Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 3307-3328.e19 |
| Journal | Cell |
| Volume | 185 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 1 Sept 2022 |
Bibliographical note
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).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.
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology