Bacterial Lipopolysaccharide,Lipopolysaccharide-Binding Protein,and Other Inflammatory Markers in Obesity and After Bariatric Surgery

Abstract

Obesity is associated with altered gut microbiota and low-grade inflammation. A key factor in the inflammatory process is endotoxin lipopolysaccharide (LPS). Plasma LPS levels and sensory agent lipopolysaccharide-binding protein (LBP) are shown to be elevated in obesity. This elevation may be due to increased intestinal permeability and incorporation of a high-fat diet accompanied by overfeeding. Bariatric surgery has become a popular treatment option that results in stable weight loss and improvement of obesity-related conditions. Studies outlined in this review show reduced LPS and LBP levels after different bariatric procedures. LPS receptor CD14 and mRNA expression toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) were also shown to have reduced levels following surgery. Changes in LPS and LPS components after bariatric surgery are shown to be linked to the surgical technique of the procedure and restriction of caloric intake. Additionally, changes in the gut microbiota provide some insight to the reduction of inflammatory markers after surgery. The beneficial effects of bariatric surgery are not dependent on weight loss alone. The inflammatory pathway plays a key role in the improvement of metabolic complications following surgery that should be further examined. Additional research is needed to evaluate short- and long-term changes of LPS and LPS components after bariatric surgery, including how those assessments can be applied to clinical practice.

Introduction

Bacterial-derived lipopolysaccharide (LPS) plays an essential role in the inflammatory process and onset of diseases associated with obesity.^1,2 LPS molecules are unique glycolipids in the outer membrane of Gram-negative bacteria, consisting of an inner lipid A core and a number of branched polysaccharide chains. The lipid A core anchors LPS into the bacterial membrane and is considered the most inflammatory component of the molecule.^3
–5

A substantial proportion of the gut microbiota in mammals is composed of LPS and LPS sensory agents, such as lipopolysaccharide-binding protein (LBP), CD14, and toll-like receptor 4 (TLR4).^6,7 LPS is bound in the blood to LBP and transferred through CD14 to TLR4 resulting in activation of immune signaling and production of proinflammatory cytokines.^3,5,7 Circulating LPS levels occur naturally in healthy individuals. Persistent elevated LPS levels cause metabolic endotoxemia and are found in chronic diseases, indicating a putative link between LPS and microbial inflammation, obesity, and other metabolic conditions.^8,9

Bariatric surgery is an effective treatment option for patients with morbid obesity and type 2 diabetes. Improvements in glycemic control are observed shortly after surgery and well before clinically significant weight loss has occurred.^10,11 Research suggests that improvements in the chronic inflammatory state may be mediated by a source other than the adipose tissue. LPS is a potential source of persistent chronic inflammation that has been shown to be reduced after bariatric surgery.¹¹ Understanding the inflammatory process of LPS provides insight on the mechanisms associated with improved metabolic complications seen after bariatric surgery. The aim of this review is to examine LPS and LPS components in obesity, as well as changes in LPS and associated inflammatory markers after bariatric surgery.

Research Methods

An extensive literature search of PubMed, CINAHL, and Web of Science was conducted on LPS in obesity and after bariatric surgery. The advanced search feature was used for the following Medical Subject Heading terms: LPS and bariatric surgery, LPS and obesity, LPS and microbiota, and LPS and inflammation. Contributing components to LPS, such as LBP, CD14, and TLR4 were also included to provide detailed information on LPS involvement in chronic inflammation. Eight research studies published between 2002 and 2015 were identified and included in this review. The inclusion criteria were: adequate sample size, sound methodology, generalizability of findings, and adherence to Medical Subject Heading categorization. Studies that did not discuss LPS levels or associated inflammatory components after bariatric surgery were excluded.

