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Abstract

Background:

Bile acids (BAs) are traditionally associated with lipid absorption and phase II detoxification by forming various BA conjugates. Recently, it has been discovered that BAs also regulate glucose metabolism, and the increase in BAs in patients following bariatric surgery may contribute to the post-surgery improvement in insulin resistance (IR). However, while Roux-en-Y gastric bypass can increase BA concentrations post-surgery, this may not be the case after laparoscopic sleeve gastrectomy (LSG). We hypothesized that the profiling of BAs that include the conjugated BA species could detect post-surgery BA changes after LSG. To test our hypothesis, we performed comprehensive profiling of BAs in Asian individuals with morbid obesity at baseline, and at 6 months following LSG.

Methods:

Fourteen subjects scheduled for LSG were recruited. Anthropometric measurements, oral glucose tolerance test, and biochemistry tests were performed at baseline and at 6 months after LSG. BAs were profiled using liquid chromatography–mass spectrometry.

Results:

At 6 months, subjects lost significant weight from 117.4±5.4 to 92.1±3.8 kg and demonstrated significant improvement in IR. HOMA-IR decreased from 6.2±0.7 to 2.0±0.2 and the Matsuda index increased from 1.9±0.3 to 3.3±0.3. We did not detect any significant post-operative change in the levels of total BAs (5237.1±1219.4 vs. 3631.7±457.9, p=0.181) or non-sulfated BAs after LSG. However, sulfated BA species increased significantly after LSG.

Conclusion:

Our study showed that the serum concentrations of sulfated BA species in morbidly obese Asian individuals increased significantly 6 months after LSG; the increase in sulfated BAs after LSG might contribute to the post-surgery improvement of metabolic health.

Keywords

Bile acids insulin resistance laparoscopic sleeve gastrectomy Asian morbid obesity

Introduction

Bile acids (BAs) are the main components of bile. Primary BAs are synthesized in the liver and are conjugated with glycine or taurine before being excreted into the intestine. Here, conjugated primary BAs are further metabolized by gut microbiota into secondary BAs. Most secondary BAs are reabsorbed into the enterohepatic circulation, but a small amount is excreted into feces. BAs are recognized for their roles in the absorption of lipids and in the regulation of cholesterol metabolism. BAs also participate in the phase II detoxification pathway by forming water-soluble conjugates with various compounds such as sulfates for excretion from the human body.¹ Most recently, BAs have been discovered to regulate glucose and lipid metabolism through Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) signaling pathways.^2,3 The discovery of these new mechanistic pathways may be important, as several studies have found altered BA concentrations and composition among individuals with insulin resistance (IR).^4,5

Bariatric surgery is the most effective treatment for obesity and leads to a significant reduction in IR. However, the mechanism for IR improvement following bariatric surgery is not well understood and multiple mechanisms could be involved.⁶ In this regard, changes in the concentration and composition of BAs after bariatric surgery have been postulated as a possible mechanism.^7,8 Roux-en-Y gastric bypass surgery (RYGB) is the most commonly performed malabsorptive bariatric surgery technique, and the level of BAs appears higher after surgery. One study reported a significant increase in fasting total BA and deoxycholic acid (DCA) levels, but a decrease in taurine/glycine conjugation ratio at 1 year after RYGB.⁹ Similarly, a separate study involving RYGB patients also reported that fasting total, primary, secondary, unconjugated and conjugated BAs trended higher post-surgery, while the 12 alpha-hydroxylated/non-12 alpha-hydroxylated ratio was significantly elevated.¹⁰

Laparoscopic sleeve gastrectomy (LSG) is an alternative bariatric surgery technique and has emerged as the most commonly performed bariatric surgery procedure in recent years.¹¹ Interestingly, although LSG appeared to be as effective as RYGB in reducing weight and improving IR in the short term,^12,13 studies investigating the changes of BAs following LSG are scarce. Further, the restrictive nature of LSG may have a different effect on BA concentration and composition compared with RYGB. Presently, the few studies that have described changes in BAs after LSG have reported conflicting results.^14,15 One study reported an increase in total concentration of BAs with a change in composition, while another observed no change in concentration of BAs after LSG.^14,15 The lack of changes in post-surgery BA concentrations may be a result of the increase in excretion of various BAs from the circulating pool due to the conjugation of various BAs with polar compounds such as taurine, glycine, glucose, glucuronic acid, glutathione and sulfate. Differences in conjugated bile acids involving taurine, glycine and glucose have been reported in bariatric surgery patients,¹⁶ but little is known about the impact of surgery on the composition of sulfated BAs.

