Ученые создали пероральные пробиотики, автоматически снижающие уровень сахара у диабетиков

Abstract Sustained and controlled delivery of glucose-lowering agents using engineered designer cells is recognized as an effective strategy for diabetes therapy1. However, current technologies rely on external signal control or have been programmed into mammalian cells using synthetic gene networks, which pose safety concerns arising from transplantation2,3. Here we developed an engineered oral-deliverable glucose-sensing and functional response probiotic living drug for ‘sense-and-respond’-based control of diabetic blood glucose. We created a glucose sensor based on a synthetic gene circuit that incorporates the glucose-responsive transcriptional regulator HexR, coupled with a synthetic promoter. Upon oral administration of the engineered probiotics carrying the sensor, the cells reside temporarily in the intestine and regulate the expression of therapeutic transgenes in response to glucose levels that exceed the normal threshold. We show efficacy from the engineered probiotics for glycaemic control in multiple diabetic mouse and non-human primate models, demonstrating that long-term oral administration drives clear improvements in lipid profiles, while also attenuating development of multiple diabetic complications. Our probiotics-based living drug enables therapeutic dosing in response to real-time blood glucose levels, providing a programmable, orally deliverable sense-and-respond platform for metabolic therapy without transplantation. This is a preview of subscription content, access via your institution Access options Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $32.99 / 30 days cancel any time Subscribe to this journal Receive 52 print issues and online access $199.00 per year only $3.83 per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. USD 39.95 Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others Subjects Data availability All data supporting this study are provided in the main text and Supplementary Information. The 16S rRNA gene sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA1023002. Source data are provided with this paper. References - Bashor, C. J., Hilton, I. B., Bandukwala, H., Smith, D. M. & Veiseh, O. Engineering the next generation of cell-based therapeutics. Nat. Rev. Drug Discov. 21, 655–675 (2022). - Zhou, Y. et al. A small and highly sensitive red/far-red optogenetic switch for applications in mammals. Nat. Biotechnol. 40, 262–272 (2022). - Xie, M. et al. β-cell-mimetic designer cells provide closed-loop glycemic control. Science 354, 1296–1301 (2016). - Roden, M. & Shulman, G. I. The integrative biology of type 2 diabetes. 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Funding H.Y. discloses support for the research of this work from the National Natural Science Foundation of China (32430064, 32521009 and 32261160373), the Science and Technology Commission of Shanghai Municipality (23HC1410100 and 25HC2830300), and the Fundamental Research Funds for the Central Universities. H.Y. is a SANS Exploration Scholar. N.G. discloses support for the research of this work from the National Key R&D Program of China (2025YFC3408700 and 2025YFA0923300), the National Natural Science Foundation of China (32571656), and the Science and Technology Commission of Shanghai Municipality (25J22800100 and 25ZR1402121). D.K. discloses support for the research of this work from the China Postdoctoral Science Foundation (2025M772641 and BX20250150) and the Science and Technology Commission of Shanghai Municipality (24YF2735700). Y.Z. discloses support for the research of this work from the Young Scientists Fund of the National Natural Science Foundation of China (32300458), the Science and Technology Commission of Shanghai Municipality (23YF1410700) and the Natural Science Foundation of Chongqing (CSTB2023NSCQ-MSX0126). Ethics declarations Competing interests H.Y., N.G. and X.G. are inventors on patent applications submitted by East China Normal University that cover the new glucose sensor, including a Chinese patent application (202210326236.9) and a Patent Cooperation Treaty application (PCT/CN2023/081232), which has entered the national phase in the USA (application no. 18/852,503) and Europe (application no. 23777819.6). The other authors declare no competing interests. Peer review Peer review information Nature thanks Andreas Birkenfeld, Tal Danino, Aleksandar Kostic and the other, anonymous, reviewers for their contribution to the peer review of this work. Peer reviewer reports are available. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data figures and tables Extended Data Fig. 1 Optimization and characterization of the glucose sensor. a, Optimization of the constitutive HexR expression level. HexR was controlled by different constitutive promoters with increasing expression strength, including PJ23100, PLac, and PTac. The resulting transrepressor expression vectors were co-transformed with pGN11 (PHexR1-sfGFP) into EcN-competent cells and cultivated for 12 h before the fluorescence intensity of cell culture was quantified. EcN transfected with only pGN11 (-) was used as a control. b, Optimization of the glucose-responsive promoter. The number of tandem operator repeats within PHexR was increased from one (PHexR1) to five (PHexR5). c, Screening of various ribosome binding sites (RBSs) for HexR expression. d, e, Transcriptional profile of genes involved in glucose metabolism in GIFT cells in response to glucose. d, The relative ratios of genes in the Embden-Meyerhof-Parnas (EMP) pathway, Entner-Doudoroff (ED) pathway, and tricarboxylic acid (TCA) cycle are shown for glucose-responsive expression (GIFT with glucose versus GIFT without glucose). e, Differentially expressed genes >2-fold induction (in red) or 2-fold repression (in green) are defined as significant. f, sfGFP expression from the glucose sensor in response to different carbon sources. GIFTGFP cells were cultured with PBS, succinate (45 μM), citrate (0.2 mM), pyruvate (0.1 mM), lactate (3 mM), glycerol (0.15 mM), fructose (0.1 mM), galactose (0.1 mM), or glucose (20 mM) for 12 h. g, Reporter expression from the GIFT cells. sfGFP, RFP, Luciferase, and LacZ were expressed by GIFT induced by 0 to 20 mM glucose for 12 h. Fluorescence images or images of the cell culture were captured using a ChemiScope 4300 Pro imaging equipment after adding D-luciferin (for Luciferase) or X-gal (for LacZ). h, i, Glucose-induced sfGFP expression from the glucose sensor in cells cultured in simulated human intestinal fluid (SIF) under aerobic (h) or microaerobic (i) conditions. Data in a-c, e, f, h, and i are expressed as means ± s.d.; n = 3 independent experiments. Panel g shows representative images from three independent experiments. P-values in f were calculated using one-way ANOVA followed by Dunnett’s multiple comparisons test. ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 2 The distribution and colonization of GIFT in mice after oral delivery. a, b, Bacterial biodistribution in the intestinal tract (a) and major organs (b) of mice. C57BL/6 mice were orally administered with GIFTGFP (109 CFU/mouse/day) continuously for 1, 3, 7, and 15 days, and the intestinal tract and major organs, including heart, liver, spleen, lung, and kidney were collected 24 h after the final administration. The homogenates were plated on an LB solid medium and cultured at 37 °C for 12 h before colony counting. Sample measures in the dash area denote mice where the bacteria were not detectable at a limit of detection of Log10 of 2. c, Colonization of GIFTGFP in mice orally administered with GIFTGFP (109 CFU/mouse/day) continuously for 1, 3, 7, and 15 days. The feces of mice were collected every day for five days after the final administration. The homogenates were plated on an LB solid medium and cultured at 37 °C for 12 h before colony counting. Data are expressed as means ± s.e.m.; n = 5 mice. Extended Data Fig. 3 Characterization of GIFT intestinal colonization coated with tannic acid (TA) and poloxamer 188 (F68). a, Schematic representation of the preparation process for coated GIFT (GIFT@TAF68). GIFTGFP cells were sequentially treated with TA and F68 for 5 min, followed by an additional 25 min of F68 treatment with continuous stirring throughout the encapsulation process. b, Scanning electron microscope (SEM) images of uncoated GIFTGFP and GIFTGFP@TAF68. Scale bar, 1 μm. c, Confocal scanning laser microscopy (CSLM) images of GIFTGFP and GIFTGFP@TAF68. The red channel represents rhodamine B-labeled TA, while the green channel shows sfGFP expressed by GIFTGFP. Scale bar, 10 μm. d, Growth curves of GIFTGFP and GIFTGFP@TAF68 cultured in LB broth at 37 °C. OD600 was recorded using a microplate reader. e, Cell viability of GIFTGFP and