Review of Literature—Mechanisms for Elevated LPS Levels in Obesity

Studies have shown that an altered gut microbiota and translocation of LPS could be early triggers of insulin resistance, diabetes, and obesity.¹² The proportion of LPS in the microflora is shown to be higher in obese individuals than in lean individuals. The increased systemic LPS levels associated with obesity are hypothesized to be caused by LPS reaching circulation due to increased gut permeability. Additionally, LPS can be transported over the gut wall by triglyceride-rich chylomicrons.¹² Intestinal permeability has been suggested to be influenced by obesity, host–microbe interactions of the intestinal tract, dietary patterns, and nutritional deficiencies.¹³

The proinflammatory activity of LPS is increased by the metabolic concentrations of plasma LBP, which is also higher in obesity. LBP levels peak shortly after endotoxemia and remain elevated up to 72 hr. Circulating LBP forms a complex with LPS that enhances binding of LPS to CD14 receptors, involving both LBP and CD14 in the immune regulation triggered by LPS.⁶

LPS is naturally present in the microbiota and is partly translocated into the bloodstream during lipid digestion. Inflammation is observed with hypercaloric diets in the postprandial period, suggesting that morbidly obese patients present postprandial endotoxemia after a fat load.¹⁴ Dietary composition influences the endotoxin absorption process. High-fat and high-calorie diets have been shown to favor the colonization of the intestine with Gram-negative microbiota.^4,13 Chylomicrons, secreted from intestinal epithelial cells or through increased intestinal permeability, take up LPS and enter the bloodstream. A high-fat diet increases chylomicron formation, resulting in greater LPS transport.^2,15

One study demonstrated that an 8-week overfeeding period in nonobese humans increased the LBP and soluble CD14 (sCD14) ratio in the fasting state and increased the postprandial accumulation of LPS. The results of this study indicated that overfeeding increases postprandial endotoxemia, but the inflammatory outcome may depend on the ability of the plasma to handle the LPS levels.¹⁴ Another study found that a high-fat, high-carbohydrate meal consisting of 910 calories, 41% carbohydrate, 17% protein, and 42% fat, increased plasma LPS levels, LBP levels, and TLR4 expression over a 3-hour period.¹⁶

Experimental data suggest that fat is more efficient in transporting LPS from the gut to the bloodstream than carbohydrates. The type of fat may also have different effects on the inductions of endotoxemia. For example, fatty acid oleate promotes absorption of bioactive LPS through the induction of chylomicron formation. Butyrate, on the other hand, enters circulation without chylomicron formation and does not increase endotoxemia.¹⁷ The different fatty acids involved in LPS absorption should be further explored. However, these observations confirm that the contribution of fat and chylomicron formation plays a major role in endotoxin translocation.¹⁷

LPS can target various tissues such as macrophages, adipose, skeletal muscle, and liver. Specific receptors on these tissues interact with LPS and induce the secretion of inflammatory cytokines and negatively regulate insulin signaling.¹⁸ Gut microbiota is involved in the management of type 2 diabetes and prevention of other diseases. However, the gut microbiota also plays a role in the production of LPS. LPS is considered the initiator of metabolic impairment in type 2 diabetes and obesity.¹⁹ Bariatric surgery results in substantial and long-term weight loss and is an effective treatment for obesity. Early metabolic improvement after bariatric surgery is observed apart from weight reduction, suggesting other participating mechanisms. Bariatric surgery results in modified gut microbiota and increased bacterial diversity, influencing circulating LPS levels.²⁰

Bariatric procedures are classified as either being restrictive or malabsorptive, both reducing oral intake and promoting weight loss.²¹ Currently, there are five types of procedures for bariatric surgery, which include laparoscopic adjustable gastric band (LAGB), vertical sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and biliopancreatic diversion (BPD), and BPD with duodenal switch (BPD-DS).^21,22 Vertical banded gastroplasty (VBG) is another bariatric procedure that was at one time the most frequently performed restrictive operation before the introduction of LAGB.^23,24 Table 1 provides a detailed description for each bariatric procedure.

Table 1.

