Surgery for Obesity and Related Diseases ] (2015) 00–00
Original article
Lipopolysaccharide and lipopolysaccharide-binding protein levels and their relationship to early metabolic improvement after bariatric surgery Mercedes Clemente-Postigo, M.Sc.a,*, Maria del Mar Roca-Rodriguez, M.D., Ph.D.a, Antonio Camargo, Ph.D.b, Luis Ocaña-Wilhelmi, M.D., Ph.D.c, Fernando Cardona, Ph.D.a, Francisco J Tinahones, M.D., Ph.D.a,* a
Unidad de Gestión Clínica Endocrinología y Nutrición. Instituto de Investigación Biomédica de Málaga (IBIMA), Complejo Hospitalario de Málaga (Virgen de la Victoria)/Universidad de Málaga (Spain); CIBER Pathophysiology of obesity and nutrition (CB06/03), Spain b Lipid and Atherosclerosis Research Unit (IMIBIC). Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain c Unidad de Gestión Clínica de Cirugía General, Digestiva y Trasplantes. Instituto de Investigación Biomédica de Málaga (IBIMA), Complejo Hospitalario de Málaga (Virgen de la Victoria), Málaga, Spain Received June 17, 2014; accepted November 26, 2014
Abstract
Background: Bariatric surgery usually results in metabolic improvements within a few days from intervention, but the underlying mechanism is not completely understood and may vary depending on the bariatric procedure. Lipopolysaccharides (LPS) from gut microbiota have been proposed as a triggering factor for the inflammatory state in obesity. Roux-en-Y Gastric Bypass (RYGB) leads to a LPS decrease in the medium-term. Objective: To analyze LPS and LPS-binding protein (LBP) in normoglycemic (NG) and diabetic morbidly obese patients in the short-term after 2 different bariatric surgery procedures. Setting: University Hospital, Spain. Methods: Fifty morbidly obese patients underwent bariatric surgery: 24 with sleeve gastrectomy (SG) and 26 with biliopancreatic diversion (BPD). Patients were classified according to their glycemic status as NG or prediabetic/diabetic. LPS and LBP levels and biochemical and anthropometric variables were determined before and at days 15 and 90 after surgery. Results: A significant LPS reduction was seen only in the prediabetic/diabetic patients at 90 days after SG. LBP levels rose at 15 days after BPD but at 90 days returned to baseline in both NG and prediabetic/ diabetic patients. At 90 days after SG, LBP levels significantly decreased compared to baseline in NG and prediabetic/diabetic patients. After multivariate analysis only the change in BMI was independently associated with the change in LBP levels at 90 days. None of the changes in biochemical or anthropometrical variables were significantly associated with the changes in LPS levels at 15 days or 90 days. Conclusion: This is the first study showing that the short-term LPS decrease after bariatric surgery depends on the surgical procedure used as well as on the previous glycemic status of the patient, with SG having the greatest short-term effect on LPS and LBP levels. LBP is closely related to anthropometric variables and may be an inflammatory marker in bariatric surgery patients (Surg Obes Relat Dis 2015;]:00–00.) r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Lipopolysaccharide; Lipopolysaccharide-binding protein; Bariatric surgery; Obesity
*
Correspondence: M Clemente-Postigo and FJ Tinahones. Laboratorio Investigación Biomédica 1st Planta, Hospital Universitario Virgen de la Victoria, Campus de Teatinos s/n 29010 Malaga, Spain. Tel.: þ34 951032648; fax: þ34 951924651. E-mail: [email protected]; [email protected]
Obesity has become a worldwide epidemic, and it is usually related to a number of co-morbidities, such as Type 2 Diabetes Mellitus (T2DM), insulin resistance (IR), or dyslipidemia [1]. Furthermore, obesity is characterized by a
http://dx.doi.org/10.1016/j.soard.2014.11.030 1550-7289/r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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M. Clemente-Postigo et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
chronic low-grade inflammatory state, which is considered a key factor for the development of obesity-related co-morbidities [2]. In recent years, lipopolysaccharides (LPS), a component of the Gram-negative bacteria cell wall, have been proposed as the triggering factor for low-grade inflammation in obesity and diabetes [3,4]. The gut microbiota has been proposed as the major source of LPS in metabolic endotoxemia [5] and small amounts of gut microbiotaderived LPS are translocated from the gut to the circulation even in healthy patients [3,6,7]. LPS translocation is enhanced by high-fat meals [6,8] and this has been suggested as the reason, together with a different microbiota composition [9], because LPS and lipopolysaccharidebinding protein (LBP) levels are higher in obesity and diabetes [7,10,11], and decreased after weight loss [10]. Bariatric surgery (BS) is an effective treatment for obesity that consistently achieves and sustains substantial weight reduction [12]. Apart from a reduction in nutrient absorption, BS improves or resolves many obesity-related co-morbidities [12–14]. Interestingly, the improvement in carbohydrate metabolism occurs even before significant weight loss could intervene. Thus, other mechanisms must be participating, apart from weight reduction, which explain early metabolic improvement after surgery [13–17]. There are several different bariatric procedures such as Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion (BPD), sleeve gastrectomy (SG), and adjustable gastric banding. It has been suggested that the mechanism by which the metabolic improvement takes place may differ depending on the bariatric technique [12]. Recent studies have found a significant reduction in endotoxemia and proinflammatory mediators after BS in patients with morbid obesity and T2DM at 6 months [15] and at 1 year [16] together with an improvement in carbohydrate metabolism and weight reduction. Concordantly, previous data have demonstrated that BS is also able to modify gut microbiota, increasing bacterial diversity, which might influence circulating levels of LPS [9]. However, there are no data on the effect of BS on endotoxemia and its consequences on the early metabolic improvements, which occur o 3 months after surgery [13,18]. Thus, the aim of this study was to analyze the effect of 2 different surgical procedures (BPD versus SG) on LPS and LBP levels as well as to study the influence of endotoxemia in the short-term metabolic improvement after BS.
Methods Study patients and design The study included 50 morbidly obese patients and was performed concurrently using 2 different BS procedures: 26 patients underwent BPD and 24 underwent SG. All patients who underwent SG between 2011 and 2013 were included, and a sample was taken of patients, comparable in age and BMI, who underwent BPD. There was no loss to follow-up.
