We are privileged to move on now to the last talk of this session and happy to report that we're within a minute or two of being on time. Dr. Pichamon-Quiropinho is from the Brigham Women's Hospital and is on the faculty of Harvard Medical School, where she is actively engaged in research and clinical care with these therapies that Dr. Mundewitz has just talked about. She's going to talk today about mechanisms of action for endoscopic therapies, how do they work, and does it matter? I'd like to thank my course co-directors, Dr. Kaplan and Dr. Sullivan, for the invitation. I'm honored and excited to talk about one of my favorite topics, which is mechanisms of action for endoscopic therapies, how do they work, and does it matter? Here are my disclosures. Now that you're convinced by Dr. Edmundowitz that bariatric endoscopy may be fit into your obesity practice, you may wonder, how do they work mechanistically? Do they work more similarly to pharmacotherapy that Dr. Kaplan just discussed, or are they more similar to bariatric surgery? The goal of this talk is to help you understand the mechanisms underlying weight loss and improvement in metabolic comorbidities following each endoscopic bariatric and metabolic therapy. Here is an outline of the talk. We're going to start with a brief overview of EBMTs. We'll then spend more time discussing mechanisms of action of gastric followed by small bowel interventions. Here is a summary of EBMTs as of 2021. The left side is gastric interventions. We have balloons, transpyloric shuttle, endoscopic sleeve, which can be broken down into ESG and post, and aspiration therapy. For small bowel devices, we have duodenal jejunal bypass liner, also known as endobarrier, and duodenal mucosal resurfacing, or Revita. Both of these small bowel devices are undergoing US pivotal trials. When you see patients with obesity, you care not only about helping them lose weight, but also improving their comorbidities. So in general, for gastric interventions, they have a direct effect on weight loss, which leads to improvement in metabolic outcomes. In contrast, small bowel interventions have a direct impact on metabolic improvement with or without weight loss, suggesting that they work through different mechanisms. Some of you may think that bariatric endoscopy is investigational. Actually, this field has been around for about 20 years. There are several randomized controlled trials, some of which were sham controlled, that were conducted in the US. You'll hear about these procedures and studies in more details in the next session. But overall, gastric balloons and transpyloric shuttle give you about 10% total weight loss, while endoscopic sleeve and aspiration therapy give you somewhere between 15% and 20%. For small bowel devices, the US trials are ongoing, but international data look promising with 19% total weight loss and 3% total weight loss at one year for patients with obesity and concomitant diabetes. When you look at metabolic outcomes, study shows significant improvements in hemoglobin A1c, HOMA-IR, which is a surrogate of insulin resistance, and AOD, which is a surrogate of insulin resistance, and AOD, which is one of the indirect surrogates of fatty liver. We also noted two interesting observations. First, in Dr. Shariah's recent study, she found that HOMA-IR improved as early as one week following ESG, even before patients experienced any significant weight loss. Secondly, for Revita, patients experienced minimal weight loss of about 2-3%, but had significant improvement in A1c, insulin resistance, and fatty liver. Therefore, this suggests that there may be some weight loss-independent mechanisms following certain endoscopic procedures. Let's start with gastric devices. A lot of you are familiar or have seen this diagram, which represents the gut-brain axis. It basically shows that there are several ways that the GI tract communicates with the brain to tell the brain that you're full or hungry, similar to how weight loss medications work by affecting some neuronal pathways. Our endoscopic procedures work by altering this gut-brain axis. For gastric interventions, they appear to work on gastric emptying and gut hormones. The relationship between gastric emptying and obesity has been described since 1983. In the study by Dr. Wright, he looked at gastric emptying of 77 subjects. 