AIM: The metabolic performance of the gut microbiota contributes to the onset of type 2 diabetes. However, targeted dietary interventions are limited by the highly variable inter-individual response. We hypothesized (1) that the composition of the complex gut microbiome and metabolome (MIME) differ across metabolic spectra (lean-obese-diabetes); (2) that specific MIME patterns could explain the differential responses to dietary inulin; and (3) that the response can be predicted based on baseline MIME signature and clinical characteristics. METHOD: Forty-nine patients with newly diagnosed pre/diabetes (DM), 66 metabolically healthy overweight/obese (OB), and 32 healthy lean (LH) volunteers were compared in a cross-sectional case-control study integrating clinical variables, dietary intake, gut microbiome, and fecal/serum metabolomes (16 S rRNA sequencing, metabolomics profiling). Subsequently, 27 DM were recruited for a predictive study: 3 months of dietary inulin (10 g/day) intervention. RESULTS: MIME composition was different between groups. While the DM and LH groups represented opposite poles of the abundance spectrum, OB was closer to DM. Inulin supplementation was associated with an overall improvement in glycemic indices, though the response was very variable, with a shift in microbiome composition toward a more favorable profile and increased serum butyric and propionic acid concentrations. The improved glycemic outcomes of inulin treatment were dependent on better baseline glycemic status and variables related to the gut microbiota, including the abundance of certain bacterial taxa (i.e., Blautia, Eubacterium halii group, Lachnoclostridium, Ruminiclostridium, Dialister, or Phascolarctobacterium), serum concentrations of branched-chain amino acid derivatives and asparagine, and fecal concentrations of indole and several other volatile organic compounds. CONCLUSION: We demonstrated that obesity is a stronger determinant of different MIME patterns than impaired glucose metabolism. The large inter-individual variability in the metabolic effects of dietary inulin was explained by differences in baseline glycemic status and MIME signatures. These could be further validated to personalize nutritional interventions in patients with newly diagnosed diabetes.

1st Faculty of Medicine Charles University Prague Czech Republic

Ambis University Department of Economics and Management Prague Czech Republic

Department of Internal Medicine Kralovske Vinohrady University Hospital and 3rd Faculty of Medicine Charles University Prague Czech Republic

Division of Food and Nutrition Science Department of Biology and Biological Engineering Chalmers University of Technology Goteborg Sweden

Faculty of Forestry and Wood Sciences Czech University of Life Sciences Prague Czech Republic

Heidelberg Institute of Global Health Medical Faculty and University Hospital Heidelberg University Heidelberg Germany

Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Global Food Security Queen's University Belfast Belfast UK

Institute of Microbiology of the CAS Prague Czech Republic

Mendel University Department of Chemistry and Biochemistry Brno Czech Republic

RECETOX Faculty of Science Masaryk University Brno Czech Republic

See more in PubMed

Cheng HL, Medlow S, Steinbeck K. The health consequences of obesity in young adulthood. Curr Obes Rep. 2016;5:30–7. doi: 10.1007/s13679-016-0190-2. PubMed DOI

Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31. doi: 10.1038/nature05414. PubMed DOI

Cornejo-Pareja I, Munoz-Garach A, Clemente-Postigo M, Tinahones FJ. Importance of gut microbiota in obesity. Eur J Clin Nutr. 2019;72:26–37. doi: 10.1038/s41430-018-0306-8. PubMed DOI

Lim YY, Lee YS, Ooi DSQ. Engineering the gut microbiome for treatment of obesity: a review of current understanding and progress. Biotechnol J. 2020;15:e2000013. doi: 10.1002/biot.202000013. PubMed DOI

Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60. doi: 10.1038/nature11450. PubMed DOI

Nuli R, Cai J, Kadeer A, Zhang Y, Mohemaiti P. Integrative analysis toward different glucose tolerance-related gut microbiota and diet. Front Endocrinol. 2019;10:295. doi: 10.3389/fendo.2019.00295. PubMed DOI PMC

