e Scatterplot of predicted and measured host ME on the MBD; predicted host ME was obtained from the model selection procedure which estimated that 6-day fecal propionate and 16S rRNA gene copy number (a surrogate of biomass) jointly explained 58% of the variance in host ME. 19, 5571 (2021). Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). Syst. For variables not from the same family (e.g., colonic transit, SCFA), we retained variables unless correlations prohibitively high (i.e., Pearson or Spearmans rho 0.75). Cell Metab. PubMed Am. Standards were made by cloning the E. coli 16S rRNA gene using the ThermoFisher TOPO TA Cloning Kit. Additionally, COD is advantageous because it simultaneously measures electrons available to humans and microbes, thus enabling electron balances to quantify energy flow23. Any fecal sample not needed for method-specific aliquots were stored (sealed) in the original collection container at 20C within 60min of collection. Cite this article. Gastroenterol. Metab. 7, 281290 (2021). J. Funct. The authors declare no competing interests. This is a surrogate of high-quality sleep that we use to minimize the effects of small amounts of involuntary motion during sleep on sleep energy expenditure20. 1). Appl. Nearing, J. T. et al. To ensure that fecal energy was accurately reflective of 24-hour fecal production, we utilized the non-absorbable, non-digestible fecal marker polyethylene glycol (PEG). 6a) and BlandAltman plot (Supplementary Fig. Adverse events were monitored at each contact with the participant and reported according to Institutional Review Board guidelines. https://doi.org/10.1038/s41467-023-38778-x, DOI: https://doi.org/10.1038/s41467-023-38778-x. MBD Microbiome Enhancer Diet (green), SCFA short-chain fatty acids, WD Western Diet (purple). Nat Commun 14, 3161 (2023). d The percentage of COD absorbed as SCFAs adjusted for total energy intake (in gCOD/day). The energy balance model of obesity: beyond calories in, calories out. The findings highlight the significance of gut microbiota in brain health and provide insights into the underlying mechanisms of Alzheimer's disease. Plasmid copy number was then calculated using the following formula: 16S rRNA gene copy numbers per gram of feces were used to calculate daily copy numbers by multiplying by fecal weight and adjusting to PEG recovery. Biol. CAS Clostridium bolteae sp. We explored several potential mechanisms by which the gut microbiome might regulate body weight beyond the observed negative energy balance. The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA). Bacteria in the Gut can Influence Brain Function and Mood Disorders Sample weights were tracked upon collection and as aliquots were prepared. BrayCurtis and Jaccard distance matrices were calculated on the rarefied count data using vegan (Version 2.6-40). Methods 86, 351356 (2011). ADS DNA was sequenced on the Illumina HiSeq 4000 PE 150 platform. Science 307, 19551959 (2005). Microbiol. Rev. An obesity-associated gut microbiome with increased capacity for energy harvest. Host-diet-gut-microbiome-interactions-modelling: initial release of host-diet-gut microbiome interactions model (v1.0.0). Diet and Dementia: Study Uncovers Gut-Brain Link to Alzheimer's The . Blood, urine, and fecal samples were collected in our metabolic unit using standard protocols (Translational Research Institute, Orlando, FL, USA). Given the small sample size of our precisely controlled study, selection bias may limit generalizability to other populations. Sonnenburg, E. D. et al. The measurement assay was performed at the Pennington Biomedical Research Center (Baton Rouge, LA, USA). This review will discuss the complex relationship between the gut microbiome and intestinal barrier function and examine the possible implications for stress-related psychiatric disorders. Diet-induced extinctions in the gut microbiota compound over generations. An HPLC-MS method was used for the separation and detection of PEG3350 in human fecal samples75. We limited foods containing resistant starch on the WD and then estimated the content on both diets based on published estimates of resistant starch content of common foods74. Song, Y. et al. Khandekar, N., Berning, B. Sci. PubMed Microorganisms 8, 573 (2020). Although significant correlations between gut microbiota and human and animal health have been