BPD consisted of distal gastrectomy with a long Roux-en-Y reconstruction with the enteroenteric anastomosis performed 50 cm proximal to the ileocecal valve and the gastroenteric anastomosis 250 cm proximal to the ileocecal valve, with 200 mL of gastric volume. SG is a technique that involves a longitudinal section parallel to the gastric lesser curvature supervised by a Fouche probe (12 mm or 14 mm). The vascularization of the stomach is not compromised, because the arterial supply of the celiac trunk remains intact [13]. All patients were examined before surgery (baseline) and 15 and 90 days postoperatively. Participants were classified according to their glycemic profile as normoglycemic (NG) patients, with fasting glucose levels o100 mg/dL and HOMA-IR (calculated as described below) o3.5; or prediabetic/diabetic (P/D) patients, with fasting glucose levels higher than 100 mg/ dL [19]. Patients were excluded if they had cardiovascular disease, arthritis, acute inflammatory disease, infectious disease or were receiving drugs that could alter the lipid profile or the metabolic parameters at inclusion in the study [13]. All the participants gave their written informed consent, and the study was reviewed and approved by the ethics and research committee of Virgen de la Victoria University Hospital (Malaga, Spain). Laboratory measurements Blood samples were obtained from the antecubital vein and placed in vacutainer tubes (BD vacutainer™, London, UK) after an overnight fast. The serum was separated by centrifugation for 10 min at 4000 rpm and frozen at 801C until analysis. Serum glucose, cholesterol, triglycerides, HDL cholesterol, C-Reactive Protein (CRP) and transaminases were measured in a Dimension autoanalyzer (Dade Behring Inc., Deerfield, IL) by enzymatic methods (Randox Laboratories Ltd., UK and Wako Bioproducts, Richmond, VA). LDL cholesterol was calculated using the Friedewald formula. Insulin concentrations were quantified by radioimmunoassay supplied by BioSource S.A. (Nivelles, Belgium). IR was calculated from the homeostasis model assessment of IR (HOMA-IR) with the formula: HOMA-IR ¼ [fasting serum insulin(μU/mL) fasting blood glucose(mmol/L)]/22.5 [8,13]. Leptin and adiponectin were analyzed by ELISA kits (DSL, Webster, TX, and DRG Diagnostics, respectively). LBP was measured using an immunoassay kit (HyCult Biotechnology) according to the manufacturer’s protocol. Plasma concentrations of LPS were measured by endotoxin assay, based on a Limulus amebocyte extract with a chromogenic LAL assay (QCL-1000, Lonza Group Ltd.) as previously described [8]. Statistical analysis The sample size was determined with the ENE 3.0 statistical program (GlaxoSmithKline). To detect mean
Short-term Endotoxemia Changes After BPD and SG / Surgery for Obesity and Related Diseases ] (2015) 00–00
differences for LPS concentrations of 30% with a conservative SD of .03, at least 7 patients per group were required to complete the study (α risk ¼ .05; power ¼ .8). The results are given as the mean ⫾ SD. Comparisons of the anthropometric and biochemical characteristics as well as LPS and LBP levels between the study groups were made with ANOVA and Duncan’s post hoc tests. The paired Student t test was used for comparisons between baseline, 15 days and 90 days. Pearson’s correlation analyses were done to analyze associations between the changes from baseline at 15 days and 90 days in the study variables. Multiple linear regression analysis was performed to evaluate the contribution of the study variables to the change in both LPS and LBP levels. Those variables found to be associated with the changes in LPS or LBP at 15 days and 90 days in the univariate analysis were included as independent variables in the multivariate analysis, together with any other variables considered to be clinically relevant (i.e., age, BMI, HOMA-IR, glucose levels). Dependent variables were the changes in LPS and the changes in LBP at 15 days and 90 days. Values were considered to be statistically significant when P o .05. Analyses were performed with SPSS, version 15.0 for Windows (SPSS Iberica, Spain). Results The biochemical and anthropometric characteristics of each study group at baseline, 15 days and 90 days are summarized in Table 1. From the BPD group, 35.3% were prediabetic patients and 64.7% were diabetic patients, whilst in the SG group, 46.2% were prediabetic and 53.8% were diabetic patients. The BMI significantly decreased at days 15 and 90 compared to baseline in all 4 study groups. Glucose levels diminished significantly only in the P/D patients. However, there was a significant decrease in insulin and HOMA-IR levels in all 4 study groups. GPT and GGT levels significantly increased at day 15 compared to baseline, but at day 90 diminished in all 4 study groups. The P/D patients undergoing both BPD and SG showed an increase in CRP levels at day 15 and a decrease at day 90. There were no significant differences between the 4 study groups in LPS or LBP levels (Fig. 1). The P/D patients undergoing SG were the only group that showed a significant decrease at day 90 in LPS levels (Fig. 1a). LBP levels increased at day 15 after BPD, significantly so in NG patients, but significantly decreased at day 90 compared to LBP levels at day 15 (Fig. 1b). LBP levels significantly decreased at day 90 after SG in both the NG and the P/D patients (Fig. 1b). Association between both the changes in LPS and LBP levels and the changes in biochemical and anthropometrical variables at 15 days and 90 days were evaluated. The change in LBP levels was significantly correlated with the
