Roux-En-Y Gastric Bypass Improved Intestinal Permeability by Regulating Gut Innate Immunity in Diet-Induced Obese Mice

doi:10.21203/rs.3.rs-132279/v1

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Roux-En-Y Gastric Bypass Improved Intestinal Permeability by Regulating Gut Innate Immunity in Diet-Induced Obese Mice

https://doi.org/10.21203/rs.3.rs-132279/v1

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published 21 Jul, 2021

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Roux-en-Y gastric bypass (RYGB) has been proven to be the most effective treatment for morbid obesity, yet the impact of RYGB on intestinal permeability is fully unknown. In this work, we subjected obese mice to RYGB and sham operation procedures. Serum lipopolysaccharide (LPS), inflammatory cytokines and intestinal permeability were measured at 8 weeks postsurgery. In contrast to sham surgery, RYGB reduced body weight, improved glucose tolerance and insulin resistance, and decreased serum levels of LPS, IL6 and TNFα. Intestinal permeability of the common limb and colon was significantly improved in the RYGB group compared to the sham group. The mRNA levels of IL1β, IL6, and TLR4 of the intestine were significantly decreased in the RYGB group compared with the sham group. The expression of intestinal islet-derived 3β (REG3β), islet-derived 3γ (REG3γ) and IAP was higher in the RYGB group than in the sham group. In conclusion, in a diet-induced obesity (DIO) mouse model,RYGB improved intestinal permeability and attenuated systemic inflammation by downregulating intestinal inflammation and innate immunity, which might result from enhanced production of IAP and antimicrobial peptides.

Endocrinology & Metabolism

Surgery

Roux-en-Y gastric bypass

Intestinal permeability

Innate immunity

Intestinal alkaline phosphatase

Antimicrobial peptides

To date, accumulating evidence has suggested that crosstalk between the microbiota and intestine is essential for body weight homeostasis^1–3. Intestinal bacterial-derived pathogens such as lipopolysaccharide (LPS) play an important role in obesity-related metabolic disorders⁴. A wide range of studies have found that LPS appears to induce chronic low-grade inflammation and regulate fat deposition, which causes insulin resistance and type 2 diabetes mellitus (T2DM)^5,6.

The gastrointestinal tract confines intestinal bacterial invasion through its physical, chemical and immune barriers, while maintaining proper permeability for the absorption of nutrients⁷. A large number of studies have found impairment of intestinal barrier function in patients with morbid obesity, mainly presenting as increased gut permeability, which might lead to systemic inflammation^3,8. Moreover, gut-derived inflammation exerted a profound influence on intestinal permeability.

Roux-en-Y gastric bypass (RYGB) surgery is the most effective and sustainable treatment for obesity and its comorbidities, such as T2DM and cardiovascular disease ⁹. Furthermore, growing body of literature has revealed that the RYGB procedure improves the state of chronic low-grade inflammation in obesity^10,11. The alimentary tract was realigned after RYGB, which led to fundamental changes in nutrient digestion and absorption, intraluminal environment and intestinal epithelial cells. Meanwhile, intestinal alkaline phosphatase (IAP) and antimicrobial peptides produced by enterocytes play a pivotal role in neutralizing toxicity from intestinal microbiota as part of the innate immune system and subsequently maintaining intestinal homeostasis^12,13. Hence, we hypothesized that intestinal permeability was improved by RYGB. In this study, we first report the alteration of intestinal permeability in different intestinal limbs after RYGB in a DIO mouse model, with mechanistic investigation from the perspective of intestinal inflammation and innate immunity.

Experimental Animals

Fourteen male C57BL/6 mice were purchased from SLAC Laboratory Animal Inc. (Shanghai, China) at seven-weeks-old. All animals received water and normal chow (SLAC, Laboratory Animal Inc., Shanghai, China) ad libitum after birth. At the age of 8 weeks, all animals were fed a high-fat diet (HFD) (60 kcal% fat, #D12492; Research Diets Inc., New Brunswick, NJ, USA) for 12 weeks and subsequently allocated to two body weight-matched groups (sham and RYGB) before undergoing surgery. All mice were housed under a 12-h light/12-h dark cycle at room temperature (21±2°C). The procedures of all animal investigations were performed according to Central South University guidelines for the use of animals, with the approval of the Institutional Animal Care and Use Committee in Central South University. This study was carried out in compliance with the ARRIVE guidelines.