revealed, the specific roles of each gut bacterium in shapi Blautiaa new functional genus with potential probiotic properties? Insights into the direction and extent of gut microbiome dysbiosis in PubMed Central The overall goal of our study was to modulate the gut microbiome and employ a quantitative paradigm with enough precision to detect within-participant responses to the diet intervention. Relevant to our results, fecal acetate and butyrate were highly intercorrelated with propionate. COD is typically used for microbial bioenergetics in environmental biotechnology16. We eliminated independent variables that were highly correlated to each other and selected only variables with reasonable correlations with host metabolizable energy (P value<0.2 for Pearson or Spearman correlation coefficients) for inclusion in a general linear regression variable selection procedure. Nutr. PubMed Butyrate plays important roles in host energy balance by stimulating the release of satiety hormones such as GLP-158 and accelerating CTT59. Surveillance of adverse events revealed minimal gastrointestinal or other side effects that did not differ by diet (Supplementary Data1). Mukherjee, A., Lordan, C., Ross, R. P. & Cotter, P. D. Gut microbes from the phylogenetically diverse genus Eubacterium and their various contributions to gut health. Leroux, S. J. Gut, gutjnl-2022-328166, https://doi.org/10.1136/gutjnl-2022-328166 (2022). Therefore, despite less total energy being absorbed by the host on the MBD, a larger proportion was derived from SCFAs. 4b, c). Google Scholar. In order to balance sex, we randomly assigned 3 blocks to each sex. Beta-dispersion was calculated, and the results tested for significance with the ANOVA-like permutation test and Tukeys HSD in vegan (Version 2.6-40). Species shown in this figure were significantly different by diet (Pvalues were corrected to produce Qvalues using the BenjaminiHochberg method; Q<0.05), and the diet difference had an effect size 2. Jumpertz, R. et al. CAS J. Clin. Trials Commun. For panels c and d, data reported as mean with error bars showing the s.e.m. Adherence was equivalent between diets during the metabolic ward period (99.60.19% on MBD vs. 99.90.10% on WD, P=0.27; Supplementary Fig. Briefly, COD was measured per manufacturers protocol using a reactor digestion method with high-range digestion vials followed by a colorimetric assay (HACH, Loveland, CO; Product # 2125925). Although we previously showed that weight was stable within individuals during each domiciled calorimetry period when the diets were consumed in random order12, we uncovered a small, clinically insignificant body weight reduction on both diets during the metabolic ward periods, and the loss was greater on the MBD than on the WD (625.6196.5g MBD; 134.4156.1g WD; P=0.04; Fig. The model estimates human dietary absorption for the general population and humans who had sections of small intestines and large intestines surgically removed. The model also estimates the amount of SCFAs absorbed by the host due to microbial fermentation in the colon and the associated biomass14. Relationship between the gut microbiome and brain function It has become increasingly evident in recent years that the gut microbiome and the brain communicate in a bidirectional manner, with each possibly affecting the other's functions. Bioinformatics 32, 28472849 (2016). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Langmead, B. Further experiments should pursue this hypothesis. Appetite regulation and weight control: the role of gut hormones. The scientific community has recently reoriented itself towards population interventions that promote small changes in energy intake and expenditure as a means of preventing weight gain54. Key modifications include quantitation based on the +2 charged PEG3350 polymers instead of the +4 charged polymers and the inclusion of an internal standard. The range translates to 73390 non-metabolized kcals/day (vs. 59185 kcals/day on the WD), a clinically meaningful quantitative difference that could tip the scale towards a greater negative energy balance. On the prevalence of uninformative parameters in statistical models applying model selection in applied ecology. Microbiome differential abundance methods produce different results across 38 datasets. Vandeputte, D. et al. Quantitative microbiome profiling