GIFTGFP@TAF68. f, Quantification of sfGFP expression by GIFTGFP and GIFTGFP@TAF68 after 12 h of culture with 10 mM glucose. g, Measurement of GLP-1 secretion by GIFTGLP-1 and GIFT GLP-1@TAF68 after 12 h of culture with 15 mM glucose. h-k, Bacterial colony counts in the gastrointestinal tract of mice. C57BL/6 mice were orally administered 109 CFU of either GIFTGFP or GIFTGFP@TAF68 cells. Tissue samples from the stomach, small intestine, colon, and cecum were harvested at 4 (h), 12 (i), 24 (j), and 36 h (k) post-administration, samples were homogenized and plated on LB agar. After 12 h of incubation at 37 °C, bacterial colonies were counted. l, Bioluminescence images of mice. EcN constitutively expressing LuxCDABE (EcN-Lux) (109 CFU) were orally administered to C57BL/6 mice, and imaging was performed at 4, 6, 8, 12, 24, and 36 h using an in vivo imaging system. m, Quantification of bioluminescence signals from l. Panels b, c show representative images from three independent experiments. Data in d-g are expressed as means ± s.d.; n = 3 independent experiments. Data in h-k and m are expressed as means ± s.e.m.; n = 4 mice for h-k, n = 5 mice for m. P-values were calculated by two-way ANOVA followed by Sidak’s multiple comparisons test (d-f), or two-tailed unpaired t-test (g-k, m). NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 4 Assessment of the safety of GIFT after oral delivery to mice. a, Body weight of mice after gavage with 109 CFU of GIFTGFP for 3, 7, and 15 days. b, c, Cytokine abundance for TNF-α (b) and IL-6 (c) from the serum of treated mice. C57BL/6 mice were orally administered with GIFTGFP (109 CFU/mouse/day) continuously for 1, 3, 7, and 15 days. Blood was collected at the indicated time points post-oral administration, and the cytokine abundance was quantified using ELISA kits. d-k, 24 h after the final administration, the blood of mice was collected for complete blood count and blood biochemical analysis. (d) Counts for total red blood cells (RBC), (e) white blood cells (WBC), and (f) hemoglobin (HGB). g, h, kidney function analysis, (g) blood urea nitrogen (BUN), (h) creatinine (CRE). i-k, Hepatic function analysis. (i) alanine aminotransferase (ALT), (j) aspartate aminotransferase (AST), (k) albumin/globulin ratio (A/G). Data are expressed as means ± s.e.m.; n = 6 mice for a-c, n = 5 mice for d-k. P-values in b-k were calculated by one-way ANOVA followed by Tukey’s multiple comparisons test. NS, not significant. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 5 Characterization of GIFTGLP-1 in vitro and in vivo. a, Measurement of intestinal glucose concentrations in wild-type and db/db mice. Following a 4-hour fasting period, the blood glucose levels of the mice were measured. The mice were then euthanized, and their intestines were harvested; the mucosal lining of the intestines was collected. Glucose content was measured using a commercial glucose assay kit. b, Time-dependent glucose-inducible GLP-1 expression of GIFTGLP-1. GIFTGLP-1 was induced with 15 mM glucose for different time periods as indicated, and the GLP-1 secreted to the supernatant of culture was analyzed by ELISA kit. c, Schematic representation of biological activity detection of GLP-1 produced by GIFTGLP-1. The GLP-1 produced by GIFTGLP-1 induces a conformational change of the GLP-1 receptor, leading to signaling through the cyclic adenosine monophosphate (cAMP) secondary messenger and, thus, PCRE-driven SEAP production. d, Schematic of the time schedule for detection of the biological activity of GLP-1 produced by GIFTGLP-1. HEK−293T cells were transfected with the GLP-1 receptor (PSV40-GLP1R-pA) and the corresponding reporter (PCRE-SEAP-pA). e, SEAP production of HEK-293T cells treated with the culture supernatant of GIFT induced with (+) or without (−) glucose. f, Blood glucose of db/db mice orally administered with different doses of GIFT. db/db mice were orally administered with PBS, 109, 1010, and 1011 CFU GIFTGLP-1. Blood glucose was detected 12 h following gavage. Data in a and f are expressed as means ± s.e.m.; n = 5 mice for a, n = 4 mice for f. Data in b and e are expressed as means ± s.d.; n = 3 independent experiments. P-values in a, e, f were calculated by two-way ANOVA followed by Sidak’s multiple comparisons test. NS, not significant; ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 6 Effects of long-term oral administration of GIFTGLP-1 on db/db mice. db/db