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change in insulin (r ¼ -.279; P ¼ .037), HOMA-IR (r ¼ -.271; P ¼ .043) and adiponectin (r ¼ -.414; P ¼ .023) levels at 15 days, and tended to correlate with the change in BMI (r ¼ .232; P ¼ .088), CRP (r ¼ .325; P ¼ .074) and cholesterol levels (r ¼ -.221; P ¼ .099) at 15 days. However, none of the variables were independently associated with the change in LBP at 15 days in the multiple linear regression analysis. Regarding the changes in LPS levels at 15 days, no independent association with the changes in biochemical or anthropometrical variables was found. The changes in LBP at 90 days were significantly correlated with the change in BMI (r ¼ .428; P ¼ .001) and in waist circumference (r ¼ .330; P ¼ .025), and tended to correlate with the changes in cholesterol (r ¼ -.259; P ¼ 0.051) and HDL-C levels (r ¼ -.248; P ¼ .065). In the multiple linear regression analysis, the change in BMI was the only variable that remained significantly and independently associated with the change in LBP levels at 90 days (R2 ¼ .362; β ¼ .382; P ¼ .019). None of the biochemical or anthropometrical variables was independently associated with the change in LPS levels at 90 days. Discussion The results of this study show that the short-term effect of BS on LPS levels depends on the type of surgical procedure and the previous glycemic status of the patient. To our knowledge, this is the first study comparing the short-term effect of BPD and SG on LPS and LBP levels taking into account the glycemic status of morbidly obese patients, finding that LPS levels diminished only at day 90 after SG in the P/D patients. This supports the hypothesis that postoperative metabolic improvement is due to different mechanisms depending on the surgical technique. In addition, we found that LBP could be an inflammatory marker in the short-term after BS. It is well known that BS achieves substantial weight loss even in the short term [12–14] which agrees with our study where a reduction in BMI was seen from day 15, independently of the procedure or the glycemic status of the patients. Moreover most bariatric procedures are also able to improve metabolic diseases even before significant weight loss occurs [13,14]. An improvement in carbohydrate metabolism has been described both for BS procedures that imply food rerouting along the gastrointestinal tract and for those procedures that do not [13,15,17,20–25]. The weight and glucose metabolism improvements seem to be independent of each other, since it has been reported that there is significant weight loss in diabetic and nondiabetic patients after RYGB [20] and diabetes remission is also achieved in 40% of nonobese diabetic patients, with an improvement in insulin sensitivity after BPD [21]. Comparisons between the 2 surgical procedures suggest that gastric bypass is more efficient in improving carbohydrate metabolism than SG, since a higher remission of diabetes [24] as
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Table 1 Anthropometric and biochemical variables of the study groups before and at days 15 and 90 after bariatric surgery BPD
Age (years) BMI (Kg/m2)
Waist (cm)
Weight loss (%)
Glucose (mmol/L)
Insulin (pmol/L)
HOMA-IR
TG (mmol/L)
Chol (mmol/L)
HDL-C (mmol/L)
LDL-C (mmol/L)
GOT (units/L)
GPT (units/L)
GGT (units/L)
Leptin (ng/mL)
Adiponectin (ng/mL)
CRP (mg/L)
Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d
SG
NG (n ¼ 9)
P/D (n ¼ 17)
NG (n ¼ 11)
P/D (n ¼ 13)
38.88 ⫾ 7.68 51.35 ⫾ 3.64 47.07 ⫾ 3.54 a,b* 42.11 ⫾ 3.92 a,b*† 139.00 ⫾ 12.92 131.54 ⫾ 11.26 a,b 119.68 ⫾ 11.42 a,b*† 9.18 ⫾ 5.04 18.86 ⫾ 5.09† 4.98 ⫾ 0.31a 4.99 ⫾ 0.32 a 4.81 ⫾ 0.32 a 139.66 ⫾ 70.77 82.37 ⫾ 24.59* 62.71 ⫾ 23.61* 4.52 ⫾ 2.45 2.62 ⫾ 0.74 a* 1.96 ⫾ 0.86* 1.28 ⫾ 0.51 1.75 ⫾ 0.47a,b* 1.28 ⫾ 0.30a,b† 4.85 ⫾ 1.19 3.87 ⫾ 0.81a* 3.57 ⫾ 0.63a* 1.09 ⫾ 0.29 0.76 ⫾ 0.13a* 0.89 ⫾ 0.32a 2.81 ⫾ 0.62 2.12 ⫾ 0.54a* 1.97 ⫾ 0.68a* 24.08 ⫾ 11.99 37.33 ⫾ 10.67* 29.17 ⫾ 12.28 50.25 ⫾ 21.87 83.83 ⫾ 22.15* 57.00 ⫾ 19.69† 36.25 ⫾ 17.45 a,b 108.00 ⫾ 86.73 a* 33.17 ⫾ 15.84† 52.97 ⫾ 21.67 25.68 ⫾ 16.03 a* 22.83 ⫾ 11.21* 8.67 ⫾ 3.24 9.32 ⫾ 4.37 12.29 ⫾ 6.29 6.29 ⫾ 3.85 10.18 ⫾ 7.10 2.36 ⫾ 1.99†
45.53 ⫾ 6.44 52.46 ⫾ 5.05 48.41 ⫾ 5.23 a* 43.57 ⫾ 4.17 a*† 143.50 ⫾ 14.69 137.08 ⫾ 9.86 a* 128.46 ⫾ 12.41a*† 7.45 ⫾ 5.84 17.35 ⫾ 4.45† 7.10 ⫾ 1.60b 5.97 ⫾ 0.67 b* 5.24 ⫾ 0.55 b*† 136.89 ⫾ 60.77 104.24 ⫾ 41.11* 70.70 ⫾ 32.99*† 6.08 ⫾ 2.63 3.95 ⫾ 1.57 b* 2.42 ⫾ 1.26*† 1.68 ⫾ 1.01 1.99 ⫾ 0.42a 1.53 ⫾ 0.48a† 5.22 ⫾ 1.15 4.20 ⫾ 0.80a,b* 3.67 ⫾ 0.69a*† 1.11 ⫾ 0.27 0.75 ⫾ 0.14a* 0.88 ⫾ 0.19a*† 3.32 ⫾ 1.03 2.48 ⫾ 0.79a,b* 2.13 ⫾ 0.75a* 22.76 ⫾ 15.35 37.35 ⫾ 24.52* 29.41 ⫾ 9.30 52.47 ⫾ 23.90 86.88 ⫾ 52.10* 58.24 ⫾ 15.54† 41.72 ⫾ 23.11 a 72.50 ⫾ 30.61 a,b* 31.00 ⫾ 16.12*† 57.45 ⫾ 14.93 37.68 ⫾ 17.16 a* 25.55 ⫾ 9.12*† 9.23 ⫾ 4.24 8.54 ⫾ 3.30 12.60 ⫾ 9.14 5.52 ⫾ 2.84 10.36 ⫾ 6.57* 3.19 ⫾ 3.19†
39.36 ⫾ 9.55 49.40 ⫾ 5.89 45.34 ⫾ 6.49 a,b* 37.58 ⫾ 12.21b*† 133.65 ⫾ 10.07 123.55 ⫾ 12.07 b* 113.50 ⫾ 13.59 b*† 8.29 ⫾ 7.03 16.97 ⫾ 5.70† 4.97 ⫾ 0.32a 4.87 ⫾ 0.60a 4.77 ⫾ 0.35a 113.06 ⫾ 86.26 83.06 ⫾ 27.50 59.73 ⫾ 19.65† 3.62 ⫾ 2.86 2.61 ⫾ 0.98a 1.83 ⫾ 0.62† 1.31 ⫾ 0.84 1.57 ⫾ 0.62b 1.16 ⫾ 0.48b† 4.44 ⫾ 0.91 4.56 ⫾ 0.91a,b 4.34 ⫾ 0.66b 1.12 ⫾ 0.32 0.84 ⫾ 0.16a,b* 1.11 ⫾ 0.30a,b† 2.80 ⫾ 1.06 2.99 ⫾ 0.81b 2.62 ⫾ 0.64ª,b† 18.25 ⫾ 8.57 28.75 ⫾ 16.94* 22.75 ⫾ 29.99 38.92 ⫾ 19.52 66.42 ⫾ 27.21* 44.08 ⫾ 33.19 22.25 ⫾ 12.01 b 57.08 ⫾ 42.92 b* 44.67 ⫾ 94.74 54.45 ⫾ 19.88 58.75 ⫾ 28.43b 30.20 ⫾ 6.91 11.39 ⫾ 30.4 11.67 ⫾ 4.40 12.63 ⫾ 6.41 4.58 ⫾ 7.20 10.49 ⫾ 5.76 2.98 ⫾ 1.38
45.67 ⫾ 10.95 48.59 ⫾ 3.98 44.33 ⫾ 3.20 b* 40.20 ⫾ 2.99 a,b*† 135.89 ⫾ 16.51 128.57 ⫾ 10.48 a,b* 118.75 ⫾ 12.80 a,b*† 8.99 ⫾ 5.61 17.81 ⫾ 4.17† 6.48 ⫾ 0.75b 6.32 ⫾ 1.06b 5.54 ⫾ 0.55b*† 128.97 ⫾ 105.36 99.59 ⫾ 40.35 67.09 ⫾ 22.99*† 5.27 ⫾ 4.11 4.09 ⫾ 1.94b 2.39 ⫾ 0.88*† 1.78 ⫾ 0.58 1.66 ⫾ 0.54a,b 1.36 ⫾ 0.43a,b*† 4.96 ⫾ 0.62 4.73 ⫾ 1.10b 4.95 ⫾ 0.92c 1.12 ⫾ 0.32 0.96 ⫾ 0.27b* 1.15 ⫾ 0.33b† 3.13 ⫾ 0.68 3.00 ⫾ 0.89 b 3.08 ⫾ 0.81b 25.88 ⫾ 11.80 28.47 ⫾ 15.35 18.41 ⫾ 12.90*† 54.76 ⫾ 29.92 69.65 ⫾ 37.45* 41.35 ⫾ 27.17*† 33.18 ⫾ 15.05 a,b 79.18 ⫾ 70.35 a,b* 25.24 ⫾ 15.39*† 56.79 ⫾ 25.65 38.65 ⫾ 13.28 a* 49.89 ⫾ 58.21 9.45 ⫾ 2.64 9.87 ⫾ 2.95 11.94 ⫾ 4.11* 4.59 ⫾ 3.02 9.70 ⫾ 6.38* 2.46 ⫾ 2.25
BMI ¼ Body mass index; BPD ¼ Biliopancreatic diversion; Chol ¼ cholesterol; CRP ¼ C-reactive protein; GGT ¼ gamma-glutamyl transferase; GOT ¼ glutamic oxalacetic transaminase; GPT ¼ glutamic pyruvate transaminase; HDL-C ¼ HDL cholesterol; LDL-C ¼ LDL cholesterol; NG ¼ normoglycemic patients; P/D ¼ prediabetic and diabetic patients; SG ¼ Sleeve gastrectomy; TG ¼ triglycerides Results are presented as the mean ⫾ SD. A different letter indicates significant differences between the study groups. The 4 groups were compared with each other according to ANOVA and Duncan’s post hoc test (rows; P o .05). * P o .05 compared to baseline (paired sample Student t test). † P o .05 15 d versus 90 d (paired sample Student t test).
Short-term Endotoxemia Changes After BPD and SG / Surgery for Obesity and Related Diseases ] (2015) 00–00
Fig. 1. Plasma LPS (A) and LBP (B) levels before and at days 15 and 90 after bariatric surgery in the study groups. Results are presented as the mean ⫾ SD *P o .05 compared to baseline. †P o .05 15 day versus 90 day. There were no significant differences between the 4 study groups. BPD ¼ Biliopancreatic diversion according to Scopinaro; SG ¼ Sleeve gastrectomy; NG ¼ normoglycemic patients; P/D ¼ prediabetic and diabetic patients; LPS ¼ lipopolysaccharide; LBP ¼ LPS-binding protein.