links gut community variation to microbial load. J. Clin. Details of the diet design, including sample menus can be found in our trial design publication12. The study shows that high cellular iron levels fostered by . Our results collectively indicate that when dietary substrates are less available to the gut microbes (as with the WD), the microbes are starved of host diet-derived substrates. Our sample size was adequate to detect a 120kcal/day difference in energy expenditure and an 80kcal/day difference in fecal COD. The following additional restrictions were implemented prior to each study period: avoidance of alcohol during outpatient feeding periods, no caffeine up to 72h before admission, no artificial sweeteners, and no strenuous physical activity 48h prior to admission. Given our primary finding that the MBD produced a significant decrease in host metabolizable energy compared to the WD, thereby reducing energy available to the host, we next evaluated the microbial phenotype associated with host energy balance. We did so with an aim to consider a limited number of factors given our sample size. The Relationship Between the Gut Microbiome and Neurodegenerative Diseases The Relationship Between the Gut Microbiome and Neurodegenerative Diseases Neurosci Bull 2021 Oct;37 (10):1510-1522. doi: 10.1007/s12264-021-00730-8. Ghosh, T. S., Shanahan, F. & OToole, P. W. The gut microbiome as a modulator of healthy ageing. 5b), with a significantly higher AUC at lunch but not at breakfast or dinner (P=0.009, 0.22 and 0.73, respectively) on the MBD compared with the WD. These four species derive their source of fermentation from host-glycans, simple sugars31,32, or fermentation products generated by other gut microbes, mainly CO233 and H234. Pract. Google Scholar. wrote the paper with critical revision and input from E.A.C., B.D., D.I., F.Y., A.M., T.L.D., R.E.P., B.E.R., R.K.-B., and S.R.S. The raw and processed metagenomic sequence data generated in this study have been deposited in the BioProject database under accession code PRJNA913183PRJNA947193. Next steps should include investigating the mechanisms by which the microbial communities in the human colon modulate energy balance and their interaction with host factors such as CTT, which will provide valuable quantitative data to drive personalized strategies to optimize host-microbiota-diet interactions and prevent or treat obesity. Physiol. . Rev. 24, 17361746 (2020). Rev. Basolo, A. et al. Otherwise, no data were excluded from the analyses. Paliy, O. An armband accelerometer was placed to measure activity and estimate free-living energy expenditure (SenseWear Pro 3 Armband, BodyMedia Inc.) as well as free-living sleep duration, as previously described12. We thank our study participants, without whom this work would not have been possible. Exp. Int. performed mathematical modeling supervised by B.E.R. World J. Gastroenterol. Therapeutic Adv. Article For enteroendocrine hormones, the iAUC for the total time of measurement (~11h) was calculated by diet. Taxonomic composition output from MetaPhlAn3 (Version 3.0.14) was processed for beta-diversity analysis using the phyloseq R package (Version 1.42.0)82. The mammalian gut senses nutrients and microbial fermentation products and is part of the larger enteroendocrine system that plays a key role in maintenance of energy homeostasis43. Although relative abundance did not differ between the diets at the phylum and family levels (Supplementary Table3), we found 53 differentially abundant taxa at the species level (P<0.05; Supplementary Fig. The results presented are from a clinical trial conducted in compliance with all applicable ethical and institutional research requirements. Advancing human gut microbiota research by considering gut transit time. Briefly, samples were prepared by a 1:1 dilution with Nanopure water and homogenized. This device has advantages to other methods (such as the use of scintigraphy or radio-opaque markers) including that it is noninvasive, generates pH, temperature and pressure data, provides whole gut and regional data, and importantly, the test is standardized to improve reliability of interindividual and longitudinal assessments39. Rao, S. S. et al. Fecal sample processing, nucleic acid extraction, library preparation, and whole genome shotgun sequencing were performed at the University of North Carolina at Chapel Hill Microbiome Core (Chapel Hill, NC, USA), which is supported by the following grants: Gastrointestinal Biology and Disease (CGIBD P30 DK034987) and the UNC Nutrition Obesity Research Center (NORC P30 DK056350). 