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In this experiment, we used guinea pigs as an animal model to study the effect of NNS on body growth and intestinal health by modifying gut microbiota and hypothalamus\u2010related proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>For a 28\u2010day feeding experiment a total of 40 guinea pigs were randomly divided into four groups, one control (CN) group and three treatments, in which three NNS were added to the diet: rebaudioside A (RA, 330\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>), sodium saccharin (SS, 800\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>), and sucralose (TGS, 167\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>), respectively. The TGS group exhibited significantly reduced food consumption in comparison with the CN group (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) whereas the RA group showed increased food consumption in comparison with the CN group (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Notably, Taste receptor type 1 subunit 2 (T1R2) expression in the hypothalamus was significantly higher in the RA group than in the CN group (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). The mRNA expressions of appetite\u2010stimulated genes arouti\u2010related neuropeptide (AGRP), neuropeptide Y (NPY), and thyroid stimulating hormone (TSHB) were significantly higher than those in the CN group (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) but mRNA expressions of appetite\u2010suppressed genes tryptophan hydroxylase 2(THP2) were significantly lower in the TGS group (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Furthermore, NNS in the guinea pig diets (RA, SS, TGS) significantly increased the relative abundance of Muribaculaceae but decreased the relative abundance of <jats:italic>Clostridia_vadin BB60<\/jats:italic> in comparison with the CN group (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). We also found that dietary supplementation with RA also significantly altered the relative abundance of <jats:italic>Lactobacillus<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>Our finding confirmed that dietary supplementation with RA and TGS affected body growth and intestinal health by modulating hypothalamic RNA profiles and ileum microbiota, suggesting that NNS should be included in guinea\u2010pig feeding. \u00a9 2024 Society of Chemical Industry.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jsfa.13320","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T04:08:40Z","timestamp":1707365320000},"page":"4342-4353","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of non\u2010nutritive sweeteners on growth and intestinal health by regulating hypothalamic <scp>RNA<\/scp> profile and ileum microbiota in guinea 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