46 had obesity, and 31 were normal weight. On the graph here, the y-axis represents the amount of food remaining in the stomach at each time point after eating. You see that for patients with obesity, you see that for patients with obesity, represented by the white dots, they had less food at each time point compared to patients with normal weight because they emptied faster. So, they suggested that slowing down gastric emptying may be beneficial for weight loss. Why is that? It's because the rate of gastric emptying controls how much food remains in the stomach after eating. This then affects the extent and duration of gastric distension. For example, if you have slow emptying, this prolongs gastric distension, which triggers stress and tension mechanoreceptors, which tell the brain that you're full. Additionally, the rate of gastric emptying appeared to affect the amount of gut hormone secretion. However, data are more conflicting, so we're not going to go over that in more details. Moving on to gut hormones, these are the major ones summarized in a very simplistic way. These hormones are going to keep coming back throughout the talk. The first one is ghrelin, which is secreted in the fundus of the stomach. It's the only hunger hormone. CCK and GIP are secreted in the proximal small bowel. CCK stimulates gallbladder contraction and pancreatic enzyme secretion. And GIP causes an increase in insulin secretion. GOP1, PYY, and oxytomodulin are secreted in the distal small bowel and proximal colon. They help induce satiation and satiety, and GOP1 also stimulating insulin secretion. Now we're ready to talk about each device. We're going to start off with the most common procedure worldwide, which is an intragastric balloon. You're going to hear all about balloons during Dr. Sullivan's talk in the next session, but here are what we have as of 2021. Here's a patient of mine whom I recently scoped with a fellow. She's 48 with class 1 obesity. She went to Brazil to get a spast balloon 500 cc, came in two months later with PO intolerance requesting balloon removal. During endoscopy, we found large food besorbs as shown here. So, this is not uncommon when we scope balloon patients, which suggests that there's a relationship between an intragastric balloon and gastric emptying. What's the association between balloons and besorbs? Here's an early study on mechanisms of balloons, which was published in 1983. In this study, 17 patients received an early version of OBERA balloon. They found that the time required for the stomach to empty half of the ingested meal or gastric emptying halftime increased with a balloon in place. Specifically, the emptying halftime went from 92 minutes before the balloon to 116 at one month and 157 minutes at four months. The balloon was then removed at six months and the emptying halftime went down to 118 minutes. Additionally, the study showed that fasting ghrelin decreased and remember ghrelin makes you hungry. So, lowering ghrelin level is a good thing. They also showed a positive correlation between the amount of ghrelin reduction and the amount of weight loss as shown in the upper right image. Following this study, there were follow-up studies such as those from Dr. Abudaye and Dr. Kumbhari that show similar effect of balloons on delaying gastric emptying. However, if you pump ghrelin and intragastric balloon, you'll get various results. For example, in this study, they found no change in ghrelin in both the balloon and CHAM groups despite weight loss in both groups. However, we know that when people lose weight, ghrelin goes up. So, they suggested that there might be some flaws with either study design or the way ghrelin was measured. This study showed no change in fasting or meal suppressed ghrelin. However, it measured total and not isolated ghrelin. So, most of these studies were likely flawed and misleading. So, how does the balloon affect gastric emptying and ghrelin? For a fluid-filled balloon, it can sit either in the fundus or gastric body. Therefore, a balloon weakens tonic contractions, which is generated in the fundus, or aphasic contractions, which is generated in the gastric body. This leads to inefficient gastric motility and delayed gastric emptying. This causes food to sit in the stomach longer, resulting in ghrelin suppression. There has been no study on mechanisms of gas-filled balloons. However, we think that they may work differently and may have a direct effect on ghrelin because they tend to sit in the fundus, as shown here on a fluoral image from Dr. Sullivan. Next device is transpyloric shuttle, or TPS, which consists of a large bulb and a small bulb connected by a tether. When the stomach contracts, the TPS moves to block the pylorus, preventing food from passing down to the duodenum. When the stomach releases, the TPS moves back proximally to allow food to pass by. Therefore, we think that the TPS works by delaying gastric emptying. This is supported by this endo image from Dr. Sullivan and Dr. Kushner, showing very similar findings of food bezoars to those of balloon patients. Next is endoscopic sleeves. You'll hear them all from the one who started it all, Dr. Thompson, in the next session. When we think about endoscopic sleeve, we usually compare it to surgical