Holmes Laboratory

Understanding of biological processes at the systems level requires tools for profiling dynamic, multi-compartmental metabolic responses to toxicological and pharmacological events incorporating integration of multiple spectroscopic technologies coupled with multivariate trajectory mapping, bidirectional fusion of ‘omics’ data and methods for enhanced biomarker extraction. Together with Dr. Isabel Garcia-Perez and Dr. Joram Posma, we have created new analytical methods and statistical tools for pre-processing and modelling spectral data and for integrating multi-omics data in order to interpret and understand complex human responses to their environment.

References

• Blaise BJ, Correia GDS, Haggart GA, Surowiec I, Sands C, Lewis MR, Pearce JTM, Trygg J, Nicholson JK, Holmes E, Ebbels TMD. Statistical analysis in metabolic phenotyping. Nat Protoc. 2021; 16(9):4299-4326. doi:10.1038/s41596-021-00579-1.
• Garcia-Perez I, Posma JM, Serrano-Contreras JI, Boulangé CL, Chan Q, Frost G, Stamler J, Elliott P, Lindon JC, Holmes E, Nicholson JK. Identifying unknown metabolites using NMR-based metabolic profiling techniques. Nat Protoc. 2020; 15(8):2538-2567. doi: 10.1038/s41596-020-0343-3.
• Dona AC, Jiménez B, Schäfer H, Humpfer E, Spraul M, Lewis MR, Pearce JT, Holmes E, Lindon JC, Nicholson JK. Precision high-throughput proton NMR spectroscopy of human urine, serum, and plasma for large-scale metabolic phenotyping. Anal Chem. 2014; 86(19):9887-94. doi: 10.1021/ac5025039.

Human biofluids such as urine, plasma and stool extracts contain a vast array of molecules that are made entirely or partially by our gut bacteria. Metabolic profiling can be used to map the chemical cross-talk between the microbiome and human metabolism, moving beyond next generation sequencing approaches to focus on the functionality of the microbiome. Assays have been developed to capture specific chemical classes of interest including bile acids, biogenic amines, choline degradation products, short chain fatty acids, phenols and indoles. This approach has been successfully applied to study the impact of the microbiome across a range of clinical fields including inflammatory bowel disease, cancers, and cardiometabolic diseases. A particular focus area has been the evaluation of the impact of bariatric surgery on the microbiome and the relationship with type 2 diabetes. Together with Dr. Jia Li, Dr. Hutan Ashrafian and Prof. Julian Marchesi we have explored several mechanistic angles by profiling the microbiome, metabolome and epigenome of humans  following bariatric surgery and have assessed the impact of bariatric surgery on the host-microbe profiles of infants born to mothers with previous bariatric surgery.

 References

• Li JV, Ashrafian H, Sarafian M, Homola D, Rushton L, Barker G, Cabrera PM, Lewis MR, Darzi A, Lin E, Gletsu-Miller NA, Atkin SL, Sathyapalan T, Gooderham NJ, Nicholson JK, Marchesi JR, Athanasiou T, Holmes E. Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co- metabolic phenotype. Microbiome. 2021 Jun 14;9(1):139. doi:10.1186/s40168-021-01086-x.
• West KA, et al. Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery. Gut. 2020: gutjnl-2019-319620. doi: 10.1136/gutjnl-2019-319620.
• Nicholson, J.K., et al. Host-gut microbiota metabolic interactions. Science, 2012. 336(6086): p. 1262-7.
• Kundu P, et al. Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice. Sci Transl Med. 2019; 11(518):eaau4760. doi: 10.1126/scitranslmed.aau4760. PMID: 31723038.

A mounting body of evidence points to the fact a “one-size-fits-all” approach to health is not optimal and that individuals react differently to foods and diet. Currently dietary recommendations are based on general advice which is a product of population-level statistics around response to specific foods or nutrients. In order to improve our understanding of how diet influences long-term health the team we apply a combination of metabolic phenotyping and detailed dietary study methods (carried out in collaboration with Prof Gary Frost, Dr. Isabel Garcia Perez & Dr Joram Posma) to profile objective measures of dietary intake, to assess adherence to diet, and to characterise the effect of diets on both human and gut microbial metabolism. Mapping the critical impact of diet on the co-dependent evolution of metabolism and microbial colonisation is key to understanding obesogenic mechanisms that are driving the increase in many chronic diseases. The ability to manipulate the gut microbiome at the individual level offers a tool that can be implemented within a precision or personalised nutrition setting.

References

• Penney N, Barton W, Posma JM, Darzi A, Frost G, Cotter PD, Holmes E, Shanahan F, O'Sullivan O, Garcia-Perez I. Investigating the Role of Diet and Exercise in Gut Microbe-Host Cometabolism. mSystems. 2020; 5(6):e00677-20. doi: 10.1128/mSystems.00677-20.
• Posma JM, Garcia-Perez I, Frost G, Aljuraiban GS, Chan Q, Van Horn L, Daviglus M, Stamler J, Holmes E, Elliott P, Nicholson JK. Nutriome-metabolome relationships provide insights into dietary intake and metabolism. Nat Food. 2020; 1(7):426-436. doi: 10.1038/s43016-020-0093-y.
• Garcia-Perez I, Posma JM, Gibson R, Chambers ES, Hansen TH, Vestergaard H, Hansen T, Beckmann M, Pedersen O, Elliott P, Stamler J, Nicholson JK, Draper J, Mathers JC, Holmes E, Frost G. Objective assessment of dietary patterns by use of metabolic phenotyping: a randomised, controlled, crossover trial. Lancet Diabetes Endocrinol. 2017; 5(3):184-195. doi: 10.1016/S2213-8587(16)30419-3.
• Loo RL, Zou X, Appel LJ, Nicholson JK, Holmes E. Characterization of metabolic responses to healthy diets and association with blood pressure: application to the Optimal Macronutrient Intake Trial for Heart Health (OmniHeart), a randomized controlled study. Am J Clin Nutr. 2018;107(3):323-334. doi: 10.1093/ajcn/nqx072. PMID: 29506183.
• Chan Q, Wren GM, Lau CE, Ebbels TMD, Gibson R, Loo RL, Aljuraiban GS, Posma JM, Dyer AR, Steffen LM, Rodriguez BL, Appel LJ, Daviglus ML, Elliott P, Stamler J, Holmes E, Van Horn L. Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). Am J Clin Nutr. 2022; 116(1):216-229. doi: 10.1093/ajcn/nqac067.

Our work by funded by a number of funders. 

Industry funding

• Quorn Foods
• Sosei Heptares
• Nestle
• PepsiCo

• Prof. Gary Frost
• Dr. Isabel Garcia
• Dr. Joram Posma
• Dr. Jia Li
• Dr. Anisha Wijeyesekera
• Prof Sven Petterssen

View all of Professor Holmes's publications.