PMID- 35695565 OWN - NLM STAT- MEDLINE DCOM- 20220908 LR - 20231020 IS - 2165-0497 (Electronic) IS - 2165-0497 (Linking) VI - 10 IP - 4 DP - 2022 Aug 31 TI - Comprehensive Assessment of Functional Effects of Commonly Used Sugar Substitute Sweeteners on Ex Vivo Human Gut Microbiome. PG - e0041222 LID - 10.1128/spectrum.00412-22 [doi] LID - e00412-22 AB - The composition and function of the human gut microbiome are often associated with health and disease status. Sugar substitute sweeteners are widely used food additives, although many studies using animal models have linked sweetener consumption to gut microbial changes and health issues. Whether sugar substitute sweeteners directly change the human gut microbiome functionality remains largely unknown. In this study, we systematically investigated the responses of five human gut microbiomes to 21 common sugar substitute sweeteners, using an approach combining high-throughput in vitro microbiome culturing and metaproteomic analyses to quantify functional changes in different taxa. Hierarchical clustering based on metaproteomic responses of individual microbiomes resulted in two clusters. The noncaloric artificial sweetener (NAS) cluster was composed of NASs and two sugar alcohols with shorter carbon backbones (4 or 5 carbon atoms), and the carbohydrate (CHO) cluster was composed of the remaining sugar alcohols. The metaproteomic functional responses of the CHO cluster were clustered with those of the prebiotics fructooligosaccharides and kestose. The sugar substitute sweeteners in the CHO cluster showed the ability to modulate the metabolism of Clostridia. This study provides a comprehensive evaluation of the direct effects of commonly used sugar substitute sweeteners on the functions of the human gut microbiome using a functional metaproteomic approach, improving our understanding of the roles of sugar substitute sweeteners on microbiome-associated human health and disease issues. IMPORTANCE The human gut microbiome is closely related to human health. Sugar substitute sweeteners as commonly used food additives are increasingly consumed and have potential impacts on microbiome functionality. Although many studies have evaluated the effects of a few sweeteners on gut microbiomes using animal models, the direct effect of sugar substitute sweeteners on the human gut microbiome remains largely unknown. Our results revealed that the sweetener-induced metaproteomic responses of individual microbiomes had two major patterns, which were associated with the chemical properties of the sweeteners. This study provided a comprehensive evaluation of the effects of commonly used sugar substitute sweeteners on the human gut microbiome. FAU - Sun, Zhongzhi AU - Sun Z AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Wang, Wenju AU - Wang W AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Li, Leyuan AU - Li L AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Zhang, Xu AU - Zhang X AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Ning, Zhibin AU - Ning Z AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Mayne, Janice AU - Mayne J AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Walker, Krystal AU - Walker K AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Stintzi, Alain AU - Stintzi A AD - Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. FAU - Figeys, Daniel AU - Figeys D AUID- ORCID: 0000-0002-5373-7546 AD - School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. AD - Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, University of Ottawa, Ottawa, Ontario, Canada. AD - Ottawa Institute of Systems Biology, University of Ottawagrid.28046.38, Ottawa, Ontario, Canada. LA - eng GR - GPH-129340/CIHR/Canada GR - MOP-114872/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220613 PL - United States TA - Microbiol Spectr JT - Microbiology spectrum JID - 101634614 RN - 0 (Food Additives) RN - 0 (Sugar Alcohols) RN - 0 (Sweetening Agents) RN - 7440-44-0 (Carbon) SB - IM MH - Animals MH - Carbon MH - Food Additives/pharmacology MH - *Gastrointestinal Microbiome MH - Humans MH - Sugar Alcohols/pharmacology MH - Sweetening Agents/pharmacology PMC - PMC9431030 OTO - NOTNLM OT - gut microbiome OT - metaproteomics OT - sugar substitute sweetener COIS- The authors declare a conflict of interest. D.F. and A.S. have co-founded MedBiome, a clinical microbiome company. The remaining authors declare no competing interests. EDAT- 2022/06/14 06:00 MHDA- 2022/09/09 06:00 PMCR- 2022/06/13 CRDT- 2022/06/13 09:13 PHST- 2022/06/14 06:00 [pubmed] PHST- 2022/09/09 06:00 [medline] PHST- 2022/06/13 09:13 [entrez] PHST- 2022/06/13 00:00 [pmc-release] AID - 00412-22 [pii] AID - spectrum.00412-22 [pii] AID - 10.1128/spectrum.00412-22 [doi] PST - ppublish SO - Microbiol Spectr. 2022 Aug 31;10(4):e0041222. doi: 10.1128/spectrum.00412-22. Epub 2022 Jun 13.