Type and Description of Bariatric Procedures

Surgical procedure	Type	Description	Figure
VBG	Restrictive	An incision is made on the lesser curve of the stomach 6 cm from the esogastric junction. The lesser omentum is dissected followed by a 2-cm opening of the lesser sac. Dissection continues downward to 1 cm above the upper most portion of the short gastric vessels. A calibrated transgastric window is created using a circular stapler creating a 20 mL gastric pouch volume. A polypropylene band is placed around the distal part of the gastric pouch.^25,26	(Courtesy of American Journal of Health-System Pharmacy. Illustration by Marie Dauenheimer, MA, CMI)²⁷
		Poor weight loss and complications results in 25%–54% of patients seeking revision surgery.²⁴
LAGB	Restrictive	A synthetic band is placed around the upper portion of the stomach, just distal to the gastroesophageal junction. A small gastric pouch ∼20–30 mL in size is created. The band is inflated or deflated with saline to alter the level of constriction and to maintain a feeling of fullness. The amount of food and volume tolerated is restricted. When food or liquid is ingested, the pouch expands creating a pressure sensation signaling satiety.^21,22	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
		Average weight loss is about 45%–47% excess weight by 4–5 years postoperatively.²¹	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
Vertical SG	Restrictive	A vertical incision is created removing 80% of the stomach and preserving the antrum and pylorus. The sleeve creation has an impact on hormone regulation, decreasing blood ghrelin levels and enhancing a state of satiety.^21,29	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
		The average weight loss of 60% excess body weight after 2 years postoperatively, along with an improvement in associated comorbidities.²¹	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
RYGB	Restrictive and Malabsorptive	A 30 mL gastric pouch is created just below the gastroesophageal junction. A roux limb is created from the division of the proximal jejunum and the distal jejunum, which is anastomosed to the new gastric pouch. The roux limb bypasses the stomach, duodenum, and proximal jejunum encouraging malabsorption. The alteration of the jejunal anatomy prevents the mixing of food with digestive enzymes as the food travels the roux limb.^21,22,29	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
		Average weight loss for RYGB at 1 year is 70%–75% excess body weight, whereas at 3 years ∼67% across studies.²¹	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
BPD and BPD with DS	Malabsorptive	The BPD procedure involves a SG with a creation of a 200–500 mL gastric pouch. A Roux-en-Y gastro ileostomy of 200 cm is formed with a common channel 50 cm from the ileocecal valve joining biliary and digestive enzymes. The combination of BPD and DS was originated shortly after the introduction of BPD. The BPD-DS involves a SG with the pylorus still left intact. A duodenal ileostomy is created resulting in a 150-cm limb and a common channel of 100 cm.^21,22	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
		Weight loss associated with the BPD and BPD-DS is the greatest among any of the other bariatric procedures with excess weight loss of 70%–80% postoperatively.^21,22	(Courtesy of Ethicon Endo-Surgery, Inc.)²⁸
		Figure shows BPD with DS.

BPD, biliopancreatic diversion; DS, duodenal switch; LAGB; laparoscopic adjustable gastric band; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy; VBG, vertical banded gastroplasty.

Research Studies Evaluating Changes in LPS and LPS Components After Bariatric Surgery

Studies assessing LPS levels after bariatric surgery are limited, but do provide valuable results forecasting future research. The research studies outlined in this review consist of mostly RYGB with the remaining, a combination of VBG, LAGB, SG, DS, and BDP. Changes in LPS and LPS components after varying types of bariatric surgery are explored. Statistical data and details of each study are listed in Table 2.

Table 2.