Zhou W, Sailani MR, Contrepois K, Zhou Y, Ahadi S, Leopold SR, et al. Longitudinal multi-omics of host-microbe dynamics in prediabetes. Nature. 2019;569:663–71. doi: 10.1038/s41586-019-1236-x. PubMed DOI PMC

Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–6. doi: 10.1038/nature15766. PubMed DOI PMC

Allin KH, Tremaroli V, Caesar R, Jensen BAH, Damgaard MTF, Bahl MI, et al. Aberrant intestinal microbiota in individuals with prediabetes. Diabetologia. 2018;61:810–20. doi: 10.1007/s00125-018-4550-1. PubMed DOI PMC

Wu H, Tremaroli V, Schmidt C, Lundqvist A, Olsson LM, Kramer M, et al. The gut microbiota in prediabetes and diabetes: a population-based cross-sectional study. Cell Metab. 2020;32:379–90.e3. doi: 10.1016/j.cmet.2020.06.011. PubMed DOI

Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut. 2014;63:1513–21. doi: 10.1136/gutjnl-2014-306928. PubMed DOI

Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS ONE. 2013;8:e71108. doi: 10.1371/journal.pone.0071108. PubMed DOI PMC

Bhute SS, Suryavanshi MV, Joshi SM, Yajnik CS, Shouche YS, Ghaskadbi SS. Gut microbial diversity assessment of Indian type-2-diabetics reveals alterations in Eubacteria, Archaea, and Eukaryotes. Front Microbiol. 2017;8:214. doi: 10.3389/fmicb.2017.00214. PubMed DOI PMC

Zhao L, Lou H, Peng Y, Chen S, Zhang Y, Li X. Comprehensive relationships between gut microbiome and faecal metabolome in individuals with type 2 diabetes and its complications. Endocrine. 2019;66:526–37.. doi: 10.1007/s12020-019-02103-8. PubMed DOI

Zhong H, Ren H, Lu Y, Fang C, Hou G, Yang Z, et al. Distinct gut metagenomics and metaproteomics signatures in prediabetics and treatment-naive type 2 diabetics. EBioMedicine. 2019;47:373–83. doi: 10.1016/j.ebiom.2019.08.048. PubMed DOI PMC

Wang L, Yu X, Xu X, Ming J, Wang Z, Gao B, et al. The fecal microbiota is already altered in normoglycemic individuals who go on to have type 2 diabetes. Front Cell Infect Microbiol. 2021;11:598672. doi: 10.3389/fcimb.2021.598672. PubMed DOI PMC

Letchumanan G, Abdullah N, Marlini M, Baharom N, Lawley B, Omar MR, et al. Gut microbiota composition in prediabetes and newly diagnosed type 2 diabetes: a systematic review of observational studies. Front Cell Infect Microbiol. 2022;12:943427. doi: 10.3389/fcimb.2022.943427. PubMed DOI PMC

Gaike AH, Paul D, Bhute S, Dhotre DP, Pande P, Upadhyaya S, et al. The gut microbial diversity of newly diagnosed diabetics but not of prediabetics is significantly different from that of healthy nondiabetics. mSystems. 2020;5:e00578-19. doi: 10.1128/mSystems.00578-19. PubMed DOI PMC

Li L, Li C, Lv M, Hu Q, Guo L, Xiong D. Correlation between alterations of gut microbiota and miR-122-5p expression in patients with type 2 diabetes mellitus. Ann Transl Med. 2020;8:1481. doi: 10.21037/atm-20-6717. PubMed DOI PMC

Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103. doi: 10.1038/nature12198. PubMed DOI

Diener C, Reyes-Escogido ML, Jimenez-Ceja LM, Matus M, Gomez-Navarro CM, Chu ND, et al. Progressive shifts in the gut microbiome reflect prediabetes and diabetes development in a treatment-naive Mexican cohort. Front Endocrinol. 2020;11:602326. doi: 10.3389/fendo.2020.602326. PubMed DOI PMC