well as an earlier improvement in fasting glucose and insulin levels and HOMA-IR are seen with BPD than with SG [13,17]. This is in line with our study, which showed that insulin levels and HOMA-IR were significantly decreased at day 15 after BPD in both the NG and the P/ D patients, but they were not significantly reduced until day 90 after SG. The same behavior was observed in the P/D patients in regard to glucose levels. However, others did not find such clear differences between these 2 procedures regarding carbohydrate metabolism [25]. Nutrient-sensing mechanisms in the gut that trigger the gut-brain-liver axis to lower glucose production and food intake are impaired in obesity and diabetes, but evidence suggests that after BS the gut-brain-liver axis signaling is reprogrammed and glycemia normalized rapidly [26]. This would explain, at least in part, the early weight lossindependent metabolic improvement after surgery. Some procedures imply the restructuring of the gastrointestinal
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tract such as BPD, and consequently involve obvious changes in neuro-hormonal signaling. By contrast, other procedures such as SG are initially based on restricting the amount of food that passes through the gastrointestinal tract, and although the gastric emptying mechanism and normal digestion are preserved to some extent, this kind of surgery also involves physiologic changes that improve metabolic diseases [27]. Among the hypotheses proposed to explain the early resolution of diabetes and IR are the modifications in the secretion pattern of gut hormones, microbial ecology or bile acid secretion [26,28]. It is noteworthy that not all BS procedures lead to the same gastrointestinal tract and physiologic changes, with different gut signaling pathways being affected [23] and the precise mechanisms and molecular mediators involved after each procedure remain unclear. All this together suggests that the mechanism leading to early metabolic improvements after BS varies depending on the type of procedure [12,14,27]. Recently, it has been proposed that a reduction in LPS levels after BS could also be involved in the improvement in carbohydrate metabolism [15,16]. There is increasing evidence suggesting that LPS could be a key factor in the low-grade inflammation seen in obesity [3,6,8]. The gut microbiota has been suggested as the main source of circulating LPS in the absence of infectious diseases. It has been shown that high-fat meals promote LPS translocation from the gut, probably by means of chylomicron particles [8]. Moreover, it has been proposed that increased gut permeability in obesity also enhances LPS translocation [3,29]. This would lead to a rise in plasma LPS levels and consequently to the low-grade inflammation state in obesity, which contributes to the development of IR and diabetes. However, previous studies dealing with LPS and BS have only analyzed long-term changes (6 months and 1 year) in LPS levels [15,16], not defining whether the reduction in endotoxemia is also involved in the early metabolic improvements in the first few days after surgery. In addition, although Trøseid et al. have reported data on 2 different types of surgery (RYGB and duodenal switch), they have not compared whether these 2 procedures have a different effect on endotoxemia or whether there is a different evolution depending on the glycemic status [16]. By contrast, our study analyzed the short-term effect of BS on LPS levels and compared one procedure that modifies the anatomy of the gastrointestinal tract to another that does not imply food rerouting, taking into account the previous glycemic status of the participants. We found a significant reduction in LPS levels only at day 90 after surgery in those P/D patients who had undergone SG. This suggests that the early LPS reduction depends on both the surgical procedure and the previous metabolic status of the patient, and although a long-term reduction in LPS levels might help in the sustained improvement of T2DM [16], further studies will be necessary to determine the precise role of endotoxemia in the early metabolic improvements after each type of
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bariatric procedure. One possible explanation for the different effects of BPD and SG on LPS levels might be specific modifications in gut microbiota ecology. In the last few years, multiple roles affecting gut function have been attributed to gut microbiota: regulation of hormone release from enteroendocrine cells, activation of vagal afferent signaling, regulation of production of bile acids, as well as modification of intestinal permeability [26]. Consequently, the change in gut microbiota composition might modify endotoxemia directly by decreasing LPS production and/or indirectly by affecting the gut function. Although it has been reported that RYGB is able to modify gut microbiota leading to a healthy bacterial profile [9,26], to our knowledge there are no previous studies analyzing the changes in gut microbiota after BPD and SG, thus future studies should be conducted to confirm this hypothesis. LBP is an acute-phase protein, synthesized primarily by the liver, which is involved in the systemic response to LPS. LBP binds LPS and presents it to CD14, enhancing the cell response to LPS [30]. However, LBP is also a lipid transfer protein able to transfer LPS to lipoproteins minimizing the LPS response [31]. Several recent studies have shown a relationship between LBP and metabolic diseases. High levels of LBP have been associated with obesity and with the degree of IR [10,11]. In our study, this relationship was also seen with the BMI after the multivariate analysis. The lack of association with the biochemical variables has been described previously in BS patients [32]. Similarly, we found no significant differences in LBP levels between the NG and the P/D patients, although different behavior was seen after surgery depending on the procedure; there was a transient rise in LBP levels after BPD that did not occur after SG. In addition, LBP decreased at day 90 compared to baseline after SG but not after BPD. These results agree with previous studies that have described an increase in inflammation in the short-term after BPD, probably due to the major restructuring carried out in BPD [33]. Concordantly, it has been shown that LBP and other acute-phase protein levels remained elevated during the first 6 months after gastric banding and decreased from 12 months [34], which corroborates the hypothesis that the short-term changes in acute-phase proteins after BS depend on the procedure. In spite of these differences in the short-term, a recent study comparing minigastric bypass, RYGB, SG and AGB showed that 1 year postoperatively, LBP levels decreased significantly after all 4 procedures [32], which is probably due to the general metabolism improvement described after 1 year from surgery that includes the amelioration of the inflammatory state [34]. Interestingly, we did not observe a parallel response in LPS and LBP levels. Although LBP has been described as an endotoxemia marker, it is necessary to take into account that surgery involves tissue injury, which also stimulates inflammation and the secretion of liver acute-phase reactants such as CRP. In fact, CRP levels also increased transiently at 15 days with a decrease at 90 days, in agreement with previous
studies that describe a transient short-term increase in CRP after BPD and SG [13] and a significant decrease in CRP levels at 3 months after BPD and RYGB [9,13] and at 6 months after RYGB [15]. In addition, previous studies have also shown a transient increase in transaminases after RYGB [35] and BPD which is restored after 6 months [36], indicating that LBP behavior in the short-term after BPD seems to be more related to the liver response to the surgery itself than to the endotoxemia response, and the greater LBP response after BPD is likely more pronounced due to the major tissue damage that BPD involves and that SG does not. One of the limitations of this study was the small sample size that might reduce the statistical power, but we preferred to include only patients from the 2 last years to guarantee greater homogenization of the surgical technique. It is noteworthy that, in spite of the sample size, we were able to detect significant differences in both LPS and LBP levels at 90 days after SG. Another aspect to take into account is that the short follow-up period did not allow us to evaluate if medium or long-term surgery-derived complications are occurring and if so, could these also be related to the LPS or LBP levels, especially after BPD. However, we were interested in analyzing the short-term changes of LPS and LBP after the 2 different surgical procedures to see if these 2 variables were related to the early metabolic improvement that occurs o 3 months after surgery. In conclusion, this is the first study showing that the short-term LPS decrease after BS depends on the surgical procedure as well as on the previous glycemic status of the patient, with SG having the greatest short-term effect on LPS and LBP levels. In addition, LBP shows a close relationship with the improvement in BMI and it may be an inflammatory marker in patients who have undergone BS. Disclosures The authors have no financial or other contractual agreements that might cause conflicts of interest or be perceived as causing conflicts of interest. Acknowledgments MCP was a recipient of a FPU grant (AP2009-4537) from the Ministry of Education (Madrid, Spain), MMRR was a recipient of a fellowship from ISCIII (Rio Hortega CM11/00030), Spanish Ministry of Economy and Competitiveness, (Madrid, Spain) and FC was supported by “Miguel Servet Type II” program (CP13/00023) from the ISCIII, Madrid (Spain). The authors wish to thank all the patients for their collaboration, and FIMABIS. We also gratefully acknowledge the help of Maria Repice and Ian Johnstone for their expertise in preparing this manuscript, Juan Alcaide-Torres (IBIMA) for his technical contribution and Olga Perez (FIMABIS) for her statistical support. This study was supported by “Centros de Investigación En Red” (CIBER, CB06/03/0018) of the “Instituto de Salud
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Carlos III” (ISCIII), Madrid (Spain), PI12/02355 from ISCIII, and P11-CTS-08181 from Consejeria de Economia, Innovacion, Ciencia y Empleo (Junta de Andalucía, Spain). References [1] Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res 2005;2:105–12. [2] Barbarroja N, López-Pedrera R, Mayas MD, et al. The obese healthy paradox: is inflammation the answer? Biochem J 2010;430:141–9. [3] Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–103. [4] Pussinen PJ, Havulinna AS, Lehto M, et al. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 2011;34:392–7. [5] Manco M, Putignani L, Bottazzo GF. Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocr Rev 2010;31:817–44. [6] Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 2007;86:1286–92. [7] Cani PD, Amar J, Iglesias MA, Poggi M, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56: 1761–72. [8] Clemente-Postigo M, Queipo-Ortuño MI, Murri M, et al. Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients. J Lipid Res 2012;53:973–8. [9] Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 2010;59: 3049–57. [10] Moreno-Navarrete JM, Ortega F, Serino M, et al. Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesityrelated insulin resistance. Int J Obes (Lond) 2012;36:1442–9. [11] Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharidebinding protein (LBP) in the adult population: the role of obesity. PLoS One 2013;8:e54600. [12] Stefater MA, Wilson-Pérez HE, Chambers AP, Sandoval DA, Seeley RJ. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev 2012;33:595–622. [13] Garrido-Sanchez L, Murri M, Rivas-Becerra J, et al. Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy. Surg Obes Relat Dis 2012;8:145–50. [14] Mingrone G. Role of the incretin system in the remission of type 2 diabetes following bariatric surgery. Nutr Metab Cardiovasc Dis 2008;18:574–9. [15] Monte SV, Caruana JA, Ghanim H, et al. Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Rouxen-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus. Surgery 2012;151:587–93. [16] Trøseid M, Nestvold TK, Rudi K, Thoresen H, Nielsen EW, Lappegård KT. Plasma lipopolysaccharide is closely associated with glycemic control and abdominal obesity: Evidence from bariatric surgery. Diabetes Care 2013;36:3627–32. [17] Tsoli M, Chronaiou A, Kehagias I, Kalfarentzos F, Alexandrides TK. Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study. Surg Obes Relat Dis 2013;9:667–77.