We hypothesized that the profiling of BAs that include the conjugated BA species could detect post-surgery changes in BAs among patients undergoing LSG. To test our hypothesis, we performed comprehensive profiling of BAs in Asian individuals with morbid obesity at baseline, and at 6 months following LSG.

Materials and methods

Study subjects

Fourteen morbidly obese individuals scheduled for LSG were recruited from the Singapore General Hospital’s weight management clinic. Our selection criteria include: body mass index (BMI) ⩾ 37.5 or ⩾ 32.5 kg/m² with obesity-related complications and failure to respond to medical treatment. Subjects with diabetes (defined as fasting glucose > 6.9 mmol/l or >11.0 mmol/l in the 2-hour oral glucose tolerance test (OGTT)) were excluded from the study, as our main study goal was to investigate the alterations in BAs following LSG. Differences in diabetes control and treatment between subjects at baseline and changes in diabetes treatment after surgery may affect BA metabolism independent of the surgical procedure. Subjects were also excluded if they had any cardiovascular, kidney or liver disorders, or if they are taking medications which might affect glucose and BAs metabolism.

Study protocol

All subjects underwent metabolic evaluations, including biochemistry tests, anthropometric measurements, and OGTT at baseline and 6 months after bariatric surgery. All subjects were seen by a dietitian before and after bariatric surgery as part of routine clinical practice. We recruited patients without a history of diabetes or any severe medical co-morbidities. Hence, they received the same dietary advice according to standard clinical guidelines both before and after bariatric surgery.

Laboratory measurements

All subjects were fasted for 8 h, and venous blood samples were taken for measurements of total cholesterol (TC), triglycerides (TG), high-density cholesterol (HDL), low-density cholesterol (LDL), alanine transferase (ALT), and aspartate transferase (AST). All of the above were measured using standard biochemical methods. Fasting glucose concentrations were measured using the glucose oxidase method (YSI Inc, Yellow Springs, OH, USA) and insulin concentrations using carbonylmetalloimmune assay (Abbott Diagnostics, Wiesbaden, Germany). Samples were also taken for measurement of serum concentration of fasting BAs. Concentrations of BAs were measured with liquid chromatography–mass spectrometry using the operation parameters and analytical methods described by Han et al.¹⁷

Anthropometric measurements

Anthropometric measurements including height, weight, weight circumference (WC), hip circumference (HC) and blood pressure were measured three times and averaged. Body composition including fat mass (FM), fat-free mass (FFM) and FM percentage were estimated with tetrapolar bioelectric impedance analysis (Tanita Body Composition scale, model TBF-300, Tanita Corporation, Tokyo, Japan).

Oral glucose tolerance test

Participants were given 75 g oral glucose after 8 h of fasting. Their venous blood samples were taken at 0, 15, 30, 60, 90 and 120 min after glucose intake to measure serum concentrations of glucose and insulin.

Calculations

IR was represented by the surrogate marker homeostasis model assessment for insulin resistance (HOMA-IR), and insulin sensitivity was defined by the Matsuda index. HOMA-IR was calculated as fasting glucose multiplied by fasting insulin divided by 22.5.¹⁸ Matsuda index was calculated by dividing 100,000 using the square root of the product of fasting glucose, fasting insulin, mean glucose and mean insulin concentration.¹⁹ Area under curve (AUC) for glucose and insulin concentration following OGTT was calculated using trapezoidal rule.