Ghaemi F, Fateh A, Sepahy AA, Zangeneh M, Ghanei M, Siadat SD. Intestinal microbiota composition in Iranian diabetic, pre-diabetic and healthy individuals. J Diabetes Metab Disord. 2020;19:1199–203. doi: 10.1007/s40200-020-00625-x. PubMed DOI PMC

Chen PC, Chien YW, Yang SC. The alteration of gut microbiota in newly diagnosed type 2 diabetic patients. Nutrition. 2019;63-64:51–6. doi: 10.1016/j.nut.2018.11.019. PubMed DOI

Prochazkova M, Budinska E, Kuzma M, Pelantova H, Hradecky J, Heczkova M, et al. Vegan diet is associated with favorable effects on the metabolic performance of intestinal microbiota: a cross-sectional multi-omics study. Front Nutr. 2021;8:783302. doi: 10.3389/fnut.2021.783302. PubMed DOI PMC

Colantonio AG, Werner SL, Brown M. The effects of prebiotics and substances with prebiotic properties on metabolic and inflammatory biomarkers in individuals with type 2 diabetes mellitus: a systematic review. J Acad Nutr Diet. 2020;120:587–607.e2. doi: 10.1016/j.jand.2018.12.013. PubMed DOI

Davis LM, Martinez I, Walter J, Goin C, Hutkins RW. Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans. PLoS ONE. 2011;6:e25200. doi: 10.1371/journal.pone.0025200. PubMed DOI PMC

Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018;359:1151–6. doi: 10.1126/science.aao5774. PubMed DOI

Wareham NJ. Personalised prevention of type 2 diabetes. Diabetologia. 2022;65:1796–1803. PubMed PMC

Le DS, Brookshire T, Krakoff J, Bunt JC. Repeatability and reproducibility of the hyperinsulinemic-euglycemic clamp and the tracer dilution technique in a controlled inpatient setting. Metabolism. 2009;58:304–10. doi: 10.1016/j.metabol.2008.09.029. PubMed DOI PMC

DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–23. PubMed

Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–3. doi: 10.1038/nmeth.3869. PubMed DOI PMC

Han J, Lin K, Sequeira C, Borchers CH. An isotope-labeled chemical derivatization method for the quantitation of short-chain fatty acids in human feces by liquid chromatography-tandem mass spectrometry. Anal Chim Acta. 2015;854:86–94. doi: 10.1016/j.aca.2014.11.015. PubMed DOI

Dieterle F, Ross A, Schlotterbeck G, Senn H. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. Anal Chem. 2006;78:4281–90. doi: 10.1021/ac051632c. PubMed DOI

R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. 2017.

Sam QH, Ling H, Yew WS, Tan Z, Ravikumar S, Chang MW, et al. The divergent immunomodulatory effects of short chain fatty acids and medium chain fatty acids. Int J Mol Sci. 2021;22:6453. PubMed PMC

Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6. doi: 10.1038/nature12506. PubMed DOI

Nissen L, Samaei SP, Babini E, Gianotti A. Gluten free sourdough bread enriched with cricket flour for protein fortification: Antioxidant improvement and Volatilome characterization. Food Chem. 2020;333:127410. doi: 10.1016/j.foodchem.2020.127410. PubMed DOI

Luscombe VB, Lucy D, Bataille CJR, Russell AJ, Greaves DR. 20 years an orphan: is GPR84 a plausible medium-chain fatty acid-sensing receptor? DNA Cell Biol. 2020;39:1926–37. doi: 10.1089/dna.2020.5846. PubMed DOI