Measures of Inflammatory Markers Pre- and Post-Bariatric Surgery

Author	Subjects and procedure	Assessments	Points of evaluation	Results	Strengths	Limitations
Trøseid et al.¹²	49 obeseRYGB—BMI <50 kg/m² DS—BMI >50 kg/m² 17 controls with BMI ≤28 kg/m² who underwent elective laparoscopic procedures	Plasma LPSsCD14HbA_1c Mesenteric, omental, and subcutaneous adipose tissue bacterial DNABMISystolic blood pressureQuantified bacterial DNA	BaselinePreoperatively (3 months of lifestyle intervention)1 year postop	LPS reduced after 1 year postop(P = 0.010) compared to preop(P = 0.013)Baseline LPS levels and HbA_1c (r = 0.56; P = 0.001)Baseline LPS levels and intra-abdominal fat(r = 0.61; P < 0.001)Baseline LPS levels and subcutaneous fat(r = 0.33; P = 0.038)Baseline LPS levels and BMI(r = 0.37; P = 0.017)Baseline LPS levels and systolic blood pressure(r = 0.40; P = 0.009)Relative difference in bacterial load among adipose tissue compartments at baseline ∼0.3 log, or twofoldLPS levels and HbA_1c 1 year postop (r = 0.85; P > 0.001)LPS levels and fasting triglycerides 1 year postop(r = 0.76; P < 0.001)No data on gut microbiota available	Prospective, longitudinal designPresence of a control groupQuantification of adipose tissue volumes and available biopsy samples	Small sample sizeImbalance between male and female participantsNo specification of RYGB or DS in resultsDifference between plasma LPS in obese and control group underestimateLack of biopsy specimens and quantification of adipose tissue volumes for postop evaluation
Trøseid et al.³⁰	49 obeseRYGB—BMI <50 kg/m² DS—BMI >50 kg/m² 17 controls with BMI ≤28 kg/m² who underwent elective laparoscopic procedures	LPSsCD14ADMASDMA	BaselinePreoperatively (3 months of lifestyle intervention)1 year postop	sCD14 and ADMA at baseline(r = 0.49; P = 0.025)sCD14 and SDMA at baseline(r = 0.60; P = 0.004)LPS and ADMA at baseline(r = −0.47; P = 0.034)LPS and SDMA at baseline(r = −0.54; P = 0.012)LPS and sCD14 levels in obese subjects(r = −0.50, P < 0.001)ADMA 1 year postop mean change(0.02 ± 0.13 μM, P = 0.475)SDMA 1 year postop mean change(−0.0 2 ± 0.09 μM, P = 0.166)No data on gut microbiota available	sCD14 is independently associated with ADMA and SDMA	Small sample sizeLack of direct measure of endothelial functionUnknown and unmeasured factors: socioeconomic status, lifestyle factors, dietary intake, medication regimen, gut microbiota composition1 year follow-up may not be sufficient to assess long-term vascular effects of bariatric surgery
Cottam et al.³¹	26 obeseRYGB10 controls with BMI ≤25 kg/m² and no comorbidities	CD14	Baseline1 month postop3 months postop6 months postop12 months postop	CD14 in obese group compared with control group at baseline(1129 vs. 719 gmf, P = 0.004)CD14 at 1 month(1150 gmf, P = 0.014)CD14 at 3 months(775 gmf, P = 0.718)CD14 at 6 months(894 gmf, P = 0.338)CD14 at 12 months(681 gmf, P = 0.647)Significant difference between preop levels compared to 12 months postop (P = 0.004)No data on gut microbiota available	Presence of a control groupSignificant results supporting that chronic inflammation and immune function can be reversed within 6 months of bariatric surgery	Patient compliance on diet and exercise after surgery was not monitoredMedications were taken into consideration, but could not be completely avoided
Blum et al.³²	20 obese womenSG6 healthy controls	PEC's with added LPS	Baseline3 months postop	Postop pool induced significantly less mRNA expression of IL-6 (22.7%, P = 0.02) and E-selectin (28.8%, P = 0.005) compared with preop poolReduced mRNA expression of E-selectin (34.1%, P = 0.01)Reduced mRNA expression of TNF-α (47.9%, P = 0.02)No significant effect of serum induced with LPS on antioxidant enzymes (data not shown)No data on gut microbiota available	Presence of a control groupSignificant results to show the importance of the inflammatory pathway and improvements following bariatric surgery	Small sample size and short-term follow-up period
Clemente-Postigo et al.²⁰	50 obese26 BPD24 SG	LPSLBPInsulinBMICholesterolWaist circumference	Baseline15 days postop90 days postop	LBP at 15 days and insulin(r = −0.279; P = 0.037)LBP at 15 days and cholesterol(r = −0.221; P = 0.099)LBP at 15 days and BMI(r = 0.232; P = 0.088)LBP at 90 days and BMI(r = 0.428; P = 0.001)LBP at 90 days and waist circumference(r = 0.330; P = 0.025)LBP at 90 days and cholesterol(r = −0.259; P = 0.051)Multiple linear regression analysis with change in BMI and LBP at 90 days (R ² = 0.362; β = 0.382; P = 0.019)No data on gut microbiota available	Significant differences found in both LPS and LBP levels at 90 days after SGAnalysis of short-term follow-up on LPS and LBP levels after bariatric surgeryComparison of restrictive bariatric procedure (SG) versus malabsorptive procedure (BPD)	Small sample sizeNo control groupShort-term follow-up did not allow for evaluation of surgery-induced complications and if that would affect LPS and LBP levels
Yang et al.³³	178 obese89 mini bypass47 RYGB32 SG10 LAGB38 normal weight controls	LBPBMILeukocyte count	Baseline1 year postop	LBP levels were higher in preop participants compared with controls.(49.9 ± 15.7 μg/mL vs. 25.2 ± 7.5 μg/mL; P < 0.001)Decreased LBP levels with operations (49.9 ± 15.7 to 35.1 ± 22.6 μg/mL, 29.6%)LBP levels correlated with BMI(r = 0.167; P = 0.41)LBP levels correlated with leukocyte(r = 0.190; P = 0.018)No data on gut microbiota available	Change of LBP concentration in different bariatric surgeries	Small sample sizeResults may be confoundingSubjects were not screened for chronic inflammatory diseases preoperatively
van Dielen et al.³⁴	26 obese11 VBG15 LAGB	LBPBMI	Baseline3 months6 months12 months24 months	BMI preop 46.7 ± 5.8 kg/m² to 24 months postop 33 ± 4.8 kg/m² (P < 0.001)LBP preop 134.7 ± 98.2 μg/mLNo significant change at 6 monthsLBP 12 months postop 107.6 ± 77.4 μg/mL and 24 months postop 78.9 ± 39.4 μg/mL (P < 0.05)No data on gut microbiota available	Change of LBP concentration after restrictive bariatric surgery	Small sample sizeNo control groupVBG tends to be no longer used as a bariatric procedure and may alter the significance of results
Monte et al.¹¹	15 obese with T2DMRYGB	LPSCD14TLR4TLR2	Baseline6 months postop	LPS was reduced by 20% ± 5%(0.567 ± 0.033 to 0.443 ± 0.022 EU/mL, P < 0.05)TLR4, TLR2, CD14 P < 0.05TLR4 levels reduced by 25% ± 9%TLR2 levels reduced by 42% ± 8%CD14 levels reduced by 27% ± 10%LPS and change in weight(r ² = 0.298; P = 0.041)No data on gut microbiota available	Consistency of results ensures data are biologically significant	Limited controls for comparisonAbsence of sequential data during 6-month period