mice were treated with PBS, GIFTLux, or GIFTGLP−1 cells (orally administered at a dose of 109 CFU/mouse/day) for 30 days. a, Hepatic glycogen levels of db/db mice. b, Epididymal fat to body weight ratio analysis. c, Representative pictures of db/db mice treated with PBS, GIFTLux, or GIFTGLP-1 for 30 days. d-f, Evaluation of body weight, fat mass, and lean mass (d), serum triglycerides (TG) content (e), and serum total cholesterol (T-CHO) content (f) in db/db mice (sampled on day 30). g-q, Metabolic characterization of db/db mice treated with PBS, GIFTLux, or GIFTGLP-1 for 30 days. Mice were individually housed in indirect calorimetry cages. g, Food intake. h, i, Oxygen consumption (VO2). j, k, Carbon dioxide production (VCO2). l, m, Respiratory exchange rate (RER, calculated by dividing VCO2 by VO2). n, o, Energy expenditure. p, q, Regression-based analysis of energy expenditure relative to lean body mass. The black x-axis line segments represent the 12-hour dark phases. Data in a, b, and d-q are expressed as means ± s.e.m.; n = 5 mice. P-values were calculated by one-way ANOVA (a, b, e-g) or two-way ANOVA (d, i, k, m, o) followed by Tukey’s multiple comparisons test, or one-way ANCOVA using lean body mass as a covariate (p, q). NS, not significant; ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 7 Protective effects of GIFTGLP-1 against complications in db/db mice. a, Representative hematoxylin and eosin (H&E) staining from liver tissue sections. Scale bars, 100 μm or 50 μm. The rectangular frame indicates the area displayed at a higher magnification. b, c, Hepatic TG (b), and T-CHO (c) levels of db/db mice treated with PBS, GIFTLux, or GIFTGLP-1 for 30 days. d, e, Hepatic levels of IL-1β (d) and TNF-α (e) in db/db mice treated with PBS, GIFTLux, or GIFTGLP-1 for 30 days. f-i, Ameliorating effect of GIFTGLP-1 on oxidative stress in diabetic mouse liver. After 30 days of treatment with PBS, GIFTLux, or GIFTGLP−1, livers of db/db mice were harvested and homogenized. The levels of oxidative stress markers were measured, including MDA (f), SOD (g), GSH (h), and T-AOC (i). j, k, Renal levels of IL-1β (j) and TNF-α (k) in db/db mice treated with PBS, GIFTLux, or GIFTGLP-1 for 30 days. l-o, Ameliorating effect of GIFTGLP-1 on oxidative stress in diabetic mouse kidney. After 30 days of treatment with PBS, GIFTLux, or GIFTGLP-1, the kidneys of db/db mice were harvested and homogenized. The levels of oxidative stress markers were measured, including MDA (l), SOD (m), GSH (n), and T-AOC (o). p-u, Effect of GIFTGLP-1 on alleviating renal damage. After 30 days of treatment with PBS, GIFTLux, or GIFTGLP-1, serum levels of creatinine (CRE) (p), blood urea nitrogen (BUN) (q), and urine protein (r) in db/db mice were measured. Kidneys were harvested and weighed, and the kidney-to-body weight ratios (s) were calculated. Histopathological analyses of kidney sections, including H&E staining, Masson’s trichrome staining, and PAS staining (t), were performed. Scale bars, 50 μm. u, Masson’s trichrome staining to quantify glomerular fibrosis (20 glomeruli per mouse were analyzed, n = 5 mice per group). v, w Colonic IL-1β (v), and TNF-α (w) levels of db/db mice treated with PBS, GIFTLux, or GIFTGLP-1 for 30 days. x, Representative H&E staining from colon tissue section. Scale bars, 100 μm. Representative images from three independent experiments with similar results are shown in a, t, x. Data in b-e, j, k, p-s, u-w are expressed as means ± s.e.m.; n = 5 mice. For box-and-whisker plots in f-i, l-o, the centre line denotes the median, the box bounds indicate the 25th and 75th percentiles, and the whiskers extend from the minimum to maximum values. P-values in b-s, u-w were calculated using one-way ANOVA followed by Tukey’s multiple comparisons test. NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 8 Impact of oral administration of varying concentrations of glucose and different sugary foods on blood glucose levels and GIFT-mediated gene expression dynamics in wild-type mice. a, Wild-type mice were orally administered GIFTLux cells (109 CFU). Thirty minutes post-gavage, the mice were administered intragastrically (i.g.) with varying glucose concentrations (0, 0.1, 1, and 5 g/kg). Blood glucose levels (b) and bioluminescence signal intensity (c) were monitored every 15 min. d, Wild-type mice were orally administered GIFTLux cells (109 CFU). Thirty minutes post-gavage, the