Preoperative Preparation

Fourteen mice were randomly allocated into two groups: the RYGB group (RYGB surgery, n=7), and the sham group (sham operation, n=7). All animals fasted overnight presurgery. The surgical procedures were performed under anesthesia with isoflurane (3-4% for induction and 1-2% for maintenance).

Surgery

All animal surgeries were performed under an approved surgical model protocol¹⁴. In brief, a 1.0-cm midline incision was made on the upper abdomen. For mice in the RYGB group, the jejunum was transected 4.0 cm distal to the Treitz ligament, and the proximal part was the biliopancreatic limb. Four centimeters of the distal part was measured and designated as the alimentary limb and then anastomosed to the biliopancreatic limb in an end-to-side fashion by interrupted suture. The gastroesophageal junction was ligated to exclude the stomach, and then a longitudinal incision of 0.2 cm was made on the distal esophagus. The alimentary limb was anastomosed to the distal esophagus in side-to-side pattern by running sutures. The abdominal incision was closed followed by postoperative care. Mice in the sham group underwent jejunal transection and reanastomosis in situ, and the operating time was extended to be the same as that of the RYGB group.

Postoperative Care

After surgery, all animals were placed on a heating pad after injection of 1.0 ml 0.9% of saline and 1.0 mg/kg buprenorphine. Mice received a liquid diet (ENSURE, Abbott, Zwolle, Netherlands) for 24 hours after surgery and then were switched to HFD.

Body Weight, IPGTT, and ITT

Mouse body weight was measured weekly at 11:00-12:00 a.m to the nearest 0.1 g. After 16 hours of fasting at postoperative week 7, an intraperitoneal glucose tolerance test (IPGTT) was performed after administering glucose solution (1.5 g/kg body weight) by intraperitoneal injection. The insulin tolerance test (ITT) was conducted with intraperitoneal injection of insulin at 0.75 u/kg body weight after 4 hours of fasting. At 0, 15, 30, 60, 90 and 120 min after injection, mouse blood was retrieved from the tail vein for blood glucose measurement using an ACCU-CHEK Performa glucometer (Roche, Mannheim, Germany).

Plasma IL-6, TNFα and LPS

Mice were euthanized at 8 weeks postsurgery, followed by the collection of blood and tissue samples. Plasma IL6 and TNFα levels were measured with the relevant enzyme-linked immunosorbent assay kits (BiomeTech, Greifswald, Germany) and plasma LPS concentrations were determined using the limulus amebocyte lysate (LAL) test (Associates of Cape Cod, East Falmouth, MA, USA).

RNA Extraction and Quantitative Real-time PCR

The intestine of RYGB mice was divided into four segments after RYGB, including the alimentary limb, biliopancreatic limb, common limb and colon, which were rapidly frozen in liquid nitrogen after sampling and then stored at -80°C for further analysis. The common limb of RYGB mice is equal to the lower small bowel of Sham mice. RNA was extracted from snap-frozen specimens with TRIzol reagent (Invitrogen, CA, USA). Reverse transcription of RNA was performed using cDNA synthesis kits (Thermo Fisher Scientific, NY, USA). SYBR green dye was used as a fluorochrome forquantitative real-time PCR (qPCR) in the ViiA7 System (Life Technology). qPCR was conducted to detect the gene expression levels in the intestine.