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[18] Papamargaritis D, le Roux CW, Sioka E, Koukoulis G, Tzovaras G, Zacharoulis D. Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis 2013;9:192–201. [19] American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2013;36(Supplement 1):s11–66. [20] Jørgensen NB, Jacobsen SH, Dirksen C, et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab 2012;303:E122–31. [21] Astiarraga B, Gastaldelli A, Muscelli E, et al. Biliopancreatic diversion in nonobese patients with type 2 diabetes: impact and mechanisms. J Clin Endocrinol Metab 2013;98:2765–73. [22] Gill RS, Birch DW, Shi X, Sharma AM, Karmali S. Sleeve gastrectomy and type 2 diabetes mellitus: a systematic review. Surg Obes Relat Dis 2010;6:707–13. [23] Lee WJ, Chen CY, Chong K, Lee YC, Chen SC, Lee SD. Changes in postprandial gut hormones after metabolic surgery: a comparison of gastric bypass and sleeve gastrectomy. Surg Obes Relat Dis 2011;7: 683–90. [24] Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;26:67–76. [25] Yang X, Yang G, Wang W, et al. A meta-analysis: to compare the clinical results between gastric bypass and sleeve gastrectomy for the obese patients. Obes Surg 2013;23:1001–10. [26] Breen DM, Rasmussen BA, Côté CD, Jackson VM, Lam TK. Nutrient-sensing mechanisms in the gut as therapeutic targets for diabetes. Diabetes 2013;62:3005–13. [27] Berthoud HR. Medicine. Why does gastric bypass surgery work? Science 2013;341:351–2. [28] Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014;509: 183–8. [29] Gummesson A, Carlsson LM, Storlien LH, et al. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity (Silver Spring) 2011;19:2280–2. [30] Hailman E, Lichenstein HS, Wurfel MM, et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med 1994;179:269–77. [31] Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med 1994;180:1025–35. [32] 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. Surg Obes Relat Dis 2015;10: 1182–7. [33] Murri M, García-Fuentes E, García-Almeida JM, et al. Changes in oxidative stress and insulin resistance in morbidly obese patients after bariatric surgery. Obes Surg 2010;20:363–8. [34] 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. J Clin Endocrinol Metab 2004;89:4062–8. [35] Lohlun JC, Guirguis A, Wise L. Elevated liver enzymes following open Roux-en-Y gastric bypass for morbid obesity - does timing of liver retraction affect the rise in the levels of transaminases? Obes Surg 2004;14:505–8. [36] Keshishian A, Zahriya K, Willes EB. Duodenal switch has no detrimental effects on hepatic function and improves hepatic steatohepatitis after 6 months. Obes Surg 2005;15:1418–23.
Original article
Lipopolysaccharide and lipopolysaccharide-binding protein levels and their relationship to early metabolic improvement after bariatric surgery Mercedes Clemente-Postigo, M.Sc.a,*, Maria del Mar Roca-Rodriguez, M.D., Ph.D.a, Antonio Camargo, Ph.D.b, Luis Ocaña-Wilhelmi, M.D., Ph.D.c, Fernando Cardona, Ph.D.a, Francisco J Tinahones, M.D., Ph.D.a,* a
Unidad de Gestión Clínica Endocrinología y Nutrición. Instituto de Investigación Biomédica de Málaga (IBIMA), Complejo Hospitalario de Málaga (Virgen de la Victoria)/Universidad de Málaga (Spain); CIBER Pathophysiology of obesity and nutrition (CB06/03), Spain b Lipid and Atherosclerosis Research Unit (IMIBIC). Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain c Unidad de Gestión Clínica de Cirugía General, Digestiva y Trasplantes. Instituto de Investigación Biomédica de Málaga (IBIMA), Complejo Hospitalario de Málaga (Virgen de la Victoria), Málaga, Spain Received June 17, 2014; accepted November 26, 2014
Abstract
Background: Bariatric surgery usually results in metabolic improvements within a few days from intervention, but the underlying mechanism is not completely understood and may vary depending on the bariatric procedure. Lipopolysaccharides (LPS) from gut microbiota have been proposed as a triggering factor for the inflammatory state in obesity. Roux-en-Y Gastric Bypass (RYGB) leads to a LPS decrease in the medium-term. Objective: To analyze LPS and LPS-binding protein (LBP) in normoglycemic (NG) and diabetic morbidly obese patients in the short-term after 2 different bariatric surgery procedures. Setting: University Hospital, Spain. Methods: Fifty morbidly obese patients underwent bariatric surgery: 24 with sleeve gastrectomy (SG) and 26 with biliopancreatic diversion (BPD). Patients were classified according to their glycemic status as NG or prediabetic/diabetic. LPS and LBP levels and biochemical and anthropometric variables were determined before and at days 15 and 90 after surgery. Results: A significant LPS reduction was seen only in the prediabetic/diabetic patients at 90 days after SG. LBP levels rose at 15 days after BPD but at 90 days returned to baseline in both NG and prediabetic/ diabetic patients. At 90 days after SG, LBP levels significantly decreased compared to baseline in NG and prediabetic/diabetic patients. After multivariate analysis only the change in BMI was independently associated with the change in LBP levels at 90 days. None of the changes in biochemical or anthropometrical variables were significantly associated with the changes in LPS levels at 15 days or 90 days. Conclusion: This is the first study showing that the short-term LPS decrease after bariatric surgery depends on the surgical procedure used as well as on the previous glycemic status of the patient, with SG having the greatest short-term effect on LPS and LBP levels. LBP is closely related to anthropometric variables and may be an inflammatory marker in bariatric surgery patients (Surg Obes Relat Dis 2015;]:00–00.) r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Lipopolysaccharide; Lipopolysaccharide-binding protein; Bariatric surgery; Obesity
*
Correspondence: M Clemente-Postigo and FJ Tinahones. Laboratorio Investigación Biomédica 1st Planta, Hospital Universitario Virgen de la Victoria, Campus de Teatinos s/n 29010 Malaga, Spain. Tel.: þ34 951032648; fax: þ34 951924651. E-mail: [email protected]; [email protected]
Obesity has become a worldwide epidemic, and it is usually related to a number of co-morbidities, such as Type 2 Diabetes Mellitus (T2DM), insulin resistance (IR), or dyslipidemia [1]. Furthermore, obesity is characterized by a
http://dx.doi.org/10.1016/j.soard.2014.11.030 1550-7289/r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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chronic low-grade inflammatory state, which is considered a key factor for the development of obesity-related co-morbidities [2]. In recent years, lipopolysaccharides (LPS), a component of the Gram-negative bacteria cell wall, have been proposed as the triggering factor for low-grade inflammation in obesity and diabetes [3,4]. The gut microbiota has been proposed as the major source of LPS in metabolic endotoxemia [5] and small amounts of gut microbiotaderived LPS are translocated from the gut to the circulation even in healthy patients [3,6,7]. LPS translocation is enhanced by high-fat meals [6,8] and this has been suggested as the reason, together with a different microbiota composition [9], because LPS and lipopolysaccharidebinding protein (LBP) levels are higher in obesity and diabetes [7,10,11], and decreased after weight loss [10]. Bariatric surgery (BS) is an effective treatment for obesity that consistently achieves and sustains substantial weight reduction [12]. Apart from a reduction in nutrient absorption, BS improves or resolves many obesity-related co-morbidities [12–14]. Interestingly, the improvement in carbohydrate metabolism occurs even before significant weight loss could intervene. Thus, other mechanisms must be participating, apart from weight reduction, which explain early metabolic improvement after surgery [13–17]. There are several different bariatric procedures such as Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion (BPD), sleeve gastrectomy (SG), and adjustable gastric banding. It has been suggested that the mechanism by which the metabolic improvement takes place may differ depending on the bariatric technique [12]. Recent studies have found a significant reduction in endotoxemia and proinflammatory mediators after BS in patients with morbid obesity and T2DM at 6 months [15] and at 1 year [16] together with an improvement in carbohydrate metabolism and weight reduction. Concordantly, previous data have demonstrated that BS is also able to modify gut microbiota, increasing bacterial diversity, which might influence circulating levels of LPS [9]. However, there are no data on the effect of BS on endotoxemia and its consequences on the early metabolic improvements, which occur o 3 months after surgery [13,18]. Thus, the aim of this study was to analyze the effect of 2 different surgical procedures (BPD versus SG) on LPS and LBP levels as well as to study the influence of endotoxemia in the short-term metabolic improvement after BS.
Methods Study patients and design The study included 50 morbidly obese patients and was performed concurrently using 2 different BS procedures: 26 patients underwent BPD and 24 underwent SG. All patients who underwent SG between 2011 and 2013 were included, and a sample was taken of patients, comparable in age and BMI, who underwent BPD. There was no loss to follow-up.