analogs, which are surgical sleeve or sleeve gastrectomy and gastric placation. For endoscopic sleeve, we have ESG, which refers to when we use the Apollo suturing device to create a sleeve, and POST, which is when we use the USGI placation device to create a sleeve. Let's start with how a surgical sleeve works. We conducted a meta-analysis looking at mechanisms of a surgical sleeve, which demonstrated that ghrelin decreased, so you're less hungry, and GLP-1 and PYY increased, so you feel full sooner and longer. Studies also show that gastric emptying was faster after a surgical sleeve. The first study on mechanisms of endoscopic sleeve came from the Technion Group in Spain in 2016. They looked at 18 patients who underwent POST using the traditional pattern where the IOP system was used to reduce the fundic size. At two months, patients experienced a delay in gastric emptying compared to baseline. Shortly after, Dr. Abadaye from Mayo showed similar results for ESG using the overstitch device. In this study, four patients experienced a delay in gastric emptying at three months. Here, the blue line represented the baseline emptying rate, and the red line was at three months after ESG. You see that there's more food remaining in the stomach after a meal following ESG. What about gut hormones and endoscopic sleeve? In the same study from Technion in Spain, they showed an increase in fasting ghrelin, likely due to significant weight loss. However, post-prandial ghrelin inhibition was significantly enhanced. This means that after you eat, ghrelin drops much more significantly, which then suppresses your hunger more dramatically. Additionally, post-prandial PYY stimulation increased following POST, which means that as soon as you eat, PYY increases more dramatically, causing you to feel full sooner. For ESG, we have this 12-patient study from Dr. Lopez-Nava from Madrid, which showed no change in ghrelin, GLP-1, and PYY. More studies on this procedure are needed. You may wonder why endoscopic sleeve works differently than surgical sleeve. For example, surgical sleeve accelerates emptying while endoscopic sleeve delays it. Or, ghrelin decreases after surgical sleeve but increases after our endoscopic approach. The answer is the fundus. On the top row is a patient of mine with sleeve gastrectomy whom I did an endoscopy on in preparation for an endoscopic revision. You see that the sleeve is quite dilated, and on retroflexion, there's no fundus. On the bottom row is another patient of mine whom I did a distal POST on a few months ago now. She came in with abdominal pain, which prompted this endoscopy. You see the intact placations in the gastric body, and on retroflexion, the fundus remains intact. So after a surgical sleeve, when you don't have the fundus, there's no accommodation. So food immediately passed into the gastric body and antrum. In contrast, when you have the fundus, food, especially solids, will reside in the fundus first during the lag phase before getting ground by the gastric body. Last but not least for the gastric category is aspiration therapy. We now know that reduction in calories from aspiration alone explains only 80% of the weight loss. This was shown in Dr. Sullivan and Dr. Emendovitz's original gastro paper. So we believe that the other 20% of weight loss is explained by a reduction in total daily caloric intake, likely from behavioral changes. Many of our patients reported eating more healthily and chew more in order to prevent clocking the A-tube. Furthermore, gut hormones may play a role. Specifically, the gastric portion of the A-tube tends to reside in the fundus as shown here. And there's a mice work showing that stroking the cardia causes a spike in CCK, which is one of the satiety hormones. I know you care about not only helping your patients lose weight, but also improving their comorbidities like diabetes, fatty liver, which are very prevalent in our patients. So the next section is going to be very exciting. These small bowel therapies are not yet available but are undergoing trials in the U.S. You're going to hear them all from Dr. Rothstein in the next session. For small bowel interventions, there appear to be several other players that link the GI tract and the brain. And we'll go over most of them during the second half of the lecture. First and foremost, the increase in effect. This refers to when you ingest glucose orally, there's a higher spike in insulin secretion compared to when you get glucose intravenously. This is thought to be due to some gut-derived factors that drive that insulin spike. For patients with type 2 diabetes, their increase in effect is blunted, so their insulin spike is lower even after oral glucose ingestion. This study came from Dr. Nogg originally back in 1986. To date, we know that the two major