foundation ; Estate of Bernard Bishin for the WIS-Clalit Program ; Jeanne and Joseph Nissim Center for Life Sciences Research ; Miel de Botton ; Swiss Society Institute for Cancer Prevention Research ; Belle S. and Irving E. Meller Center for the Biology of Aging; Sagol Institute for Longevity Research ; Sagol Weizmann-MIT Bridge Program ; Norman E Alexander Family M Foundation Coronavirus Research Fund ; Mike and Valeria Rosenbloom Foundation ; Daniel Morris Trust ; Isidore and Penny Myers Foundation ; Vainboim Family ; and by grants funded by the European Research Council ; Israel Science Foundation ; Israel Ministry of Science and Technology ; Israel Ministry of Health ; the German-Israeli Helmholtz International Research School : cancer-TRAX ( HIRS-0003 ); Helmholtz Association’s Initiative and Networking Fund ; Minerva Foundation ; Garvan Institute ; European Crohn’s and Colitis Organization ; Deutsch-Israelische Projektkooperation ; IDSA Foundation ; WIS-MIT grant ; Emulate ; Charlie Teo Foundation ; Mark Foundation for Cancer Research , and Wellcome Trust . E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial chair of Immunology; a senior fellow, Canadian Institute of Advanced Research (CIFAR); and an international scholar, the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI).
Funding Information:
We thank the members of the Elinav lab, Weizmann Institute of Science, and members of the DKFZ microbiome and cancer division for insightful discussions; Carmit Bar-Nathan for dedicated germ-free mouse husbandry; Hadar Ariely, Gili Weinberg, and Dana Regev-Lehavi for coordinating the clinical trial. J.S. is the recipient of the Strauss Institute research fellowship. M.H. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 438122637). S.M. and M.I. work was supported by Vera and John Schwartz Family Center for Metabolic Biology. H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. E.E. is supported by The Leona M. and Harry B. Helmsley Charitable Trust; Adelis Foundation; Ben B. and Joyce E. Eisenberg Foundation; Estate of Bernard Bishin for the WIS-Clalit Program; Jeanne and Joseph Nissim Center for Life Sciences Research; Miel de Botton; Swiss Society Institute for Cancer Prevention Research; Belle S. and Irving E. Meller Center for the Biology of Aging; Sagol Institute for Longevity Research; Sagol Weizmann-MIT Bridge Program; Norman E Alexander Family M Foundation Coronavirus Research Fund; Mike and Valeria Rosenbloom Foundation; Daniel Morris Trust; Isidore and Penny Myers Foundation; Vainboim Family; and by grants funded by the European Research Council; Israel Science Foundation; Israel Ministry of Science and Technology; Israel Ministry of Health; the German-Israeli Helmholtz International Research School: cancer-TRAX (HIRS-0003); Helmholtz Association's Initiative and Networking Fund; Minerva Foundation; Garvan Institute; European Crohn's and Colitis Organization; Deutsch-Israelische Projektkooperation; IDSA Foundation; WIS-MIT grant; Emulate; Charlie Teo Foundation; Mark Foundation for Cancer Research, and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial chair of Immunology; a senior fellow, Canadian Institute of Advanced Research (CIFAR); and an international scholar, the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). J.S. and E.E. conceived the study and designed the intervention; directed the human trial and data collection; designed, performed, analyzed, and interpreted experiments and computational analysis; and wrote the manuscript. Y.C. headed and performed all computational analyses, analyzed and interpreted the results, wrote the manuscript, and equally contributed to the study. R.V.-M. and U.M. performed computational analyses and provided essential tools and insights. M.D.-B. performed sample processing and next-generation DNA sequencing. S.F. H.S. A.L. R.L. and M.H. performed and assisted in experiments and sample processing. N.Z. participated in study design and protocol development. A.B. M.Z. R.B.-Z.B. S.E.-M. A.M. R.F. and O.S. coordinated the randomized-controlled trial, including data and sample collection; and recruiting, training, and following up on participants. S.M. and M.I. performed metabolomics experiments. N.S. and A.H. supervised all GF experiments. C.K.S.-T. contributed key insights and tools. E.S. and E.E. co-supervised the study. E.S. is a scientific co-founder of DayTwo. E.E. is a scientific co-founder of DayTwo and BiomX, and a paid consultant to Hello Inside and Aposense. E.E. is a member of the Cell scientific advisory board.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert; however, animal studies suggest that they may impact the microbiome and downstream glycemic responses. We causally assessed NNS impacts in humans and their microbiomes in a randomized-controlled trial encompassing 120 healthy adults, administered saccharin, sucralose, aspartame, and stevia sachets for 2 weeks in doses lower than the acceptable daily intake, compared with controls receiving sachet-contained vehicle glucose or no supplement. As groups, each administered NNS distinctly altered stool and oral microbiome and plasma metabolome, whereas saccharin and sucralose significantly impaired glycemic responses. Importantly, gnotobiotic mice conventionalized with microbiomes from multiple top and bottom responders of each of the four NNS-supplemented groups featured glycemic responses largely reflecting those noted in respective human donors, which were preempted by distinct microbial signals, as exemplified by sucralose. Collectively, human NNS consumption may induce person-specific, microbiome-dependent glycemic alterations, necessitating future assessment of clinical implications.
AB - Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert; however, animal studies suggest that they may impact the microbiome and downstream glycemic responses. We causally assessed NNS impacts in humans and their microbiomes in a randomized-controlled trial encompassing 120 healthy adults, administered saccharin, sucralose, aspartame, and stevia sachets for 2 weeks in doses lower than the acceptable daily intake, compared with controls receiving sachet-contained vehicle glucose or no supplement. As groups, each administered NNS distinctly altered stool and oral microbiome and plasma metabolome, whereas saccharin and sucralose significantly impaired glycemic responses. Importantly, gnotobiotic mice conventionalized with microbiomes from multiple top and bottom responders of each of the four NNS-supplemented groups featured glycemic responses largely reflecting those noted in respective human donors, which were preempted by distinct microbial signals, as exemplified by sucralose. Collectively, human NNS consumption may induce person-specific, microbiome-dependent glycemic alterations, necessitating future assessment of clinical implications.
KW - artificial sweeteners
KW - hyperglycemia
KW - metabolic syndrome
KW - metabolomics
KW - metagenomics
KW - microbiome
KW - non-nutritive sweeteners
UR - http://www.scopus.com/inward/record.url?scp=85136550174&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136550174&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2022.07.016
DO - 10.1016/j.cell.2022.07.016
M3 - Article
C2 - 35987213
AN - SCOPUS:85136550174
SN - 0092-8674
VL - 185
SP - 3307-3328.e19
JO - Cell
JF - Cell
IS - 18
ER -