Saresella M, Marventano I, Barone M, La Rosa F, Piancone F, Mendozzi L, et al. Alterations in circulating fatty acid are associated with gut microbiota dysbiosis and inflammation in multiple sclerosis. Front Immunol. 2020;11:1390. doi: 10.3389/fimmu.2020.01390. PubMed DOI PMC

Brayden DJ, Maher S, Bahar B, Walsh E. Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol. Eur J Pharm Biopharm. 2015;94:194–206. doi: 10.1016/j.ejpb.2015.05.013. PubMed DOI

Halama A, Suleiman NN, Kulinski M, Bettahi I, Hassoun S, Alkasem M, et al. The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population. Sci Rep. 2020;10:17164. doi: 10.1038/s41598-020-73723-8. PubMed DOI PMC

Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ, et al. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE. 2010;5:e10883. doi: 10.1371/journal.pone.0010883. PubMed DOI PMC

Song J, Yang X, Yan LJ. Role of pseudohypoxia in the pathogenesis of type 2 diabetes. Hypoxia. 2019;7:33–40. doi: 10.2147/HP.S202775. PubMed DOI PMC

Kumar J, Rani K, Datt C. Molecular link between dietary fibre, gut microbiota and health. Mol Biol Rep. 2020;47:6229–37. doi: 10.1007/s11033-020-05611-3. PubMed DOI

Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012;15:606–14. doi: 10.1016/j.cmet.2012.01.024. PubMed DOI PMC

Rossmeislova L, Gojda J, Smolkova K. Pancreatic cancer: branched-chain amino acids as putative key metabolic regulators? Cancer Metastasis Rev. 2021;40:1115–39. doi: 10.1007/s10555-021-10016-0. PubMed DOI

Gojda J, Cahova M. Gut microbiota as the link between elevated BCAA serum levels and insulin resistance. Biomolecules. 2021;11:1414. PubMed PMC

Le Bastard Q, Chapelet G, Javaudin F, Lepelletier D, Batard E, Montassier E. The effects of inulin on gut microbial composition: a systematic review of evidence from human studies. Eur J Clin Microbiol Infect Dis. 2020;39:403–13.. doi: 10.1007/s10096-019-03721-w. PubMed DOI

Diether NE, Willing BP. Microbial fermentation of dietary protein: an important factor in diet(-)microbe(-)host interaction. Microorganisms. 2019;7:19. PubMed PMC

Yao CK, Muir JG, Gibson PR. Review article: insights into colonic protein fermentation, its modulation and potential health implications. Aliment Pharm Ther. 2016;43:181–96. doi: 10.1111/apt.13456. PubMed DOI

Vandeputte D, Tito RY, Vanleeuwen R, Falony G, Raes J. Practical considerations for large-scale gut microbiome studies. FEMS Microbiol Rev. 2017;41:S154–S67. doi: 10.1093/femsre/fux027. PubMed DOI PMC

Healey G, Murphy R, Butts C, Brough L, Whelan K, Coad J. Habitual dietary fibre intake influences gut microbiota response to an inulin-type fructan prebiotic: a randomised, double-blind, placebo-controlled, cross-over, human intervention study. Br J Nutr. 2018;119:176–89. doi: 10.1017/S0007114517003440. PubMed DOI

Rechkemmer G, Ronnau K, von Engelhardt W. Fermentation of polysaccharides and absorption of short chain fatty acids in the mammalian hindgut. Comp Biochem Physiol A Comp Physiol. 1988;90:563–8. doi: 10.1016/0300-9629(88)90668-8. PubMed DOI

Muller M, Hernandez MAG, Goossens GH, Reijnders D, Holst JJ, Jocken JWE, et al. Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans. Sci Rep. 2019;9:12515. doi: 10.1038/s41598-019-48775-0. PubMed DOI PMC

Tang C, Ahmed K, Gille A, Lu S, Grone HJ, Tunaru S, et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med. 2015;21:173–7. doi: 10.1038/nm.3779. PubMed DOI

Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165:1332–45. doi: 10.1016/j.cell.2016.05.041. PubMed DOI