BPD consisted of distal gastrectomy with a long Roux-en-Y reconstruction with the enteroenteric anastomosis performed 50 cm proximal to the ileocecal valve and the gastroenteric anastomosis 250 cm proximal to the ileocecal valve, with 200 mL of gastric volume. SG is a technique that involves a longitudinal section parallel to the gastric lesser curvature supervised by a Fouche probe (12 mm or 14 mm). The vascularization of the stomach is not compromised, because the arterial supply of the celiac trunk remains intact [13]. All patients were examined before surgery (baseline) and 15 and 90 days postoperatively. Participants were classified according to their glycemic profile as normoglycemic (NG) patients, with fasting glucose levels o100 mg/dL and HOMA-IR (calculated as described below) o3.5; or prediabetic/diabetic (P/D) patients, with fasting glucose levels higher than 100 mg/ dL [19]. Patients were excluded if they had cardiovascular disease, arthritis, acute inflammatory disease, infectious disease or were receiving drugs that could alter the lipid profile or the metabolic parameters at inclusion in the study [13]. All the participants gave their written informed consent, and the study was reviewed and approved by the ethics and research committee of Virgen de la Victoria University Hospital (Malaga, Spain). Laboratory measurements Blood samples were obtained from the antecubital vein and placed in vacutainer tubes (BD vacutainer™, London, UK) after an overnight fast. The serum was separated by centrifugation for 10 min at 4000 rpm and frozen at 801C until analysis. Serum glucose, cholesterol, triglycerides, HDL cholesterol, C-Reactive Protein (CRP) and transaminases were measured in a Dimension autoanalyzer (Dade Behring Inc., Deerfield, IL) by enzymatic methods (Randox Laboratories Ltd., UK and Wako Bioproducts, Richmond, VA). LDL cholesterol was calculated using the Friedewald formula. Insulin concentrations were quantified by radioimmunoassay supplied by BioSource S.A. (Nivelles, Belgium). IR was calculated from the homeostasis model assessment of IR (HOMA-IR) with the formula: HOMA-IR ¼ [fasting serum insulin(μU/mL) fasting blood glucose(mmol/L)]/22.5 [8,13]. Leptin and adiponectin were analyzed by ELISA kits (DSL, Webster, TX, and DRG Diagnostics, respectively). LBP was measured using an immunoassay kit (HyCult Biotechnology) according to the manufacturer’s protocol. Plasma concentrations of LPS were measured by endotoxin assay, based on a Limulus amebocyte extract with a chromogenic LAL assay (QCL-1000, Lonza Group Ltd.) as previously described [8]. Statistical analysis The sample size was determined with the ENE 3.0 statistical program (GlaxoSmithKline). To detect mean
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differences for LPS concentrations of 30% with a conservative SD of .03, at least 7 patients per group were required to complete the study (α risk ¼ .05; power ¼ .8). The results are given as the mean ⫾ SD. Comparisons of the anthropometric and biochemical characteristics as well as LPS and LBP levels between the study groups were made with ANOVA and Duncan’s post hoc tests. The paired Student t test was used for comparisons between baseline, 15 days and 90 days. Pearson’s correlation analyses were done to analyze associations between the changes from baseline at 15 days and 90 days in the study variables. Multiple linear regression analysis was performed to evaluate the contribution of the study variables to the change in both LPS and LBP levels. Those variables found to be associated with the changes in LPS or LBP at 15 days and 90 days in the univariate analysis were included as independent variables in the multivariate analysis, together with any other variables considered to be clinically relevant (i.e., age, BMI, HOMA-IR, glucose levels). Dependent variables were the changes in LPS and the changes in LBP at 15 days and 90 days. Values were considered to be statistically significant when P o .05. Analyses were performed with SPSS, version 15.0 for Windows (SPSS Iberica, Spain). Results The biochemical and anthropometric characteristics of each study group at baseline, 15 days and 90 days are summarized in Table 1. From the BPD group, 35.3% were prediabetic patients and 64.7% were diabetic patients, whilst in the SG group, 46.2% were prediabetic and 53.8% were diabetic patients. The BMI significantly decreased at days 15 and 90 compared to baseline in all 4 study groups. Glucose levels diminished significantly only in the P/D patients. However, there was a significant decrease in insulin and HOMA-IR levels in all 4 study groups. GPT and GGT levels significantly increased at day 15 compared to baseline, but at day 90 diminished in all 4 study groups. The P/D patients undergoing both BPD and SG showed an increase in CRP levels at day 15 and a decrease at day 90. There were no significant differences between the 4 study groups in LPS or LBP levels (Fig. 1). The P/D patients undergoing SG were the only group that showed a significant decrease at day 90 in LPS levels (Fig. 1a). LBP levels increased at day 15 after BPD, significantly so in NG patients, but significantly decreased at day 90 compared to LBP levels at day 15 (Fig. 1b). LBP levels significantly decreased at day 90 after SG in both the NG and the P/D patients (Fig. 1b). Association between both the changes in LPS and LBP levels and the changes in biochemical and anthropometrical variables at 15 days and 90 days were evaluated. The change in LBP levels was significantly correlated with the