7, 11281140 (2022). The gut microbiome has emerged as a control center for host energy balance through its impacts on energy harvest from food, gut hormones, and signaling through metabolites such as short chain fatty acids (SCFAs)5. 94, 158163 (2008). Such a simple principle could be a useful population-level tool to fight the global obesity epidemic. 39, 13311338 (2015). Bland, J. M. & Altman, D. G. Statistical methods for assessing agreement between two methods of clinical measurement. Since propionate had the strongest correlation with host metabolizable energy, it was selected as the representative SCFA. Suriano, F. et al. 26, 493501 (2015). Mean daily fecal weight was higher on the MBD (P=1.24 105; Supplementary Fig. Participants were enrolled by the study coordinator. Furthermore, systematic and proportional biases were minimized, as shown by a BlandAltman plot (Supplementary Fig. No. Res. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance. Host metabolizable energy was highly variable on the MBD. Alpha-diversity assessed by species richness and evenness did not differ between diets (Supplementary Fig. K.D.C. Nutrition and the foods we eat can affect our hormones and contribute to issues like insomnia and sleep . By submitting a comment you agree to abide by our Terms and Community Guidelines. Nature 551, 507511 (2017). Kang, H. The prevention and handling of the missing data. J. Gastroenterol. Google Scholar. 1b). 109, 276281 (2012). Article PubMed Mol. Stat. Personalized nutrition by prediction of glycemic responses. b Host metabolizable energy based on the proportion of fecal COD to dietary intake. To quantify fecal energy loss, we used chemical oxygen demand (COD), a measure of electron equivalents in organic carbon23 and adjusted the result to PEG recovery. Compound Poisson multivariate linear models were used to account for zero-inflated data26. ICRP 36, 25327, iii, https://doi.org/10.1016/j.icrp.2006.03.004 (2006). Environ. A.M. and T.D. 7a, b). Nutr. J. Mol. d Energy expenditure (sleep metabolic rate extrapolated to 24-h); e, f Colonic transit time and median colonic pH; n=17 per diet for all panels. We explored whether the differential host metabolizable energy was associated with changes in weight/body composition, gut motility, appetite, and/or hormonal secretion from the gut, adipose and pancreas. Nat. 22, 3 (2021). ASU-HTM-center. Byrne, C. S., Chambers, E. S., Morrison, D. J. Distinct polysaccharide utilization determines interspecies competition between intestinal Prevotella spp. Nutr. D6305), and Gut Microbiome Standard (Cat. Metab. Beghini, F. et al. and R.K.B.). For this narrative review, a total of n = 17 relevant human research items of a possible 1765 published between January 2010 and November 2018 were identified. n=17 per diet for all panels. The last participant visit occurred in October of 2019. ISSN 2041-1723 (online). The lower 16S rRNA gene copy number on the WD suggests a decrease in microbial biomass due in part to lower fermentable substrate availability to the microbes from the diet. To obtain We then improved the model by using the measured CTT and evaluated the impact of this change by comparing actual versus modeled data. We did not find a statistically significant difference in CTT by diet (29.74.4h on MBD vs. 39.26.2h on WD; P=0.14; Fig. Acetaminophen (1,500mg) was administered at nominal timepoint zero12. Nat. Diets were prepared in our metabolic kitchen based on kcals needed to maintain energy balance as determined by whole-room indirect calorimetry. Book Rev. Valero-Mora, P. M. ggplot2: elegant graphics for data analysis. Dtsch. ADS This differs from other approaches that have evaluated gut microbiome-CTT interactions40 and is an important advancement given the critical role of diet composition and quantity on both the gut microbiome and CTT. Miketinas, D. C., Tucker, W. J., Douglas, C. C. & Patterson, M. A. Duplicate meals were prepared during all calorimetry days and evaluated for energy content as a quality-control step (Eurofins, Madison, WI). Zou, M. L., Moughan, P. J., Awati, A. On the second-to-last day of each