New methods
Experimental endoscopy
Gastric mucosal devitalization is safe and effective in reducing body weight and visceral adiposity in a porcine model

https://doi.org/10.1016/j.gie.2018.02.022Get rights and content

Background and Aims

The early improvement in metabolic profile after sleeve gastrectomy (SG) indicates that the significant benefits of metabolic surgery are gastric in origin. We have previously demonstrated that devitalization of the gastric mucosa (without a reduction in gastric volume) in metabolically disturbed obese rats results in an improvement of obesity and its associated comorbidities. The aims of this study were to assess the technical feasibility, efficacy, and safety of gastric mucosal devitalization (GMD) in a large animal (porcine) model.

Methods

A 3-arm (GMD versus SG versus sham [SH]) prospective randomized controlled trial with an 8-week follow-up period was performed. The primary endpoint was relative weight loss. Secondary endpoints were absolute body weight, abdominal visceral adiposity, abdominal subcutaneous adiposity, organ lipid content, and serum ghrelin level.

Results

GMD resulted in a significant relative weight loss of 36% over SH at 8 weeks (P < .05). There was no significant difference in relative weight loss between GMD and SG at 4 weeks; however, SG resulted in a 29% superior relative weight loss at 8 weeks (P < .05). With regard to visceral adiposity, there was a significant benefit of GMD over SH at 8 weeks. Despite differences in relative weight loss, there was no significant difference in visceral adiposity between SG and GMD at 8 weeks. Significant improvements in GMD over SH were noted with regard to skeletal and heart muscle lipid content. GMD pigs at 8 weeks demonstrated regeneration of the gastric mucosa without ulceration or significant scarring. Despite mucosal regeneration, the abundance of serum ghrelin was significantly lower in the GMD cohort compared with the SG and SH cohorts.

Conclusions

GMD was technically feasible and resulted in relative weight loss and an improvement in visceral adiposity. The benefits noted were out of proportion to what would be expected with weight loss alone.

Introduction

The worldwide prevalence of overweight and obesity in children, adolescents, and adults has reached pandemic proportions.1 Metabolic surgery, such as Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG), is the most effective and durable weight loss and metabolic therapy.2, 3 Metabolic surgery alters the physiologic regulation of body fat mass, demonstrating the critical role of the GI tract in the regulation of metabolic function.4 The mechanisms of action are neither mechanical restriction nor macronutrient malabsorption and remain poorly understood.5, 6 Furthermore, there appears to be weight-dependent and weight-independent mechanisms of action.7, 8 Unfortunately, because of its invasiveness and irreversibility, metabolic surgery is severely underused.9 The development of minimally invasive flexible endoscopic methods to mimic the effect of metabolic surgery provides an opportunity to fulfill the large unmet need.10

The primary site of regulation of glucose and lipid metabolism remains ambiguous. Human and rodent studies of RYGB allude to the importance of bypassing the duodenum.11 Conversely, SG does not alter nutrient flow across the duodenum yet induces similar metabolic effects to RYGB, signifying that the stomach may be a critical regulator of glucose and lipid homeostasis.2, 5 Some have proposed that the accelerated nutrient transit through the GI tract seen with SG causes more undigested nutrients to reach the distal ileum resulting in postprandial increase in glucagon-like Peptide 1; however, mechanistic evidence for this is lacking.12 A common element to both surgeries is the exclusion or resection of the gastric mucosa, an often-underappreciated neuroendocrine organ.13, 14, 15

Our group has been investigating the hypothesis that excision of the gastric mucosa is a key contributor to the improvement in obesity-related comorbidities perceived after SG.16, 17 We previously demonstrated, in an obese rat model, that the gastric mucosa is an independent regulator of glucose and lipid metabolism.18 In that study, gastric mucosal devitalization (GMD) reduced body weight and visceral adiposity, improved serum lipid and glucose profiles, and reduced liver lipid content.18 Considering those promising results, our goal was to translate our technique of GMD into a large animal model to assess its technical feasibility, efficacy, and safety. The porcine model was chosen because it has similar GI anatomy to humans and allows utilization of commercially available endoscopic equipment. Furthermore, porcine models are a familiar platform to investigate endoscopic bariatric therapies before pilot clinical studies.19, 20

Section snippets

Study design

We performed a 3-arm prospective randomized controlled trial with an 8-week follow-up period. A total of 23 healthy litter-matched male German saddleback pigs aged 11 weeks and weighing 30 to 35 kg were obtained from a commercial, closed-herd pig vendor (Lehr- und Versuchsgut Oberholz, Großpösna, Saxony, Germany). This breed of domestic pig was chosen because of their relatively high body fat mass. Two pigs underwent GMD; one was killed immediately after the procedure and the other at 4 weeks

Technical feasibility and safety

All 23 pigs successfully underwent and survived their designated interventions and were killed per protocol. There were no changes in physiologic parameters observed during or after the intervention, including electrocardiogram, heart rate, respiration rate, temperature, blood pressure, and oxygen saturation. There were no intra- or post-procedural adverse events observed. The animals were upright, alert, responsive, defecating, urinating, drinking, and tolerating oral intake within 24 hours

Discussion

The obesity pandemic, being a global public health concern, has appropriately captured the attention of the major GI societies.29 Furthermore, as the GI tract is a critical metabolic regulator of obesity and its metabolic comorbidities, GI endoscopy societies have taken special initiatives to assess currently available and future endobariatric therapies.30 Although weight reduction is an important outcome, a disproportionate emphasis has been placed on it as opposed to improvements in

Acknowledgments

The study was supported by Erbe Elektromedizin GmbH, Tübingen, Germany.

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    If you would like to chat with an author of this article, you may contact Dr Oberbach at [email protected].

    DISCLOSURE: Dr Kumbhari is a consultant for Boston Scientific, Apollo Endosurgery, ReShape Life Sciences, and Medtronic. Dr Enderle is the vice president of research and an employee of Erbe GmbH Germany. Dr Khashab is a consultant for Boston Scientific and Olympus America. Dr Kalloo is a founding Member, equity Holder, and consultant for Apollo Endosurgery. All other authors disclosed no financial relationships relevant to this publication.

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