Data analysis

The changes in metabolic and BA profiles before and 6 months after LSG were compared using paired t-test or Wilcoxon signed rank tests. Data were presented as mean ± SEM. A two-tailed p-value ⩽ 0.05 was deemed to be statistically significant. Statistical analysis was performed with SPSS version 22 (SPSS Inc., Chicago, IL, USA). This is a pilot study with exploratory intention, and the number of subjects to be recruited was based on the sample size of subjects necessary to demonstrate significant improvement in body weight and metabolic measurements.

Results

Metabolic characteristics

Subjects who underwent LSG achieved significant weight loss after 6 months, with loss in fat mass the mainly contributor to this. Accordingly, FM percentage, WC, HC, and weight–hip ratio decreased significantly following LSG. In addition, significant improvements in systolic blood pressure, triglycerides, and ALT were also seen after bariatric surgery (Table 1).

Table 1.

Characteristics of participants at baseline and six months after sleeve gastrectomy

Parameters	pre-op (n = 14)	post-op (n = 14)	p-value
Age (years)	33.8 ± 2.3
Male (%)	50
Ethnicity
Chinese	35.7%
Malay	28.6%
Indian	28.6%
Others	7.1%
Weight (kg)	117.4 ± 5.4	92.1 ± 3.8	< 0.001
BMI (kg/m²)	39.7 ± 1.0	31.5 ± 0.7	< 0.001
Fat mass (kg)	60.2 ± 3.6	37.8 ± 2.2	< 0.001
FFM (kg)	57.2 ± 4.8	54.2 ± 3.4	0.117
FM (%)	51.7 ± 2.9	40.7 ± 2.1	< 0.001
SBP (mmHg)	128.1 ± 2.4	117.4 ± 2.5	0.006
DBP (mmHg)	77.7 ± 3.1	70.9 ± 2.2	0.106
HC (cm)	128.1 ± 2.4	114.1 ± 1.7	< 0.001
WC (cm)	121.9 ± 4.1	104.0 ± 3.0	< 0.001
Waist–Hip Ratio	0.95 ± 0.02	0.91 ± 0.02	0.016
TC (mmol/l)	5.1 ± 0.2	5.0 ± 0.2	0.821
Triglycerides (mmol/l)	1.3 ± 0.1	1.0 ± 0.1	0.005
HDL (mmol/l)	1.2 ± 0.1	1.2 ± 0.1	0.732
LDL (mmol/l)	3.3 ± 0.2	3.4 ± 0.2	0.715
ALT (U/l)	33.7 ± 5.0	19.7 ± 4.3	0.035
AST (U/l)	26.6 ± 2.6	0.503

Data presented as mean ± SEM.

BMI: Body mass index; FM: Fat mass; FFM: Fat-free mass; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HC: Hip circumference; WC: Waist circumference; TC: Total cholesterol; HDL: High-density cholesterol; LDL: Low-density cholesterol; ALT: Alanine transaminase; AST: Aspartate transaminase.

Following LSG, IR of these obese non-diabetic subjects improved significantly, indicated by significant decreases in fasting serum concentration of glucose and insulin as well as HOMA-IR index. Matsuda index, an index of whole-body insulin sensitivity, also improved significantly. However, glucose and insulin AUC did not show any significant change following bariatric surgery (Table 2).

Table 2.

Insulin Resistance at baseline and six months after sleeve gastrectomy

Parameters	pre-op (n = 14)	post-op (n = 14)	p-value
Fasting glucose (mg/dl)	102.1 ± 3.3	90.0 ± 1.8	0.001
Fasting insulin (µU/ml)	25.0 ± 2.8	9.2 ± 1.0	< 0.001
HOMA-IR	6.2 ± 0.7	2.0 ± 0.2	< 0.001
Matsuda Index	1.9 ± 0.3	3.3 ± 0.3	< 0.001
glucose AUC (min·mg/dl)	19650 ± 1025	17512 ± 750	0.084
insulin AUC (min·µU/ml)	16925 ± 2813	17313± 3765	0.890

Data presented as mean ± SEM.

