Background:
Ghrelin is predominantly made in the gastric fundal mucosa. Various obesity therapies target ghrelin production, including left gastric artery embolization and surgical fundectomy, and successful weight loss without compensatory hunger increase after vertical sleeve gastrectomy is substantively driven by attenuated circulating ghrelin. To date, endoscopic ghrelin reduction has not been reported in humans. Hybrid argon plasma coagulation (HybridAPC) permits mucosal ablation while avoiding greater depth of thermal injury, providing the opportunity for accurate and safe endoscopic fundic mucosal ablation (FMA). Our objective was to assess the impact of FMA in adults with obesity. This may serve as a promising component of endoscopic bariatric therapy.

Methods:
This was a first-in-human trial (NCT05578703) of adults with BMI 30-50 kg/m² treated with endoscopic FMA with a dual-channel endoscope and HybridAPC. Subjects underwent FMA in the ambulatory setting under general anesthesia. The primary outcome was change in fasting plasma ghrelin (FPG) from baseline to 6 months. FPG, maximum tolerated volume (MTV) of a standard nutrient drink test, weight, and DAILY EATS and WEL-SF questionnaires were obtained at baseline and months 1, 2, 3, and 6. These were analyzed with paired t-tests with Bonferroni correction accounting for multiple comparisons, with p < 0.0125 considered significant at the 0.05 level. Adverse events were monitored throughout the study. All patients underwent repeat endoscopic assessment at month 6.

Results:
From November 1, 2022 to April 14, 2023, ten subjects (100.0% female, mean age 38.4 ± 4.8 years, mean BMI 40.2 ± 5.0 kg/m²) underwent technically successful FMA. Endoscopic assessment at 6 months showed a contracted fundus in all participants (Fig. 1). FPG decreased from 461.6 ± 239.9 pg/mL at baseline to 254.8 ± 113.7 pg/mL at 6 months (p = 0.006), representing a mean decrease of 48% (Fig. 2A). MTV, a reflection of satiation and accommodation, decreased from 27.3 ± 13.9 oz at baseline to 15.8 ± 7.0 at 6 months (p = 0.004; Fig. 2B). Total body weight loss was 5.7 ± 3.9% at 6 months (p = 0.126). The DAILY EATS questionnaire showed a decrease in mean hunger score from 6.2 ± 1.5 at baseline to 4.0 ± 2.1 at 6 months (p = 0.002) and a decrease in mean Eating Drivers Index from 7.0 ± 1.1 at baseline to 4.0 ± 2.1 at 6 months (p < 0.001). Composite WEL-SF score improved from 47.7 ± 16.0 at baseline to 62.4 ± 8.3 at 6 months (p = 0.001). No serious adverse events occurred.

Conclusion:
In adults with obesity, endoscopic FMA via hybrid-APC reduced fasting plasma ghrelin, gastric accommodation, and hunger, and improved the ability to resist over-eating. Further study should evaluate the addition of FMA to existing restrictive endoscopic bariatric therapies to augment efficacy and recapitulate the success of bariatric surgery.

<b>Figure 1. Endoscopic fundus mucosal ablation. </b>A. Gastric fundus prior to fundic mucosal ablation (FMA). B. Submucosal lift of gastric fundic tissue. C. Gastric fundus immediately after FMA. D. Gastric fundus 6 months after FMA.

Figure 1. Endoscopic fundus mucosal ablation. A. Gastric fundus prior to fundic mucosal ablation (FMA). B. Submucosal lift of gastric fundic tissue. C. Gastric fundus immediately after FMA. D. Gastric fundus 6 months after FMA.

<b>Figure 2. Impact of fundus mucosal ablation on ghrelin and satiation over study duration. </b>A. Fasting plasma ghrelin. B. Maximum tolerated volume (MTV), in ounces

Figure 2. Impact of fundus mucosal ablation on ghrelin and satiation over study duration. A. Fasting plasma ghrelin. B. Maximum tolerated volume (MTV), in ounces

Daniel Maselli

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