Ussing Chamber Experiments and Intestinal Permeability Assay of the Common Limb and Colon

Intestinal permeability was examined 8 weeks after surgery. For the Ussing chamber experiment, in short, it is essential to keep excised intestinal tissue fresh. The intestinal muscle layer was stripped-off and the mucosa was mounted in a Ussing chamber (WPI Instruments, Sarasota, FL, USA) containing 5 ml of circulating oxygenated Krebs buffer (136 mM NaCl, 4.3 mM KCl, 1.5 mM CaCl₂, 1.4 mM MgSO₄, 27 mM NaHCO₃, 1.6 mM KH₂PO₄, pH 7.30)¹⁵. The mucosal-to-serosal flux level of dextran conjugated to fluorescein isothiocyanate (dextran-FITC, Sigma, MO, USA) was expressed as the intestinal permeability. After the dextran probe was added, specimens of serosal buffer were retrieved at 0, 30, 60, 90 and 120 min and then was added with Krebs buffer/glucose. With respect to data analysis, the concentration was estimated in accordance with a standard curve.

Statistical Analysis

SPSS 21.0 software (SPSS Inc., Chicago, IL, USA) was used to analyze all results. Statistical analysis of the data was performed by Student’s t-test or ANOVA. All data are shown as the mean ± SEM. P ≤ 0.05 was considered to be statistically significant.

RYGB Surgery Protected Mice Against HFD-Induced Obesity and Insulin Resistance

The body weight of the RYGB group was similar to that of the sham group at the starting point (before the operation). In contrast, the weight loss of mice in the RYGB group was significantly higher than that of mice in the sham group from 1 week to 8 weeks postoperatively (Fig. 1A). According to the plasma glucose measurement, mice in the RYGB group showed significantly improved glucose tolerance (Fig. 1B, 1C) and insulin resistance compared to those in the sham group (Fig. 1D, 1E).

RYGB Surgery Improved Intestinal Permeability

The intestinal permeability of the common limb (Fig. 2A) and colon (Fig. 2B) was improved in the RYGB group compared to the sham group, according to the Ussing chamber measurement. Although the mRNA expression levels of certain tight junction proteins (TJPs) in the RYGB group showed a tendency of elevation in contrast to those in the sham group, the difference was not significant (Fig. 2C, 2D).

RYGB Surgery Attenuated Systemic and Intestinal Inflammation

Compared to those in the sham group, the plasma levels of LPS (Fig. 3A), IL6 (Fig. 3B) and TNFα (Fig. 3C) were found to be significantly reduced in the RYGB group，indicating that endotoxemia and systemic inflammation were prominently alleviated by RYGB. Regarding intestinal inflammation, the mRNA expression levels of IL1β in the common limb (Fig. 3D) and IL6 in the colon (Fig. 3E) were significantly lower in the RYGB group than the sham group, suggesting RYGB attenuated the inflammatory response of the intestine.

RYGB Surgery Regulated Innate Immunity of the Intestine by Suppressing TLR4 Expression

The mRNA expression levels of Toll-like receptors showed that the expression of TLR4 in the common limb and colon (Fig. 4A, 4B) was significantly reduced in the RYGB group compared to the sham group. Although the mRNA levels of TLR2 and TLR9 in the common limb and colon presented a decreasing trend in RYGB group, the difference did not reach significance.

RYGB Surgery Enhanced the Production of Antimicrobial Peptides and IAP from the Intestine

We found that the mRNA expression levels of antimicrobial peptides and IAP were augmented after RYGB surgery. In contrast to the sham group, REG3β mRNA levels in the common limb and the colon were remarkably increased in RYGB group (Fig. 5A, 5B), and the REG3γ mRNA expression level in the colon was significantly higher in the RYGB group than in the sham group (Fig. 5B). Moreover, the mRNA expression of IAP from both the common limb and colon was markedly enhanced by RYGB (Fig. 5C, 5D).

To our knowledge, this study is the first report on the change in intestinal permeability after RYGB in a DIO mouse model. Our data showed that gut permeability was improved by RYGB in comparison to sham surgery, with marked amelioration of intestinal and systemic inflammation. In mice receiving RYGB surgery, the small bowel was surgically partitioned into three segments, of which the alimentary and biliopancreatic limb functioned in the transport of undigested food and digestive juice, respectively¹⁶. As a result, macronutrient digestion and absorption mainly occurr within the common limb after RYGB, which might lead to profound changes in the intraluminal milieu within the common limb and colon^17,18. Therefore, our investigation mainly focused on the common limb and colon after RYGB.