Mao J, Wang D, Long J, Yang X, Lin J, Song Y, et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J Immunother Cancer. 2021;9:e003334. PubMed PMC

Fahrmann JF, Saini NY, Chia-Chi C, Irajizad E, Strati P, Nair R, et al. A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma. Cell Rep. Med. 2022;3:100720. doi: 10.1016/j.xcrm.2022.100720. PubMed DOI PMC

Sannicolo S, Giaj Levra M, Le Gouellec A, Aspord C, Boccard J, Chaperot L, et al. Identification of a predictive metabolic signature of response to immune checkpoint inhibitors in non-small cell lung cancer: METABO-ICI clinical study protocol. Respir Med Res. 2021;80:100845. PubMed

McCulloch JA, Davar D, Rodrigues RR, Badger JH, Fang JR, Cole AM, et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat Med. 2022;28:545–56. doi: 10.1038/s41591-022-01698-2. PubMed DOI PMC

Vervier K, Moss S, Kumar N, Adoum A, Barne M, Browne H, et al. Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet. Gut. 2022;71:1821–30. doi: 10.1136/gutjnl-2021-325177. PubMed DOI PMC

Busquets D, Oliver L, Amoedo J, Ramio-Pujol S, Malagon M, Serrano M, et al. RAID prediction: pilot study of fecal microbial signature with capacity to predict response to anti-TNF treatment. Inflamm Bowel Dis. 2021;27:S63–S6. doi: 10.1093/ibd/izab273. PubMed DOI

Tierney BT, Versalovic J, Fasano A, Petrosino JF, Chumpitazi BP, Mayer EA, et al. Functional response to a microbial synbiotic in the gastrointestinal system of children: a randomized clinical trial. Pediatr Res. 2022. 10.1038/s41390-022-02289-0. PubMed PMC

Vaz M, Pereira SS, Monteiro MP. Metabolomic signatures after bariatric surgery - a systematic review. Rev Endocr Metab Disord. 2022;23:503–19. doi: 10.1007/s11154-021-09695-5. PubMed DOI PMC

Wei M, Chu CQ. Prediction of treatment response: personalized medicine in the management of rheumatoid arthritis. Best Pr Res Clin Rheumatol. 2022;36:101741. doi: 10.1016/j.berh.2021.101741. PubMed DOI

Lai J, Li A, Jiang J, Yuan X, Zhang P, Xi C, et al. Metagenomic analysis reveals gut bacterial signatures for diagnosis and treatment outcome prediction in bipolar depression. Psychiatry Res. 2022;307:114326. doi: 10.1016/j.psychres.2021.114326. PubMed DOI

Li L, Li P, Xu L. Assessing the effects of inulin-type fructan intake on body weight, blood glucose, and lipid profile: a systematic review and meta-analysis of randomized controlled trials. Food Sci Nutr. 2021;9:4598–616. doi: 10.1002/fsn3.2403. PubMed DOI PMC

Odamaki T, Kato K, Sugahara H, Hashikura N, Takahashi S, Xiao JZ, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90. doi: 10.1186/s12866-016-0708-5. PubMed DOI PMC

Rodriguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Micro Ecol Health Dis. 2015;26:26050. PubMed PMC

Salazar N, Gonzalez S, Nogacka AM, Rios-Covian D, Arboleya S, Gueimonde M, et al. Microbiome: effects of ageing and diet. Curr Issues Mol Biol. 2020;36:33–62. doi: 10.21775/cimb.036.033. PubMed DOI

Feins EN, Ireland C, Gauvreau K, Chavez M, Callahan R, Jenkins KJ, et al. Pulmonary vein stenosis: anatomic considerations, surgical management, and outcomes. J Thorac Cardiovasc Surg. 2022;163:2198–207.e3. doi: 10.1016/j.jtcvs.2021.10.022. PubMed DOI