ADMA, asymmetric dimethylarginine; BMI, body mass index; HbA_1c hemoglobin A_1c; LAGB, laparoscopic adjustable gastric band; LBP, lipopolysaccharide-binding protein; LPS, lipopolysaccharide; PECs, primary endothelial cells; sCD14, soluble CD14; SDMA, symmetric dimethylarginine; T2DM, type 2 diabetes mellitus; TLR2, toll-like receptor 2; TLR4, toll-like receptor 4.

Researchers evaluated the impact of plasma LPS levels on abdominal obesity and glycemic control in patients undergoing bariatric surgery. This was a prospective observational study consisting of subjects who underwent RYGB and DS. The mean body mass index (BMI) in this study was 45.1 kg/m². At baseline, plasma LPS levels and sCD14 were elevated in obese subjects compared with the controls. LPS levels were closely correlated with intra-abdominal fat volumes, whereas only a moderate correlation with subcutaneous fat. Additionally, plasma LPS levels were positively correlated with fasting triglycerides, systolic blood pressure, and BMI.¹²

Results indicated that plasma LPS levels were reduced 1 year postsurgery with no change seen in sCD14. Reduced LPS levels and improved glycemic control measured by HbA1c were seen 1 year postsurgery. There was a strong correlation between reduced LPS levels and fasting triglycerides, but no correlation seen with the reduction of LPS levels and BMI or systolic blood pressure. Additionally, there was also a decreasing trend in bacterial load of the subcutaneous adipose tissue compartments. There was no reduction of LPS levels seen from baseline to preoperative evaluation after a period of lifestyle intervention.¹²

An association between LPS and sCD14 on markers of vascular dysfunction was investigated.³⁰ Vascular dysfunction was assessed indirectly by measuring plasma levels of asymmetric dimethylarginine (ADMA) and stereoisomer symmetric dimethylarginine (SDMA). ADMA contributes to impaired endothelial function through its inhibitory effect on nitric oxide synthase (NOS), whereas SDMA is regarded as a novel marker of vascular dysfunction. Increased ADMA levels have been shown previously to be associated with obesity. In obese subjects at baseline, there was a positive correlation between sCD14 and both ADMA and SDMA. However, a negative correlation was seen between LPS and sCD14 levels in obese subjects. LPS levels were also negatively correlated with ADMA and SDMA. One year after bariatric surgery, results show no significant changes for ADMA or SDMA, suggesting no effect of bariatric surgery on markers of vascular dysfunction. However, this study has several limitations that could have affected statistical data.³⁰