In the present study, we showed that RYGB led to significant weight loss and remission of insulin resistance, demonstrating a successful mouse model of RYGB. As chronic inflammation has been proven to play an essential role in insulin resistance and metabolic syndrome^19,20, we measured inflammatory cytokines in peripheral blood which concluded that RYGB substantially reduced systemic inflammation, as supported by the finding that IL6 and TNFα were decreased in the RYGB group. Moreover, our study found that serum LPS levels were significantly lower in the RYGB group than in the sham group, suggesting that the intestine became less permeable to gut-derived toxins, which is consistent with the findings of relieved endotoxemia after RYGB in human studies^21–23.

Intriguingly, several studies^24,25 revealed that there is an association between increased gut permeability and obesity-related metabolic disorders. Indeed, aggravated gut permeability persistently leads to the development and progression of chronic inflammation, which causes insulin resistance in obesity²⁶. Our data revealed that intestinal permeability was decreased in the common limb and colon after RYGB by the Ussing chamber, indicating that RYGB improved intestinal barrier function, which contributed to the amelioration of systemic inflammation and the remission of insulin resistance^27,28. In addition, we also found that the mRNA levels of TJPs in the common limb and colon were increased after RYGB, although the difference was not significant.

Studies have found excessive inflammation in the gastrointestinal tract of HFD-induced obese mice and patients with morbid obesity^3,29. Moreover, inflammatory stress may have an impact on the status of gut permeability. IL6, IL1β and TNFα have been widely used to assess the severity of gut inflammation³. Our data showed a significant reduction in inflammatory factors, such as IL1β and IL6, in the common limb and colon, respectively. Hence, it could be concluded that gut inflammation was markedly attenuated by RYGB, which led to improvement in intestinal barrier function and amelioration of systemic inflammation.

The crosstalk between the microbiota and gut plays a pivotal role in regulating intestinal function and permeability³⁰. A large body of evidence has revealed that a close physiological and pathological connection exists between intestinal innate immunity and gut inflammatory stress^31,32. As a consequence, to define the mechanism by which RYGB mitigated enteric and systemic inflammation, we assessed the innate immune system of the intestine. Our data demonstrated that the mRNA expression of TLR4 was significantly decreased in the common limb and colon following RYGB, suggesting the intestinal inflammation caused by the LPS-TLR4 pathway was diminished by RYGB.

IAP, a gut brush border enzyme that can dephosphorylate LPS lipid A to detoxify LPS, is secreted into the intestinal lumen by enterocytes, modulates mucosal inflammation via the TLR4 pathway³³ and maintains gut homeostasis³⁴. We found that intestinal IAP production was significantly strengthened by RYGB in the common limb and colon, suggesting that the LPS-TLR4 inflammatory pathway might be downregulated through enhanced IAP secretion. Moreover, intestinal epithelial cells can also generate antimicrobial peptides such as REG3β and REG3γ, which play a critical role in suppressing gut gram-positive bacteria^35,36. This study revealed that the expression of REG3β and REG3γ was markedly increased in the common limb and colon after RYGB surgery, which may assist inhibiting gut-derived inflammation and improve gut permeability^37,38. Taken these together, these findings indicate that augmented production of IAP and antimicrobial peptides may exert protective effects against intestinal inflammatory stress after RYGB, which results in the improvement in gut permeability.

In this study, we first demonstrated that RYGB improved gut permeability in a DIO mouse model and unveiled the association between improved intestinal permeability and enhanced production of IAP and antimicrobial peptides. This study will help to elucidate the mechanism of RYGB and provide a better understanding of the crosstalk between the gut and obesity.

Acknowledge: This study was supported by the National Nature Science Foundation of China (81670481).

Author contributions: Z.J. and K.C. have contributed equally to this work. Z.J. and K.C. conceived and carried out the experiments. Z.Z. and W.P. collected and analyzed data. W.L. conceived the experiments and reviewed the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions. W.L. is responsible for this work and all the data in the investigation.

Additional information

Competing interests: The authors declared no conflict of interests.

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Roux-En-Y Gastric Bypass Improved Intestinal Permeability by Regulating Gut Innate Immunity in Diet-Induced Obese Mice

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