increase in hormones are GIP, which is secreted in the duodenum, and GOP1, which is secreted in the ileum. They both promote insulin secretion and satiety and delay gastric emptying. What about foregut-hindgut hypothesis? This has been around for a while, but it still remains controversial. This refers to the two theories of how bariatric surgery improves metabolic outcomes. Some say it's due to proximal, some say it's due to distal small bowel. On the left is a picture of normal anatomy. The white dots represent cells that produce incretins that are distributed throughout the small bowel. Some people believe that there are cells in the proximal small bowel represented by the black dots that have an anti-incretin effect. Following Roux-en-Y gastric bypass, foregut people say you remove the proximal small bowel. So you remove those bad anti-incretin cells. Therefore, you have an enhanced effect of incretin hormones. On the other hand, just by rerouting the small bowel, the food limbs become shorter. So the hindgut people believe that because nutrients can get to the distal small bowel faster, you stimulate more GOP1 secretion. So how does endobarrier, or duodenal jejunal bypass liner work? It basically is a 60-centimeter liner that sits in the duodenum and proximal jejunum. So food can pass from the stomach into the liner directly into the jejunum. So on one hand, it may work on the foregut theory because the liner excludes the contact between food and the proximal small bowel. On the other hand, food moves faster within the liner, so it reaches the distal small bowel sooner, potentially causing a spike in GOP1. What did the data show? Here's our meta-analysis. We found seven studies that looked at gut hormones following endobarrier. Our studies show that GIP decreased while GOP1 and PYY increased, supporting the hindgut hypothesis. Ghrelin increased, which was likely due to weight loss. Now, what about bioacids? This abstract looked at the effect of endobarrier on bioacids. It showed that FGF19 went up after 10 months of endobarrier. FGF19 is stimulated by bioacids and acts as a hormone to inhibit gluconeogenesis and stimulate glycogenesis in the liver. So similar functions as insulin. So this is one of the key facilitators between the small bowel and liver. Furthermore, a few studies showed that FGF19 may promote insulin secretion in the pancreas. Here's a study in dogs that is interesting. It looked at changes in gut microbiomes after endobarrier. On the left, each line represents each bacterial species. You see that at the time of explant, the microbiome looked more similar to the control group who were metabolically healthy. On the right, they grouped bacteria by phylum, and you see similar findings. Specifically, they found a decrease in proteobacteria and an increase in bacteroides, which is responsible for conversion of primary to secondary bioacids, which then lead to greater GIP and GOP1 release. Last but not least, duodenal mucosal resurfacing, or REVITA. This is an endoscopic procedure where we lift and then ablate duodenal mucosa. This device likely works on the foregut only. In REVITA1 study, which was a single-arm open label study, patients lost about 2% to 3% of their weight during the first four weeks, then stabilized, as shown on the left graph. However, fasting glucose, HOMA-IR, and ALT continue to improve for one year, suggesting that there's no correlation between weight loss and improvement in metabolic conditions. Given a reduction in fasting glucose without an increase in insulin, since HOMA-IR equals fasting glucose multiplied by insulin, this suggests an improvement in insulin sensitivity, potentially at the liver level. This was then confirmed on the follow-up REVITA2 study, which demonstrated a greater decrease in liver fat on an MRI in the treatment group compared to the sham group. So, in addition to being a site of GIP and some GOP1 secretion, the proximal small bowel appears to play other important roles in metabolic conditions. Specifically, studies show that for patients with obesity and metabolic diseases, the proximal small bowel appears to be more hypertrophic and leaky, so there's more bacterial translocation leading to endotoxemia and inflammation. Therefore, people believe that by ablating the mucosa, the REVITA procedure kills those deceased small bowel cells and causes the stem cells to reset and grow more metabolically healthy. In conclusion, EBMTs work via several mechanisms. Certain EBMTs have weight loss dependent, while others have weight loss independent effects on metabolic conditions. Lastly, more mechanistic studies on EBMTs are needed to help guide personalized therapy. Thank you very much.

endoscopic therapies

weight loss

metabolic comorbidities

gastric interventions

small bowel interventions

gut hormones