LPS receptor CD14 was also measured in a study with subjects who underwent RYGB. Obese subjects underwent RYGB surgery, whereas nonobese subjects with no comorbidities were used as the controls. At baseline, there was a significantly higher expression of CD14 in the obese group compared with the controls. CD14 levels continued to remain elevated 1 month after surgery, however, at 3 months the difference narrowed with levels normalizing from 6 to 12 months postoperative. There was a significant difference noted from obese preoperative levels compared with 12 months after surgery.³¹

The anti-inflammatory effects of bariatric surgery have also been investigated. It has been previously noted that there is a gender effect in relation to vascular responsiveness and inflammation. LPS levels were examined in an in vitro study that involved adding LPS to primary endothelial cells (PECs) to induce an inflammatory state in women undergoing SG. Equal volumes of serum were collected from the women before and after surgery. The serum samples were placed into a pre- and post-surgery pool. Serum samples were also taken from six healthy individuals and used as controls. PECs were obtained from the vein of umbilical cords of babies that there donated by women who signed consents. The PECs were produced using a standard protocol. PECs were then incubated with the serum pools (20% in medium) for 48 hr. During the last 4 hr, 500 ng/mL LPS was added to induce stress-like conditions. Significantly lower levels of inflammatory markers TNF-α and E-selectin were observed in the cells that had undergone bariatric surgery. After surgery, the mRNA expression of E-selectin and TNF-α were reduced compared with serum from patients before surgery. The results suggest that the proinflammatory effect of serum on endothelial cells is lower in patients postsurgery.³²

Clemente-Postigo et al. measured LPS and LBP levels in normoglycemic and diabetic morbidly obese patients after BPD and SG procedures. Subjects were classified as either normoglycemic or prediabetic/diabetic. In the BPD group, 35.3% were prediabetic and 64.7% were diabetic, whereas in the SG group, 46.2% were prediabetic and 53.8% were diabetic. In all four study groups, the BMI significantly decreased at 15 and 90 days compared with baseline. Serum glucose diminished significantly in only the prediabetic/diabetic patients, whereas insulin levels decreased in all four study groups. There were no significant differences in LPS or LBP levels between the four study groups. LPS levels decreased significantly at 90 days in the prediabetic/diabetic patients who underwent SG. Although, none of the biochemical or anthropometric variables was independently associated with the change in LPS levels at 15 and 90 days postsurgery. Results showed that LBP levels decreased at 90 days after SG in normoglycemic, prediabetic, and diabetic patients. LBP levels increased at 15 days after BPD and then significantly decreased at day 90. At day 15 postop, the change in LBP levels was significantly correlated with the change in insulin and tended to correlate with the change in BMI and cholesterol. The changes in LBP at postop day 90 were significantly correlated with the change in BMI and waist circumference and tended to correlate with changes in cholesterol levels. However, BMI was the only variable that was independently associated with the change in LBP 90 days after surgery.²⁰

LBP levels were also measured in a study comparing four different bariatric procedures. This prospective cohort study involved obese individuals who underwent a mini gastric bypass, RYGB, SG, or LAGB. LBP levels were significantly higher in preoperative bariatric patients compared with normal-weight individuals. Circulating LBP levels were reduced in all four procedures 1 year after surgery. Additionally, BMI, fasting plasma glucose, insulin, HbA1c, total cholesterol, triglycerides, leukocyte count, high-sensitivity C-reactive protein (hs-CRP), and alanine transaminase (ALT), all significantly decreased after surgery. However, only BMI and leukocyte count were correlated with postoperative LBP levels. Results also show that none of the variables was independently related to serum LBP levels in multivariate analysis.³³

The effect of weight loss was also measured on LBP levels and other acute-phase proteins before and after VBG or LAGB procedures. The researchers hypothesized that weight loss by restrictive surgery results in a reduction of metabolic stress, resulting in a decrease in inflammatory makers and acute-phase proteins. BMI decreased significantly from baseline to 24 months postoperatively with the biggest change occurring in the first 3 months after surgery. LBP levels were still enhanced at 3 months after surgery and did not significantly change, even at 6 months following surgery. However, LBP levels were drastically decreased at 12 and 24 months postoperatively compared with baseline.³⁴

LPS levels along with mRNA expression of CD14, TLR4, toll-like receptor 2 (TLR2), and markers of inflammatory stress were assessed in patients undergoing RYGB. Results showed that BMI, plasma glucose, HbA1c, and insulin concentrations decreased after surgery. Additionally, there was a reduction in LPS concentration, CD14, TLR2, and TLR4 along with a decrease in inflammation. The change in LPS was also significantly correlated with the change in weight.¹¹

