A behavioral weight-loss intervention, but not metformin, decreases a marker of gut barrier permeability: results from the SPIRIT randomized trial

Curtis Tilves, Hsin-Chieh Yeh, Nisa Maruthur, Stephen P Juraschek, Edgar R Miller, Lawrence J Appel, Noel T Mueller, Curtis Tilves, Hsin-Chieh Yeh, Nisa Maruthur, Stephen P Juraschek, Edgar R Miller, Lawrence J Appel, Noel T Mueller

Abstract

Background/objectives: Lipopolysaccharide-binding protein (LBP), a biomarker of gut barrier permeability to lipopolysaccharides, is higher in adults with obesity and type 2 diabetes. Behavioral weight loss and metformin have distinct effects on the gut microbiome, but their impact on gut permeability to lipopolysaccharides is unknown. This study's objective was to determine the effects of a behavioral weight-loss intervention or metformin treatment on plasma LBP.

Subjects/methods: SPIRIT was a randomized trial of adults with overweight or obesity. Participants were randomized to one of three arms: metformin treatment, coach-directed behavioral weight loss on a DASH diet, or self-directed care (control). Of 121 participants, a random subset (n = 88) was selected to have LBP measured at baseline, 6 months, and 12 months post intervention. Intervention effects on LBP over time were assessed using generalized estimating equations (GEE). We also examined whether the intervention effects were modified by change in diet and weight.

Results: Arms were balanced by sex (83% female), race (51% white), and age (mean 60 years), with no differences in baseline LBP (median 4.23 μg/mL). At 1 year, mean weight change was -3.00% in the metformin arm, -3.02% in the coach-directed behavioral weight-loss arm, and +0.33% in the self-directed (control) arm. The corresponding change in LBP was +1.03, -0.98, +1.03 μg/mL. The behavioral weight-loss intervention reduced LBP compared to self-directed care (β = -0.17, 95% CI: -0.33 to -0.01); no other between-arm comparisons were significant. Behavioral weight-loss participants who reduced dietary fat showed the greatest reductions in 6-month LBP (β = -2.84, 95% CI: -5.17 to -0.50).

Conclusions: Despite similar weight loss in the behavioral weight loss arm and the metformin arm, only the behavioral weight-loss intervention reduced LBP compared to control. Lifestyle weight-loss interventions that promote a DASH diet may be effective at reducing gut barrier permeability to lipopolysaccharides.

Clinical trials registration number: NCT02431676, https://clinicaltrials.gov.

Conflict of interest statement

COMPETING INTERESTS

The authors declared no conflict of interest.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Figures

Figure 1:. Change in LBP distribution over…
Figure 1:. Change in LBP distribution over time, by trial arm.
β (95%CI) and p-value from GEE model for test if intervention arm slope significantly differs from self-directed (control) arm.
Figure 2:. Stratified 6-month change in LBP…
Figure 2:. Stratified 6-month change in LBP in the intervention arms vs. self-directed weight loss arm.
Study arms were stratified by changes in percent of energy intake from dietary fat (defined as decreased % fat intake or did not decrease % fat intake). (A) Coach-directed vs. self-directed weight loss; (B) metformin vs. self-directed weight loss. Regression coefficients for the treatment arm indicator within each stratified grouping are included. *: p