mice were given either a chow diet or administered intragastrically (i.g.) with 10 μL/g of PBS, diet cola, cola (containing 10.6 g carbohydrates per 100 mL), or chocolate (containing 43 g carbohydrates per 100 g). Blood glucose levels (e) and bioluminescence signal intensity (f) were monitored every 15 min. Data in b, c, e, and f are expressed as means ± s.e.m.; n = 6 mice. P-values in b, c, e, f were calculated by two-way ANOVA followed by Dunnett’s multiple comparisons test. NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 9 GIFT-mediated diabetes and obesity management in DIO mice. a, Schematic timeline for GIFT-mediated long-term glycemic control in DIO mice. Mice were treated with PBS, GIFTLux, or GIFTGLP-1 cells (109 CFU) daily for 30 days. Serum GLP-1 and plasma insulin levels were measured 2 h after the first gavage, and fasting blood glucose was monitored every three days. Lipid profiles and plasma insulin were evaluated 24 h after the final gavage. b-i, Data for DIO mice: fasting blood glucose (b), serum GLP-1 (c), plasma insulin levels 2 h after the first gavage (d) and 24 h after the final gavage (e), body weight (f), fat mass (g), and serum TG (h) and T-CHO levels (i). Data in b-i are expressed as means ± s.e.m.; n = 5 mice. P-values in c-i were calculated by one-way ANOVA followed by Sidak’s multiple comparisons test. NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Extended Data Fig. 10 Comparative analysis of adverse effects between semaglutide injection and oral delivery of GIFTGLP-1 in db/db mice. a, Schematic of the timeline for assessing acute adverse effects. db/db mice were divided into three groups: one received oral GIFTGLP-1, another was injected with semaglutide, and the third group was left untreated. Blood samples were collected at 6 h for serum immunoglobulin E (IgE), interleukin-6 (IL-6), and Interferon beta (IFNβ) analysis, and at 12 and 24 h for complete blood count (CBC), serum biochemical analysis, and calcitonin (CT) measurement. b, Serum IgE levels in db/db mice 6 h after treatment. c-h, Serum levels of CT (c, d), alanine transaminase (ALT) (e, f), and aspartate transaminase (AST) (g, h) in db/db mice 12 and 24 h after treatment. i, j, Serum levels of IL-6 (i) and IFNβ (j) in db/db mice 6 h after treatment. k, Schematic of the timeline for the conditioned taste aversion (CTA) experiment. db/db mice were single-housed with ad libitum access to chow diet and tap water for 48 h, followed by access to 1% sucrose for 24 h. After acclimation, mice given oral GIFTGLP-1 or injected with semaglutide underwent a two-bottle preference test, choosing between tap water and 1% sucrose. Sucrose and water intake were recorded for 24 h. l, Blood glucose levels monitored 4 h after GIFTGLP-1 or semaglutide administration. m, Total sucrose intake. n, Total water intake. o, Body weight, fat mass, and lean mass of db/db mice treated with semaglutide (0.12 mg/kg/week, intramuscular injection), GIFTGLP-1 (109 CFU/day, oral administration), or left untreated for one month. p-s, Serum levels of TNF (p), IFNβ (q), IL-6 (r), and IL-1β (s) in db/db mice after two-month treatment with semaglutide (0.12 mg/kg/week, intramuscular injection), GIFTGLP-1 (109 CFU/day, oral administration), or no treatment. t, u, Serum levels of IgG1 (t) and IgG2c (u) in db/db mice after one-month treatment with PBS, GIFTLux (109 CFU/day), or GIFTGLP-1 (109 CFU/day). Data in b-j and l-u are expressed as means ± s.e.m.; n = 6 mice in b-j and o-s, n = 9 mice in l-n, n = 5 mice in t,u. P-values were calculated using one-way ANOVA (b-j, m, n, p-u) or two-way ANOVA (l, o), followed by Tukey’s multiple comparisons test. NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001. Detailed statistics are provided in Supplementary Table 16. Supplementary information Supplementary Information (download PDF ) Supplementary Figs. 1–15, Supplementary Tables 1–15, 17 and 18. Supplementary Table 16 (download XLSX ) Statistical significance values (P values) for all data panels in the study. Source Data (download ZIP ) Supplementary Figs 4, 5, 7, 11 and 15. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Guan, N., Kong, D., Gao, X. et al. Glucose-responsive probiotics for glycaemic modulation in mice and monkeys. Nature (2026). https://doi.org/10.1038/s41586-026-10909-6 - Received: - Accepted: - Published: - Version of record: - DOI: https://doi.org/10.1038/s41586-026-10909-6