Discussion

The innate immune system and metabolic pathways are functionally intertwined, making them vulnerable to inflammation that can lead to obesity and diabetes.¹ LPS is a key contributor to the metabolic impairments seen in obesity and type 2 diabetes.¹⁹ Results show that bariatric surgery reduces LPS levels, LBP levels, and other sensory agents. The changes observed in LPS and inflammatory markers after bariatric surgery are not completely understood, but are possibly due to the interruption of the chronic excessive macronutrient intake, persistent shift in the endogenous microbiota, or a combination of these factors.¹¹

Reduction in weight and abdominal fat are outcomes of bariatric surgery that improve metabolic complications. Additionally, the inflammation-mediated pathway is an important contribution to the metabolic improvements following bariatric surgery.³² Cellular abnormalities associated with chronic inflammation and obesity appears to be reversed 6 months after RYGB, although the findings do not explain the reasoning for such a rapid change. Interestingly, patients who had RYGB resumed normal immune function before they lost 25% of excess adiposity.³¹ Reduction in plasma LPS concentration and the mRNA expression of TLR4 and CD14 was also seen after RYGB surgery. Due to the binding of TLR4 and CD14 to LPS, a reduction in all three factors leads to a decrease in LPS-induced inflammation.¹¹ Improvements were also seen in TLR4 and CD14 within 3 months of surgery along with enhanced endothelial function after SG.³² Concentrations of CD14 have been reported to increase after LPS exposure in vitro, although the circumstances may be different in conditions with prolonged low-grade endotoxemia. CD14 might also be shed off in circulation by other sources beyond LPS. This suggests that patients undergoing bariatric surgery may have different inflammatory triggers.³⁰ Studies also showed no decrease in LPS levels with medical intervention, indicating that bariatric surgery is needed to reduce endotoxemia.¹²

The type of bariatric procedure seems to also have an effect on inflammatory outcomes. All bariatric procedures lead to the same gastrointestinal tract and physiological changes, with different gut signaling pathways being affected. Postoperative metabolic improvements may differ depending on the surgical technique. The short-term effect of bariatric surgery on LPS levels is shown to depend on the type of surgical procedure and previous glycemic state of the patient.²⁰ LPS is considered a potential trigger for diabetes. Reduced LPS levels seen after surgery are correlated with improved glycemic control.

Bariatric surgery also promotes remission of diabetes.¹² It is estimated that diabetes remission occurs in ∼80%–85% of patients just days after RYGB surgery.¹ Another source states that 87% of patients with type 2 diabetes achieve enhanced glycemic control and 78% achieve euglycemia after bariatric surgery.¹⁰ Weight loss has been reported in both diabetic and nondiabetic patients after RYGB, proposing that weight loss and glucose improvements are independent of each other. RYGB is more efficient in improving carbohydrate metabolism than SG, as well as earlier improvement in fasting glucose and insulin levels seen in BPD compared with SG. The rerouting of the gastrointestinal tract in RYGB and BPD procedures implies improvement in carbohydrate metabolism.²⁰ Reduced LPS levels and HbA1c are closely correlated, suggesting that reduced microbial translocation might be linked to the antidiabetic effects of bariatric surgery.¹²

Based on study results, intra-abdominal adipose tissue and plasma LPS levels support the model of translocation of gut microbiota to surrounding adipose tissue.¹² The different effects of BPD and SG procedures on LPS levels might be related to the specific modifications of the gut microbiota ecology. It has been reported that RYGB is able to modify gut microbiota after surgery, but limited information is available on the changes in gut microbiota after BPD and SG procedures.²⁰ Small intestine permeability is decreased after RYGB, leading to a decrease in the uptake of intestinal intraluminal bacterial components that drives inflammation and insulin resistance in obesity.¹³ Additionally, surgically induced weight loss reduces microparticle release that could contribute to the inflammatory state seen in obesity.¹⁰