domiciled period, we measured fasting and postprandial levels of several circulating hormones known to regulate appetite at 18 timepoints over 12-h (secondary endpoints). Our in silico mathematical model, which accurately estimated host metabolizable energy measured in our study, allowed us to predict the quantitative contribution of biomass to fecal energy harvest and the 2-fold greater uptake of microbial derived SCFAs on the MBDthan on the WD. K.D.C. The Gut: Where Bacteria and Immune System Meet - Johns Hopkins Medicine We measured the PEG concentration in fecal samples to normalize each fecal measurement to 24-h based on expected daily PEG excretion. Usual dietary fiber intake according to diabetes status in US adults: NHANES 2013-2018. Cani, P. D. Human gut microbiome: hopes, threats and promises. 6a). The performance of the model for estimating host metabolizable energy was evaluated by analyzing concordance correlation coefficient components: bias correction factor (Cb)- accuracy; Pearsons correlation coefficient (r) between measured and modeled metabolizable energy- precision; concordance coefficient correlation (c)- precision92. We are grateful for the expert data generation and statistical analyses from the core facilities at the Translational Research Institute. Lin, L. I. Source data are provided with this paper. Google Scholar. performed metagenomic analysis, supervised by R.K.-B. Nature 444, 10271031 (2006). Mouse models have shown that B. thetaiotaomicron, which normally degrades glycans from plant-based foods, consumes host-derived mucin when diet-derived glycans are not available in sufficient quantitites63. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Zenodo. ADS Lewis, S. J. Diet adherence was monitored during the 11-day outpatient phase at clinic visits 2 or 3 times per week where at least one meal was consumed on site. For validating correlations between relative abundance and metabolizable energy on the MBD only, we employed Kendalls tau-b correlation coefficient50 because it is a non-parametric test that is often used to explore the relationship between relative abundance and continuous or ordinal variables88. Guarino, M. P., Cicala, M., Putignani, L. & Severi, C. Gastrointestinal neuromuscular apparatus: an underestimated target of gut microbiota. The assay is linear as evidenced by the R2 of the calibration curve (0.9987). We postulated that we would be able to identify key parameters within our study sample that explain a portion of this variability. According to a statement by the World Health Organization, probiotics, when consumed in appropriate amounts, are benecial to human health and well-being. Nat. We hypothesized that we could reduce the models bias by incorporating measured CTT since it is a key modulator of microbial composition, fermentation, and host energy balance38. provided overall supervision for the clinical trial execution. Resistant starch intakes in the United States. We utilized a method that is slightly modified from the initial published method by Sadilek et al.75. 33, 873887 (2021). All participants provided informed consent. The linear range of the assay was from 0.1uM to 20uM with PEG3350 recovery ranging from 96.2 to 104.5%. Young, healthy, weight-stable individuals were enrolled to quantify whole-body bioenergetics without the confounding effects of age and metabolic disease16 and to establish the comparative data needed for future studies enrolling people with various health conditions (Table1). This is similar to the mean host metabolizable energy we measured on the MBD and the WD (89.50.73% and 95.40.21%, respectively; Fig. Outpatient dietary intake was evaluated using the validated food frequency questionnaire, the Diet History Questionnaire II (Diet History Questionnaire, Version 2.0. Saxena, A. R., Banerjee, A., Corbin, K. D., Parsons, S. A. 1 The benefits of probiotics include, but are not limited to, improved skin health, enhanced resistance to allergens, immune system support, reduction of pathogenic microorganisms, and protect. The role of the microbiota-gut-brain axis and intestinal microbiome Multivariable association discovery in population-scale meta-omics studies. You are using a browser version with limited support for CSS. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota.
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