HOMA-IR: homeostasis model assessment for insulin resistance; AUC: area under curve.

Concentration and composition of bile acids

Six months after bariatric surgery, total BAs trended higher. Similarly, cholic acid (CA), chenodeoxycholic acid (CDCA) and their glycine/taurine conjugated products were higher after surgery but this increase did not achieve statistical significance. Similar findings were also present in DCA, ursodeoxycholic acid (UDCA) and their glycine/taurine conjugated variants; however, lithocholic acid and its glycine/taurine conjugated products were not significantly different from pre-surgery values (Table 3).

Table 3.

Bile acid profile at baseline and six monthafter sleeve gastrectomy

Bile acids (nM)	Pre-op (n = 14)	Post-op (n = 14)	p-value
Total BA	3631.7 ± 457.9	5237.1 ± 1219.4	0.181
Primary unconjugated BA
CA	54.6 ± 12.6	75.2 ± 19.7	0.427
CDCA	202.7 ± 64.0	230.7 ± 332.5	0.816
Primary conjugated BA
GCA	114.0 ± 20.5	157.9 ± 72.7	0.497
GCDCA	613.8 ± 112.4	933.7 ± 332.5	0.350
TCA	18.1 ± 3.1	19.3 ± 7.0	0.842
TCDCA	42.6 ± 6.6	66.3 ± 24.3	0.300
Secondary unconjugated BA
DCA	97.8 ± 24.0	181.4 ± 36.9	0.074
LCA	1.9 ± 0.9	1.8 ± 0.3	0.942
UDCA	66.2 ± 16.3	73.1 ± 14.5	0.783
Secondary conjugated BA
GDCA	53.9 ± 14.5	137.8 ± 64.4	0.250
GLCA	4.6 ± 1.8	3.9 ± 1.1	0.715
GUDCA	154.2 ± 48.8	187.3 ± 56.9	0.647
TDCA	6.6 ± 1.5	16.3 ± 7.4	0.252
TLCA	0.6 ± 0.3	0.5 ± 0.2	0.794
TUDCA	3.8 ± 1.3	6.0 ± 2.4	0.382
Sulfated BA
CA-3-sulfate	15.2 ± 3.6	15.6 ± 4.7	0.892
CDCA-3-sulfate	9.4 ± 2.4	17.2 ± 3.0	0.030
GCA-3-sulfate	0.7 ± 0.2	1.2 ± 0.4	0.172
GCDCA-3-sulfate	105.8 ± 14.2	188.9 ± 36.1	0.023
TCDCA-3-sulfate	8.6 ± 1.0	16.8 ± 3.7	0.034
DCA-3-sulfate	0.8 ± 0.3	3.3 ± 0.9	0.017
LCA-3-sulfate	3.6 ± 1.4	5.3 ± 1.1	0.336
UDCA-3-sulfate	0.0 ± 0.0	0.7 ± 0.3	0.043
GDCA-3-sulfate	30.0 ± 7.4	101.0 ± 24.6	0.020
GLCA-3-sulfate	113.8 ± 26.1	245.4 ± 39.7	0.014
GUDCA-3-sulfate	134.8 ± 40.3	142.0 ± 27.2	0.868
TDCA-3-sulfate	3.2 ± 0.7	7.8 ± 1.4	0.022
TLCA-3-sulfate	1.7 ± 0.6	4.0 ± 0.8	0.027
TUDCA-3-sulfate	3.0 ± 0.7	3.7 ± 0.9	0.505

Data presented as mean ± SEM.

CA: Cholic acid; CDCA: Chenodeoxycholic acid; GCA: Glycocholic acid; GCDCA: Glycochenodeoxycholic acid; TCA: Taurocholic acid; TCDCA: Taurochenodeoxycholic acid; DCA: Deoxycholic acid; LCA: Lithocholic acid; UDCA: Ursodeoxycholic acid; GDCA: Glycodeoxycholic acid; GLCA: Glycolithocholic acid; GUDCA: Glycoursodeoxycholic acid; TDCA: Taurodeoxycholic acid; TLCA: Taurolithocholic acid; TUDCA: Tauroursodeoxycholic acid.