A high-fat diet and plasma elevations of nonesterified free fatty acids are linked to the activation of proinflammatory pathways.¹⁰ The reduced LPS levels seen after bariatric surgery could be involved in the improvement of carbohydrate metabolism.²⁰ Other studies suggest that it is the saturated fat rather than carbohydrate that induces an increase in LPS concentration, as well as TLR4 expression. Saturated fatty acids may promote low-grade inflammation and insulin resistance through a TLR4 mechanism.¹ The restriction of fat intake induced by RYGB is likely to be a significant contributor to the reduced LPS levels and a reduced inflammatory state.¹¹ Decreased inflammatory markers observed after RYGB-induced weight loss could also originate from the natural discontinuation of excessive food intake.³⁵ It is still uncertain if the proinflammatory effect of a meal alters after RYGB, which is an area of interest for future study.¹¹

Studies measuring LBP found it to be a short-term inflammatory marker after bariatric surgery, possibly due to the reconstruction process of the procedure and tissue injury.²⁰ A study found elevated LBP levels post VBG and LAGB procedures, suggesting that an enhanced inflammatory state is due to the effect of the operation and the subsequent healing process.³⁴ The studies measuring LBP were consistent with findings of increased levels in obese subjects, followed by levels remaining elevated 3–6 months postoperatively, and then decreasing significantly. LBP is essential for the rapid induction of an inflammatory response by LPS, suggesting that LBP serves as a clinical marker of effective endotoxemia. It is synthesized in the liver, gastrointestinal tract, lung, kidney, and reproductive tract, suggesting that the operation disrupted sources of LBP and altered the gut microbiota.³³ The elevated LBP levels shortly after surgery is suggestive of an ongoing inflammatory state in obese subjects. As patients become further out from surgery, BMI decreases and body weight stabilizes reducing inflammatory mediators. Improvement in the metabolic state is one possible explanation for reduced obesity-related comorbidities after weight loss surgery.³⁴

As previously mentioned, the exact mechanisms by which bariatric surgery reduces LPS levels are unknown.¹² Based on study results, there were improvements in LPS, LBP, and other inflammatory markers with all bariatric procedures. The few number of studies outlined in this review were not sufficient to determine if one bariatric procedure is more effective in reducing LPS levels compared with another. Each study also had different measures of assessments, resulting in the inability to distinguish differences or similarities among outcomes. It can be hypothesized that the malabsorptive nature and microbial changes that occur with RYGB and BPD procedures would promote greater reduction of LPS levels. However, the study by Clemente-Postigo et al. found a significant reduction in LPS levels only at 90 days after surgery in the prediabetic/diabetic patients who had undergone SG. This suggests that not only does the surgical technique play a role in the LPS response after bariatric surgery, but also the previous metabolic status of the patient.²⁰ The changes of gut microbiota after bariatric surgery were discussed among studies, but there were no supportive statistical data available. Assessing the microbial profile of individuals would be a contributing factor in further understanding the changes in LPS levels after bariatric surgery.

Implications and Future Direction

A limited sample size may have reduced statistical significance within results. Larger study cohorts may be beneficial in the future to establish validity among studies. There was also some inconsistency in study controls as well as measures for obtaining follow-up data. Regardless, all of the studies showed reduced LPS levels and improved inflammatory markers after bariatric surgery. Studies did show significant differences among variables and consistency within results. The exact mechanisms for reduced LPS and LPS components after bariatric surgery remain unknown; however, altered inflammatory markers may be responsible for improved glycemic status and other metabolic conditions after surgery. Therefore, weight loss is not the only benefit of bariatric surgery. Practitioners should focus not solely on the percentage of weight loss after bariatric surgery, but improvements in obesity-related conditions. Additional research is needed to further compare LPS levels after bariatric surgery, particularly restrictive versus malabsorptive procedures and identifying short- and long-term differences.

Conclusion

Plasma LPS levels were shown to be elevated in obesity and reduced after bariatric surgery. Increased intestinal permeability and dietary fat intake are proposed mechanisms for increased LPS levels in obesity. Bariatric surgery has been shown to reduce LPS levels and other inflammatory markers, contributing to an improved metabolic state. The type of bariatric procedure in relation to reduced LPS levels after surgery has not been thoroughly studied. Further studies comparing the different types of bariatric procedures and LPS levels are needed to determine if there is a significant difference between restrictive or malabsorptive procedures in reducing LPS levels. The type of procedure, alteration of the gut microbiota, and reduced macronutrient intake after bariatric surgery are all indicators for reduced LPS levels postoperatively. These indicators should be investigated in greater detail to further evaluate the inflammatory process after bariatric surgery and how those changes can be directly applied to clinical practice.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

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