Introduction
Chronic systemic inflammation and increased oxidative stress play a role in the pathogenesis of obesity, type 2 diabetes (T2DM) and cardiovascular disease [
1]. Plasma levels of adipokines such as adiponectin and leptin and inflammatory cytokines such as C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumour necrosis factor alpha (TNF-α) are influenced by adipose tissue mass [
2,
3]. Bariatric surgery leads to a significant reduction in adipose tissue mass and subsequent improvement in systemic inflammation [
4].
With respect to oxidative stress, there are conflicting reports in the available literature. Catoi et al. observed no change in global measures of oxidative stress; nitrite and nitrate (NOx), total oxidant status (TOS), total antioxidant response (TAR), and oxidative stress index (OSI), 6 months after sleeve gastrectomy (SG) [
5]. However, Cabrera et al. demonstrated that plasma level of glutathione (GSH) and total radical antioxidant parameter (TRAP) was increased and plasma levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were decreased in 20 patients with obesity 12 months after Roux-en-Y Gastric Bypass (RYGB) [
6]. It is important to note that in most of the published studies examining inflammation or oxidative stress, the follow-up period was up to 2 years. There is limited literature available on the long-term effect of bariatric surgery on inflammation and no literature available on long-term effect of bariatric surgery on oxidative stress.
Our previous work demonstrated that SG was associated with improvement in inflammation and oxidative stress in 55 participants with impaired glucose regulation [
7]. The primary aim of the current study was to examine the long-term (4 years) effects of bariatric surgery on adipokines (adiponectin, leptin), inflammatory cytokines (CRP, IL-6, IL-10) and global plasma measures of oxidative stress (thiobarbituric acid reactive substances [TBARS] and total antioxidant status [TAOS]) regardless of operation types. The secondary aim was to investigate changes in adipokines (adiponectin, leptin), inflammatory cytokines (CRP, IL-6, IL-10) and global plasma measures of oxidative stress at 4 years in the SG group.
Discussion
Bariatric surgery is associated with an improvement in metabolic outcomes and a reduction in cardiovascular risk factors. It is postulated that this is likely to be related to an improvement in the inflammatory environment as a result of rapid and substantial weight loss. In line with previously published studies, which had shorter follow-up duration (6 to 24 months) [
4,
8,
17], we observed a significant reduction in pro-inflammatory biomarkers (leptin, CRP, IL-6) at 4 years. These improvements were accompanied by an improvement in body weight (44% EWL), an improvement in glycaemic control (65% achieving a target HbA1c ≤ 6.5%) and improvements in cardiovascular risk factors (diastolic blood pressure and HDL-C). However, we observed no significant change in plasma adiponectin level (but numerical decrease). One possible explanation for this unexpected finding of plasma adiponectin level could be type 2 error and the other explanation might be due to small sample size.
Of note, two previous studies have examined changes in cytokines at 3 years following bariatric surgery. One study examined CRP, adiponectin, leptin, visfatin, IL-6 and TNF-α in 10 subjects with normal glucose tolerance following BPD. The authors reported that after considerable weight loss (53% EWL), leptin, CRP and IL-6 decreased but adiponectin increased significantly. No significant changes were observed in TNF-α [
18]. Another study comprising of 28 subjects with the metabolic syndrome, examined changes in adipocytokines before and 3, 6, 12 and 24 months after vertical banded gastrectomy. Of these, six subjects had 36- and 48-month follow-up. The authors reported a linear increase in levels of adiponectin and resistin along with a non-significant decrease in CRP at 36 and 48 months, and a significant decrease in leptin at 36 months compared to baseline [
19].
In the current study, there was a numerical reduction (30%) in IL-10 at 4 years compared to baseline. Although IL-10 is generally regarded as an anti-inflammatory cytokine, some human experimental studies revealed pro-inflammatory property of IL-10 [
20]. The published literature contains conflicting reports relating to the effect of bariatric surgery on IL-10. Netto et al. demonstrated that IL-10 increased by 123 ± 55% (
p = 0.02) in 41 subjects with obesity without T2DM, 6 months after RYGB [
21]. Mallipedhi et al. showed no significant changes in IL-10 concentration in 22 patients with T2DM and impaired glucose regulation 6 months after SG [
8].
With respect to oxidative stress, fasting and 120-min TAOS significantly increased at 4 years compared to the pre-operative levels. TAOS, a global measure of antioxidant status, is inversely associated with oxidative stress and obesity [
22]. Previous work by Prior et al. observed no change in TAOS in 22 participants with morbid obesity and impaired glucose regulation 6 months following SG [
14]. Two other studies also reported no changes in plasma TAOS following surgical induced weight loss. Catoi et al., examined TAOS and total antioxidant response (TAR) in patients with morbid obesity in comparison with a normal weight control group (
n = 23 each group). No significant changes were observed in TAOS 12 months after silastic ring vertical gastroplasty [
23]. Melissa et al. described no change in TAOS in 16 subjects with obesity, 6 months following intragastric balloon, despite significant reduction in body weight [
22].