No significant changes were detected in non-sulfated BAs. However, most of the sulfated BAs, including sulfation products of CDCA and its conjugated variants, DCA and its conjugated variants, UDCA, glycolithocholic acid (GLCA) and taurolithocholic acid (TLCA), demonstrated significant increase after bariatric surgery. The other sulfated BAs also showed an increasing trend, but their increase did not reach statistical significance (Table 3).

Discussion

Our study examined the changes in metabolic characteristics and concentration of fasting BAs in Asian individuals with morbid obesity 6 months after LSG. We found that while total BAs did not increase significantly after LSG, levels of sulfated BAs species were significantly higher, and these changes occurred concurrently with improvement in weight and IR.

Obesity, especially central obesity, is strongly correlated with impairment in metabolic health and IR.²⁰ In our study, individuals who underwent LSG achieved 21.5% of weight loss on average in 6 months, and the loss in FM contributed to 88.5% of the total weight loss. Central obesity, indicated by waist–hip ratio, also improved significantly. This was also associated with lower systolic blood pressure, triglycerides and AST. IR during fasting and following glucose intake, which is measured by the Matsuda index, showed significant improvement 6 months following LSG. Our findings were similar to other studies, and add to the evidence supporting the effectiveness of LSG in achieving weight loss and reversing metabolic impairment in a morbidly obese Asian population.²¹

In addition to metabolic health and IR, BA production may increase after bariatric surgery, and this can be detected by measurement of serum BA concentrations. In our study, total BA concentrations were higher at 6 months after LSG, but this increase did not reach statistical significance. Most of the non-sulfated BAs also followed the same pattern. Our study’s lack of statistical significance in values of total and non-sulfated BAs could be limited by our modest sample size to detect subtle changes in BA profile and a possible decrease in dietary BA intake post LSG. Alternatively, the increase in the production of BA-sulfates after bariatric surgery could have attenuated any increase in the post-surgery BA concentrations. The changes in BA concentration might also be more apparent with longer follow-up duration, as the increase in concentration of total BAs in one study became apparent only after a year after LSG.¹⁴ However, other studies in LSG populations also showed no change in total BAs at 6 months,^15,22 and this may represent post-surgery changes in BA metabolism that are unique to LSG during this period. This notion is supported by studies that showed consistently higher total BAs after RYGB.^9,10 The difference in findings between LSG and RYGB could be secondary to the effect of surgery on gastrointestinal reabsorption, as RYGB has both “restrictive” and “malabsorptive” effect with alteration of gut anatomy. In contrast, LSG is mainly “restrictive” in nature.

Although our study was unable to demonstrate significant changes in total and non-sulfated BAs, we found that most of the sulfated BAs increased significantly 6 months after LSG. The sulfation of BAs occurs in the liver via phase II conjugation by the enzyme SULT2A1. After sulfation, their reabsorption ability is limited via bile acid transporters in the gut,²³ and fewer sulfated BAs will enter the enterohepatic circulation. As a result, BA sulfation was found to promote fecal excretion of BAs in humans.²⁴ Sulfated BAs were also found to have a higher concentration in urine than the serum concentration, suggesting a high renal excretion of sulfated BAs due to its relatively higher hydrophilicity.²⁵ Therefore, sulfation is an important pathway for detoxification and excretion of BAs. In this regard, any increase in BA production after bariatric surgery may be attenuated by the excretion of BA from the plasma pool via the sulfation pathway, and this may explain the heterogenous serum BA concentration after bariatric surgery.