References

    1. Van Amersfoort ES, Van Berkel TJ, Kuiper J. Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clinical microbiology reviews. 2003;16(3):379–414.
    1. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–72.
    1. Grube BJ, Cochane CG, Ye RD, Green CE, McPhail ME, Ulevitch RJ, et al. Lipopolysaccharide binding protein expression in primary human hepatocytes and HepG2 hepatoma cells. The Journal of biological chemistry. 1994;269(11):8477–82.
    1. Wurfel MM, Monks BG, Ingalls RR, Dedrick RL, Delude R, Zhou D, et al. Targeted deletion of the lipopolysaccharide (LPS)-binding protein gene leads to profound suppression of LPS responses ex vivo, whereas in vivo responses remain intact. The Journal of experimental medicine. 1997;186(12):2051–6.
    1. Novitsky TJ. Limitations of the Limulus amebocyte lysate test in demonstrating circulating lipopolysaccharides. Annals of the New York Academy of Sciences. 1998;851:416–21.
    1. Ruiz AG, Casafont F, Crespo J, Cayón A, Mayorga M, Estebanez A, et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obesity surgery. 2007;17(10):1374–80.
    1. Lepper PM, Schumann C, Triantafilou K, Rasche FM, Schuster T, Frank H, et al. Association of lipopolysaccharide-binding protein and coronary artery disease in men. Journal of the American College of Cardiology. 2007;50(1):25–31.
    1. Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G, et al. Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance. International Journal of Obesity. 2012;36(11):1442–9.
    1. Liu X, Lu L, Yao P, Ma Y, Wang F, Jin Q, et al. Lipopolysaccharide binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese. Diabetologia. 2014;57(9):1834–41.
    1. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PloS one. 2013;8(1):e54600.
    1. Salden BN, Troost FJ, Wilms E, Truchado P, Vilchez-Vargas R, Pieper DH, et al. Reinforcement of intestinal epithelial barrier by arabinoxylans in overweight and obese subjects: A randomized controlled trial: Arabinoxylans in gut barrier. Clinical nutrition (Edinburgh, Scotland). 2018;37(2):471–80.
    1. González-Sarrías A, Romo-Vaquero M, García-Villalba R, Cortés-Martín A, Selma MV, Espín JC. The Endotoxemia Marker Lipopolysaccharide-Binding Protein is Reduced in Overweight-Obese Subjects Consuming Pomegranate Extract by Modulating the Gut Microbiota: A Randomized Clinical Trial. Molecular nutrition & food research. 2018;62(11):e1800160.
    1. Damms-Machado A, Louis S, Schnitzer A, Volynets V, Rings A, Basrai M, et al. Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction. Am J Clin Nutr. 2017;105(1):127–35.
    1. Ott B, Skurk T, Hastreiter L, Lagkouvardos I, Fischer S, Büttner J, et al. Effect of caloric restriction on gut permeability, inflammation markers, and fecal microbiota in obese women. Scientific reports. 2017;7(1):11955.
    1. van Dielen FM, Buurman WA, Hadfoune M, Nijhuis J, Greve JW. Macrophage inhibitory factor, plasminogen activator inhibitor-1, other acute phase proteins, and inflammatory mediators normalize as a result of weight loss in morbidly obese subjects treated with gastric restrictive surgery. The Journal of clinical endocrinology and metabolism. 2004;89(8):4062–8.
    1. Yang PJ, Lee WJ, Tseng PH, Lee PH, Lin MT, Yang WS. Bariatric surgery decreased the serum level of an endotoxin-associated marker: lipopolysaccharide-binding protein. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2014;10(6):1182–7.
    1. Clemente-Postigo M, Roca-Rodriguez Mdel M, Camargo A, Ocaña-Wilhelmi L, Cardona F, Tinahones FJ. Lipopolysaccharide and lipopolysaccharide-binding protein levels and their relationship to early metabolic improvement after bariatric surgery. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2015;11(4):933–9.
    1. Yerevanian A, Soukas AA. Metformin: Mechanisms in Human Obesity and Weight Loss. Current obesity reports. 2019;8(2):156–64.
    1. Fujimoto WY, Jablonski KA, Bray GA, Kriska A, Barrett-Connor E, Haffner S, et al. Body size and shape changes and the risk of diabetes in the diabetes prevention program. Diabetes. 2007;56(6):1680–5.
    1. Marti A, Martínez I, Ojeda-Rodríguez A, Azcona-Sanjulian MC. Higher Lipopolysaccharide Binding Protein and Chemerin Concentrations Were Associated with Metabolic Syndrome Features in Pediatric Subjects with Abdominal Obesity during a Lifestyle Intervention. Nutrients. 2021;13(2).
    1. Yeh HC, Maruthur NM, Wang NY, Jerome GJ, Dalcin AT, Tseng E, et al. Effects of Behavioral Weight Loss and Metformin on Insulin-like Growth Factors in Cancer Survivors: A Randomized Trial. The Journal of clinical endocrinology and metabolism. 2021.
    1. Appel LJ, Clark JM, Yeh H-C, Wang N-Y, Coughlin JW, Daumit G, et al. Comparative effectiveness of weight-loss interventions in clinical practice. N Engl J Med. 2011;365(21):1959–68.
    1. Irimata K, Wakim P, Li X. Estimation of correlation coefficient in data with repeated measures. SAS Conference Proceedings: SAS Global Forum 2018: SAS Institute Inc; 2018.
    1. Wickham H ggplot2: Elegant Graphics for Data Analysis: Springer-Verlag; New York; 2016.
    1. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2020.
    1. Moreno-Navarrete JM, Escoté X, Ortega F, Serino M, Campbell M, Michalski M-C, et al. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia. 2013;56(11):2524–37.
    1. Mueller NT, Differding MK, Zhang M, Maruthur NM, Juraschek SP, Miller ER 3rd, et al. Metformin Affects Gut Microbiome Composition and Function and Circulating Short-Chain Fatty Acids: A Randomized Trial. Diabetes care. 2021.
    1. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nature medicine. 2017;23(7):850–8.
    1. 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(7581):262–6.
    1. Choi J, Joseph L, Pilote L. Obesity and C-reactive protein in various populations: a systematic review and meta-analysis. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2013;14(3):232–44.
    1. Han MS, White A, Perry RJ, Camporez J-P, Hidalgo J, Shulman GI, et al. Regulation of adipose tissue inflammation by interleukin 6. Proceedings of the National Academy of Sciences. 2020;117(6):2751.
    1. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2011;1813(5):878–88.
    1. Sonis ST. The pathobiology of mucositis. Nature Reviews Cancer. 2004;4(4):277–84.

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