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change in insulin (r ¼ -.279; P ¼ .037), HOMA-IR (r ¼ -.271; P ¼ .043) and adiponectin (r ¼ -.414; P ¼ .023) levels at 15 days, and tended to correlate with the change in BMI (r ¼ .232; P ¼ .088), CRP (r ¼ .325; P ¼ .074) and cholesterol levels (r ¼ -.221; P ¼ .099) at 15 days. However, none of the variables were independently associated with the change in LBP at 15 days in the multiple linear regression analysis. Regarding the changes in LPS levels at 15 days, no independent association with the changes in biochemical or anthropometrical variables was found. The changes in LBP at 90 days were significantly correlated with the change in BMI (r ¼ .428; P ¼ .001) and in waist circumference (r ¼ .330; P ¼ .025), and tended to correlate with the changes in cholesterol (r ¼ -.259; P ¼ 0.051) and HDL-C levels (r ¼ -.248; P ¼ .065). In the multiple linear regression analysis, the change in BMI was the only variable that remained significantly and independently associated with the change in LBP levels at 90 days (R2 ¼ .362; β ¼ .382; P ¼ .019). None of the biochemical or anthropometrical variables was independently associated with the change in LPS levels at 90 days. Discussion The results of this study show that the short-term effect of BS on LPS levels depends on the type of surgical procedure and the previous glycemic status of the patient. To our knowledge, this is the first study comparing the short-term effect of BPD and SG on LPS and LBP levels taking into account the glycemic status of morbidly obese patients, finding that LPS levels diminished only at day 90 after SG in the P/D patients. This supports the hypothesis that postoperative metabolic improvement is due to different mechanisms depending on the surgical technique. In addition, we found that LBP could be an inflammatory marker in the short-term after BS. It is well known that BS achieves substantial weight loss even in the short term [12–14] which agrees with our study where a reduction in BMI was seen from day 15, independently of the procedure or the glycemic status of the patients. Moreover most bariatric procedures are also able to improve metabolic diseases even before significant weight loss occurs [13,14]. An improvement in carbohydrate metabolism has been described both for BS procedures that imply food rerouting along the gastrointestinal tract and for those procedures that do not [13,15,17,20–25]. The weight and glucose metabolism improvements seem to be independent of each other, since it has been reported that there is significant weight loss in diabetic and nondiabetic patients after RYGB [20] and diabetes remission is also achieved in 40% of nonobese diabetic patients, with an improvement in insulin sensitivity after BPD [21]. Comparisons between the 2 surgical procedures suggest that gastric bypass is more efficient in improving carbohydrate metabolism than SG, since a higher remission of diabetes [24] as
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Table 1 Anthropometric and biochemical variables of the study groups before and at days 15 and 90 after bariatric surgery BPD
Age (years) BMI (Kg/m2)
Waist (cm)
Weight loss (%)
Glucose (mmol/L)
Insulin (pmol/L)
HOMA-IR
TG (mmol/L)
Chol (mmol/L)
HDL-C (mmol/L)
LDL-C (mmol/L)
GOT (units/L)
GPT (units/L)
GGT (units/L)
Leptin (ng/mL)
Adiponectin (ng/mL)
CRP (mg/L)
Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d Baseline 15 d 90 d
SG
NG (n ¼ 9)
P/D (n ¼ 17)
NG (n ¼ 11)
P/D (n ¼ 13)
38.88 ⫾ 7.68 51.35 ⫾ 3.64 47.07 ⫾ 3.54 a,b* 42.11 ⫾ 3.92 a,b*† 139.00 ⫾ 12.92 131.54 ⫾ 11.26 a,b 119.68 ⫾ 11.42 a,b*† 9.18 ⫾ 5.04 18.86 ⫾ 5.09† 4.98 ⫾ 0.31a 4.99 ⫾ 0.32 a 4.81 ⫾ 0.32 a 139.66 ⫾ 70.77 82.37 ⫾ 24.59* 62.71 ⫾ 23.61* 4.52 ⫾ 2.45 2.62 ⫾ 0.74 a* 1.96 ⫾ 0.86* 1.28 ⫾ 0.51 1.75 ⫾ 0.47a,b* 1.28 ⫾ 0.30a,b† 4.85 ⫾ 1.19 3.87 ⫾ 0.81a* 3.57 ⫾ 0.63a* 1.09 ⫾ 0.29 0.76 ⫾ 0.13a* 0.89 ⫾ 0.32a 2.81 ⫾ 0.62 2.12 ⫾ 0.54a* 1.97 ⫾ 0.68a* 24.08 ⫾ 11.99 37.33 ⫾ 10.67* 29.17 ⫾ 12.28 50.25 ⫾ 21.87 83.83 ⫾ 22.15* 57.00 ⫾ 19.69† 36.25 ⫾ 17.45 a,b 108.00 ⫾ 86.73 a* 33.17 ⫾ 15.84† 52.97 ⫾ 21.67 25.68 ⫾ 16.03 a* 22.83 ⫾ 11.21* 8.67 ⫾ 3.24 9.32 ⫾ 4.37 12.29 ⫾ 6.29 6.29 ⫾ 3.85 10.18 ⫾ 7.10 2.36 ⫾ 1.99†
45.53 ⫾ 6.44 52.46 ⫾ 5.05 48.41 ⫾ 5.23 a* 43.57 ⫾ 4.17 a*† 143.50 ⫾ 14.69 137.08 ⫾ 9.86 a* 128.46 ⫾ 12.41a*† 7.45 ⫾ 5.84 17.35 ⫾ 4.45† 7.10 ⫾ 1.60b 5.97 ⫾ 0.67 b* 5.24 ⫾ 0.55 b*† 136.89 ⫾ 60.77 104.24 ⫾ 41.11* 70.70 ⫾ 32.99*† 6.08 ⫾ 2.63 3.95 ⫾ 1.57 b* 2.42 ⫾ 1.26*† 1.68 ⫾ 1.01 1.99 ⫾ 0.42a 1.53 ⫾ 0.48a† 5.22 ⫾ 1.15 4.20 ⫾ 0.80a,b* 3.67 ⫾ 0.69a*† 1.11 ⫾ 0.27 0.75 ⫾ 0.14a* 0.88 ⫾ 0.19a*† 3.32 ⫾ 1.03 2.48 ⫾ 0.79a,b* 2.13 ⫾ 0.75a* 22.76 ⫾ 15.35 37.35 ⫾ 24.52* 29.41 ⫾ 9.30 52.47 ⫾ 23.90 86.88 ⫾ 52.10* 58.24 ⫾ 15.54† 41.72 ⫾ 23.11 a 72.50 ⫾ 30.61 a,b* 31.00 ⫾ 16.12*† 57.45 ⫾ 14.93 37.68 ⫾ 17.16 a* 25.55 ⫾ 9.12*† 9.23 ⫾ 4.24 8.54 ⫾ 3.30 12.60 ⫾ 9.14 5.52 ⫾ 2.84 10.36 ⫾ 6.57* 3.19 ⫾ 3.19†
39.36 ⫾ 9.55 49.40 ⫾ 5.89 45.34 ⫾ 6.49 a,b* 37.58 ⫾ 12.21b*† 133.65 ⫾ 10.07 123.55 ⫾ 12.07 b* 113.50 ⫾ 13.59 b*† 8.29 ⫾ 7.03 16.97 ⫾ 5.70† 4.97 ⫾ 0.32a 4.87 ⫾ 0.60a 4.77 ⫾ 0.35a 113.06 ⫾ 86.26 83.06 ⫾ 27.50 59.73 ⫾ 19.65† 3.62 ⫾ 2.86 2.61 ⫾ 0.98a 1.83 ⫾ 0.62† 1.31 ⫾ 0.84 1.57 ⫾ 0.62b 1.16 ⫾ 0.48b† 4.44 ⫾ 0.91 4.56 ⫾ 0.91a,b 4.34 ⫾ 0.66b 1.12 ⫾ 0.32 0.84 ⫾ 0.16a,b* 1.11 ⫾ 0.30a,b† 2.80 ⫾ 1.06 2.99 ⫾ 0.81b 2.62 ⫾ 0.64ª,b† 18.25 ⫾ 8.57 28.75 ⫾ 16.94* 22.75 ⫾ 29.99 38.92 ⫾ 19.52 66.42 ⫾ 27.21* 44.08 ⫾ 33.19 22.25 ⫾ 12.01 b 57.08 ⫾ 42.92 b* 44.67 ⫾ 94.74 54.45 ⫾ 19.88 58.75 ⫾ 28.43b 30.20 ⫾ 6.91 11.39 ⫾ 30.4 11.67 ⫾ 4.40 12.63 ⫾ 6.41 4.58 ⫾ 7.20 10.49 ⫾ 5.76 2.98 ⫾ 1.38
45.67 ⫾ 10.95 48.59 ⫾ 3.98 44.33 ⫾ 3.20 b* 40.20 ⫾ 2.99 a,b*† 135.89 ⫾ 16.51 128.57 ⫾ 10.48 a,b* 118.75 ⫾ 12.80 a,b*† 8.99 ⫾ 5.61 17.81 ⫾ 4.17† 6.48 ⫾ 0.75b 6.32 ⫾ 1.06b 5.54 ⫾ 0.55b*† 128.97 ⫾ 105.36 99.59 ⫾ 40.35 67.09 ⫾ 22.99*† 5.27 ⫾ 4.11 4.09 ⫾ 1.94b 2.39 ⫾ 0.88*† 1.78 ⫾ 0.58 1.66 ⫾ 0.54a,b 1.36 ⫾ 0.43a,b*† 4.96 ⫾ 0.62 4.73 ⫾ 1.10b 4.95 ⫾ 0.92c 1.12 ⫾ 0.32 0.96 ⫾ 0.27b* 1.15 ⫾ 0.33b† 3.13 ⫾ 0.68 3.00 ⫾ 0.89 b 3.08 ⫾ 0.81b 25.88 ⫾ 11.80 28.47 ⫾ 15.35 18.41 ⫾ 12.90*† 54.76 ⫾ 29.92 69.65 ⫾ 37.45* 41.35 ⫾ 27.17*† 33.18 ⫾ 15.05 a,b 79.18 ⫾ 70.35 a,b* 25.24 ⫾ 15.39*† 56.79 ⫾ 25.65 38.65 ⫾ 13.28 a* 49.89 ⫾ 58.21 9.45 ⫾ 2.64 9.87 ⫾ 2.95 11.94 ⫾ 4.11* 4.59 ⫾ 3.02 9.70 ⫾ 6.38* 2.46 ⫾ 2.25
BMI ¼ Body mass index; BPD ¼ Biliopancreatic diversion; Chol ¼ cholesterol; CRP ¼ C-reactive protein; GGT ¼ gamma-glutamyl transferase; GOT ¼ glutamic oxalacetic transaminase; GPT ¼ glutamic pyruvate transaminase; HDL-C ¼ HDL cholesterol; LDL-C ¼ LDL cholesterol; NG ¼ normoglycemic patients; P/D ¼ prediabetic and diabetic patients; SG ¼ Sleeve gastrectomy; TG ¼ triglycerides Results are presented as the mean ⫾ SD. A different letter indicates significant differences between the study groups. The 4 groups were compared with each other according to ANOVA and Duncan’s post hoc test (rows; P o .05). * P o .05 compared to baseline (paired sample Student t test). † P o .05 15 d versus 90 d (paired sample Student t test).