A better understanding of the role of BA sulfation may have important implications for human health. Excessive hydrophobic BAs, especially LCAs, are cytotoxic, thus can disrupt the plasma and mitochondrial membranes,²⁶ disturb water and salt transportation²⁷ and promote oncogenesis.²⁸ This could explain why sulfated BAs are usually elevated in cholestatic liver disease as a compensational mechanism to promote excretion of BAs.²⁹ Moreover, the regulation of BA sulfation is related to the actions of various nuclear receptors such as the FXR¹ and TGR5, which may also participate in the improvement in metabolic health after bariatric surgery.³⁰ Sulfation of BAs can modulate TGR5 activity,³¹ and it is possible that the increase in sulfated BAs concentration after LSG could lead to improvements in metabolic health. In addition, cholic acid-7-sulfate (CA7S) is a sulfated BA species that activates TGR5 and induces glucagon-like peptide 1 (GLP-1) secretion in vitro. In mice models, CA7S was found to induce GLP-1 secretion and suppress blood glucose. Researchers have found that fecal content of cholic CA7S increased significantly in subjects post sleeve gastrectomy, despite a lack of difference in fecal total BA concentration.³² More studies examining sulfation of BAs are needed to confirm the relationship between BA sulfation and TGR5 and GLP–1.

There are several limitations to our study. First, our sample size was small, but was adequate to detect significant changes in metabolic characteristics after LSG. The sample size is also comparable to other studies investigating the changes in BAs following bariatric surgery.¹⁵ Second, IR was measured using HOMA-IR or Matsuda index instead of the gold-standard hyperinsulinemic-euglycemic clamp. However, HOMA-IR and Matsuda index are reliable markers as they correlate very well with insulin sensitivity index derived from clamp study.^19,33 Our previous study also showed that all three measurements of IR improved significantly after bariatric surgery.¹³ Third, the concentration and composition of BAs were only measured during the fasting state. Multiple measurements at different time points following diet intake will be required to understand this dynamic process better. Fourth, dietary intake of BAs might contribute to changes in concentration of BAs post bariatric surgery, and will need to be quantified in future studies. Fifth, individuals who underwent LSG were only followed up for a duration of 6 months in our study. To examine the consistency of our findings and to understand long-term changes, a longer period of follow-up will be required for studies in the future. Finally, gut microbiota may influence BA metabolism, and assessment of changes in gut microbiota should be included in future studies.

Conclusion

In conclusion, our study showed that while total non-sulfated BAs remained unchanged in morbidly obese Asian individuals 6-months after LSG, serum concentrations of sulfated BAs were significantly higher. The increase in sulfated BAs after LSG might contribute to the post-surgery improvement of metabolic health.

Footnotes

The authors would like to thank Vieon Wu Ai Ni and Valerie Lai Jia Hui for their excellent work in coordinating the study project. We would also like to thank all the study volunteers for their support.

Authors’ contributions

All authors contributed substantially to this study and were involved in literature research,protocol development,gaining ethical approval,patient recruitment and data analysis. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

J Yao and HC Tan researched literature and conceived the study. JP Kovalik,OF Lai,PC Lee,Alvin Eng,WH Chan,Eugene Lim,YM Bee and HC Tan were involved in protocol development,gaining ethical approval,patient recruitment and data analysis. J Yao wrote the first draft of the manuscript.

Availability of data and materials

The dataset analyzed during the current study is available in Redcap repository. Materials including serum samples are stored for 5 years upon collection.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethical approval for this study was obtained from Singhealth Institutional Review Board.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research,authorship,and/or publication of this article: This study was supported by the SingHealth & DUKE-NUS Collaborative Grant,SingHealth Foundation Grant,and the AM-ETHOS Duke-NUS Medical Student Fellowship.

ORCID iDs

Jie Yao

Hong Chang Tan

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Effects of laparoscopic sleeve gastrectomy on concentration and composition of bile acids in an Asian population with morbid obesity

Abstract

Background:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and methods

Study subjects

Study protocol

Laboratory measurements

Anthropometric measurements

Oral glucose tolerance test

Calculations

Data analysis

Results

Metabolic characteristics

Concentration and composition of bile acids

Discussion

Conclusion

Footnotes

Authors’ contributions

Availability of data and materials

Ethical approval

Informed consent

Conflict of interest

Funding

ORCID iDs

References