It is important to note that TAOS can be influenced by many factors such as age [
24], diet [
25], vitamin supplementation [
26] and physical activity [
27]. Possible explanations for an increase in TAOS within the current study include changes in dietary habit following bariatric surgery; vitamin supplementations following bariatric surgery; possible changes in physical activity due to weight loss; a decrease in pro-inflammatory cytokines; a better glycaemic control or an improvement in cardiovascular risk factors.
Within the current study, no significant change in TBARS was observed at 4 years, compared to the pre-operative values. However, we observed an initial decrease (but not statistically significant) in TBARS at 1 month and 6 months. There are inconsistent observations on the effect of bariatric surgery on TBARS. Uzun et al. showed a significant decrease in MDA and oxidized LDL (ox-LDL) and a strong positive relationship between MDA and BMI (
r = 0.79,
p < 0.001) in 20 subjects with obesity, 6 months after LAGB [
28]. Boesing et al. observed that RYGB was associated with an increase in TBARS, despite a significant weight loss in 20 subjects at 6 months [
29]. On the other hand, Dadalt et al. (
n = 35) described an initial decrease in TBARS at 12 months after RYGB but this was not preserved at 24 months, when 25.7% of the participants regained weight [
30].
We observed a positive correlation between Δleptin with both Δweight and ΔBMI, suggesting a change in weight was associated with a change in leptin. Leptin is an orexigenic hormone and high serum leptin concentrations are associated with high BMI and body fat mass [
31]. We also observed a negative correlation between Δ120-minute TAOS with ΔFPG and a positive correlation between Δ120 minutes TBARS with ΔHbA1c. These findings were in agreement with previous studies describing an association between oxidative stress and markers of glycaemia [
32].
In the exploratory sub-group analysis, we demonstrated that SG was associated with a significant reduction in pro-inflammatory biomarkers (leptin, CRP, IL-6) along with an improvement in body weight and glycaemic control at 4 years. Our findings were in agreement with previous studies. Zhu et al. demonstrated a reduction in leptin, CRP and IL-6 in patients with morbid obesity and subclinical hypothyroidism 12 months following SG [
33]. Similarly, Salman et al. demonstrated that the levels of serum adiponectin significantly increased, while the levels of serum leptin, resistin, CRP, plasminogen activator inhibitor-1 and serum amyloid-A significantly decreased at 6 months after SG [
34]. In contrast to previous studies [
18,
19,
34], we observed no statistically significant change in serum adiponectin levels. This might be explained by a small sample size. In our recent published study comprising 55 participants with impaired glucose regulation, we observed a significant increase in serum adiponectin level at 6 months following SG [
7]. Within the SG group, there was a significant increase in fasting TBARS as well as fasting TAOS. Since TBARS is a measure of lipid peroxidation, an increase in total cholesterol and LDL cholesterol following SG might explain an increase in fasting TBARS. Previous studies have shown that SG has no significant impact on lowering total cholesterol and LDL-C but is associated with an increase in HDL-C [
35‐
37]. An increase in TAOS reflects a reduction in global oxidative stress and an improvement in metabolic profile. Of note, plasma TAOS is correlated positively with HDL-C and negatively with glucose and HBA1c [
13].
There are limitations to the current study. The first limitation was a small sample size and a considerable drop-out at 4 years. In addition, a considerable number (
n = 8) of participants were excluded for analysis of TBARS due to haemolysis of blood sample. The second limitation was that the sample comprised of three participants who had impaired glucose tolerance, since the level of chronic inflammation and oxidative stress might differ between those with established T2DM. The third limitation was the accuracy and variability of duration of diabetes within the group (mean duration 37 ± 35 months) and this might influence the level of inflammatory makers and oxidative stress pre-operatively. The fourth limitation was that factors influencing antioxidant status such as diet history, physical activity and uric acid concentrations were also not recorded. The fifth limitation was the heterogeneity of bariatric procedure. However, previous studies demonstrated that weight lost is not dissimilar amongst SG, RYGB and BPD [
38]. Our aim was to examine long-term (4 years) changes in inflammatory biomarkers and oxidative stress following bariatric surgery irrespective of surgical technique. Since the SG was the predominate procedure in this cohort, we also reported sub-group exploratory analysis for the SG group. To our knowledge, no other studies have described changes in inflammation and oxidative stress at 4 years following bariatric surgery. The current study contributes to the current literature supporting the beneficial effect of bariatric surgery on chronic inflammation and oxidative stress at 4 years. To translate our findings into clinical setting, larger studies with adequate power and long-term follow-up are warranted.
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