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Fig. 1. Plasma LPS (A) and LBP (B) levels before and at days 15 and 90 after bariatric surgery in the study groups. Results are presented as the mean ⫾ SD *P o .05 compared to baseline. †P o .05 15 day versus 90 day. There were no significant differences between the 4 study groups. BPD ¼ Biliopancreatic diversion according to Scopinaro; SG ¼ Sleeve gastrectomy; NG ¼ normoglycemic patients; P/D ¼ prediabetic and diabetic patients; LPS ¼ lipopolysaccharide; LBP ¼ LPS-binding protein.
well as an earlier improvement in fasting glucose and insulin levels and HOMA-IR are seen with BPD than with SG [13,17]. This is in line with our study, which showed that insulin levels and HOMA-IR were significantly decreased at day 15 after BPD in both the NG and the P/ D patients, but they were not significantly reduced until day 90 after SG. The same behavior was observed in the P/D patients in regard to glucose levels. However, others did not find such clear differences between these 2 procedures regarding carbohydrate metabolism [25]. Nutrient-sensing mechanisms in the gut that trigger the gut-brain-liver axis to lower glucose production and food intake are impaired in obesity and diabetes, but evidence suggests that after BS the gut-brain-liver axis signaling is reprogrammed and glycemia normalized rapidly [26]. This would explain, at least in part, the early weight lossindependent metabolic improvement after surgery. Some procedures imply the restructuring of the gastrointestinal
5
tract such as BPD, and consequently involve obvious changes in neuro-hormonal signaling. By contrast, other procedures such as SG are initially based on restricting the amount of food that passes through the gastrointestinal tract, and although the gastric emptying mechanism and normal digestion are preserved to some extent, this kind of surgery also involves physiologic changes that improve metabolic diseases [27]. Among the hypotheses proposed to explain the early resolution of diabetes and IR are the modifications in the secretion pattern of gut hormones, microbial ecology or bile acid secretion [26,28]. It is noteworthy that not all BS procedures lead to the same gastrointestinal tract and physiologic changes, with different gut signaling pathways being affected [23] and the precise mechanisms and molecular mediators involved after each procedure remain unclear. All this together suggests that the mechanism leading to early metabolic improvements after BS varies depending on the type of procedure [12,14,27]. Recently, it has been proposed that a reduction in LPS levels after BS could also be involved in the improvement in carbohydrate metabolism [15,16]. There is increasing evidence suggesting that LPS could be a key factor in the low-grade inflammation seen in obesity [3,6,8]. The gut microbiota has been suggested as the main source of circulating LPS in the absence of infectious diseases. It has been shown that high-fat meals promote LPS translocation from the gut, probably by means of chylomicron particles [8]. Moreover, it has been proposed that increased gut permeability in obesity also enhances LPS translocation [3,29]. This would lead to a rise in plasma LPS levels and consequently to the low-grade inflammation state in obesity, which contributes to the development of IR and diabetes. However, previous studies dealing with LPS and BS have only analyzed long-term changes (6 months and 1 year) in LPS levels [15,16], not defining whether the reduction in endotoxemia is also involved in the early metabolic improvements in the first few days after surgery. In addition, although Trøseid et al. have reported data on 2 different types of surgery (RYGB and duodenal switch), they have not compared whether these 2 procedures have a different effect on endotoxemia or whether there is a different evolution depending on the glycemic status [16]. By contrast, our study analyzed the short-term effect of BS on LPS levels and compared one procedure that modifies the anatomy of the gastrointestinal tract to another that does not imply food rerouting, taking into account the previous glycemic status of the participants. We found a significant reduction in LPS levels only at day 90 after surgery in those P/D patients who had undergone SG. This suggests that the early LPS reduction depends on both the surgical procedure and the previous metabolic status of the patient, and although a long-term reduction in LPS levels might help in the sustained improvement of T2DM [16], further studies will be necessary to determine the precise role of endotoxemia in the early metabolic improvements after each type of
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M. Clemente-Postigo et al. / Surgery for Obesity and Related Diseases ] (2015) 00–00
bariatric procedure. One possible explanation for the different effects of BPD and SG on LPS levels might be specific modifications in gut microbiota ecology. In the last few years, multiple roles affecting gut function have been attributed to gut microbiota: regulation of hormone release from enteroendocrine cells, activation of vagal afferent signaling, regulation of production of bile acids, as well as modification of intestinal permeability [26]. Consequently, the change in gut microbiota composition might modify endotoxemia directly by decreasing LPS production and/or indirectly by affecting the gut function. Although it has been reported that RYGB is able to modify gut microbiota leading to a healthy bacterial profile [9,26], to our knowledge there are no previous studies analyzing the changes in gut microbiota after BPD and SG, thus future studies should be conducted to confirm this hypothesis. LBP is an acute-phase protein, synthesized primarily by the liver, which is involved in the systemic response to LPS. LBP binds LPS and presents it to CD14, enhancing the cell response to LPS [30]. However, LBP is also a lipid transfer protein able to transfer LPS to lipoproteins minimizing the LPS response [31]. Several recent studies have shown a relationship between LBP and metabolic diseases. High levels of LBP have been associated with obesity and with the degree of IR [10,11]. In our study, this relationship was also seen with the BMI after the multivariate analysis. The lack of association with the biochemical variables has been described previously in BS patients [32]. Similarly, we found no significant differences in LBP levels between the NG and the P/D patients, although different behavior was seen after surgery depending on the procedure; there was a transient rise in LBP levels after BPD that did not occur after SG. In addition, LBP decreased at day 90 compared to baseline after SG but not after BPD. These results agree with previous studies that have described an increase in inflammation in the short-term after BPD, probably due to the major restructuring carried out in BPD [33]. Concordantly, it has been shown that LBP and other acute-phase protein levels remained elevated during the first 6 months after gastric banding and decreased from 12 months [34], which corroborates the hypothesis that the short-term changes in acute-phase proteins after BS depend on the procedure. In spite of these differences in the short-term, a recent study comparing minigastric bypass, RYGB, SG and AGB showed that 1 year postoperatively, LBP levels decreased significantly after all 4 procedures [32], which is probably due to the general metabolism improvement described after 1 year from surgery that includes the amelioration of the inflammatory state [34]. Interestingly, we did not observe a parallel response in LPS and LBP levels. Although LBP has been described as an endotoxemia marker, it is necessary to take into account that surgery involves tissue injury, which also stimulates inflammation and the secretion of liver acute-phase reactants such as CRP. In fact, CRP levels also increased transiently at 15 days with a decrease at 90 days, in agreement with previous
studies that describe a transient short-term increase in CRP after BPD and SG [13] and a significant decrease in CRP levels at 3 months after BPD and RYGB [9,13] and at 6 months after RYGB [15]. In addition, previous studies have also shown a transient increase in transaminases after RYGB [35] and BPD which is restored after 6 months [36], indicating that LBP behavior in the short-term after BPD seems to be more related to the liver response to the surgery itself than to the endotoxemia response, and the greater LBP response after BPD is likely more pronounced due to the major tissue damage that BPD involves and that SG does not. One of the limitations of this study was the small sample size that might reduce the statistical power, but we preferred to include only patients from the 2 last years to guarantee greater homogenization of the surgical technique. It is noteworthy that, in spite of the sample size, we were able to detect significant differences in both LPS and LBP levels at 90 days after SG. Another aspect to take into account is that the short follow-up period did not allow us to evaluate if medium or long-term surgery-derived complications are occurring and if so, could these also be related to the LPS or LBP levels, especially after BPD. However, we were interested in analyzing the short-term changes of LPS and LBP after the 2 different surgical procedures to see if these 2 variables were related to the early metabolic improvement that occurs o 3 months after surgery. In conclusion, this is the first study showing that the short-term LPS decrease after BS depends on the surgical procedure as well as on the previous glycemic status of the patient, with SG having the greatest short-term effect on LPS and LBP levels. In addition, LBP shows a close relationship with the improvement in BMI and it may be an inflammatory marker in patients who have undergone BS. Disclosures The authors have no financial or other contractual agreements that might cause conflicts of interest or be perceived as causing conflicts of interest. Acknowledgments MCP was a recipient of a FPU grant (AP2009-4537) from the Ministry of Education (Madrid, Spain), MMRR was a recipient of a fellowship from ISCIII (Rio Hortega CM11/00030), Spanish Ministry of Economy and Competitiveness, (Madrid, Spain) and FC was supported by “Miguel Servet Type II” program (CP13/00023) from the ISCIII, Madrid (Spain). The authors wish to thank all the patients for their collaboration, and FIMABIS. We also gratefully acknowledge the help of Maria Repice and Ian Johnstone for their expertise in preparing this manuscript, Juan Alcaide-Torres (IBIMA) for his technical contribution and Olga Perez (FIMABIS) for her statistical support. This study was supported by “Centros de Investigación En Red” (CIBER, CB06/03/0018) of the “Instituto de Salud
Short-term Endotoxemia Changes After BPD and SG / Surgery for Obesity and Related Diseases ] (2015) 00–00
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