Duodenal mucosal ablation: An emerging therapeutic concept for metabolic dysfunction-associated fatty liver disease

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is currently the leading cause of end-stage liver disease and liver cancer in the world because of the obesity pandemic. Insulin resistance resulting from abdominal adiposity is the main cause of MAFLD and type 2 diabetes mellitus among these patients. Although very common, therapeutic options for MAFLD are currently limited. Metabolic and bariatric surgery is the best treatment option for weight loss that can also improve MAFLD in a very high proportion of patients. However, surgical interventions are expensive, technically challenging, and carry significant immediate and long-term postoperative risks. Duodenal mucosal ablation, a malabsorptive endoscopic bariatric intervention, has shown beneficial effects in the management of obesity with an improvement of insulin resistance. It alters the duodenal mucosal lining, which helps maintain cellular homeostasis and better intestinal endocrine function. This process helps reduce lipid deposition in the liver, maintain serum lipid levels, and promote weight loss, especially in patients with type 2 diabetes mellitus-related MAFLD. However, some of these effects were independent of weight loss and food intake. As a minimally invasive procedure, it is beneficial for patients who have not had success with drug therapy alone, though this approach needs to be tested and further developed in future clinical trials. A basic study by Yu et al in the recent issue of the World Journal of Gastroenterology on duodenal mucosal ablation using irreversible electroporation, when experimented on rats, has shown fewer complications compared to other metabolic surgeries. This editorial describes the minimally invasive endoscopic bariatric strategies for the management of obesity and MAFLD in light of this experimental study.

Key Words: Duodenal mucosal ablation; Endoscopic bariatric procedure; Type 2 diabetes mellitus; Metabolic and bariatric surgery; Obesity; Hepatic steatosis; Metabolic dysfunction-associated fatty liver disease

Core Tip: Metabolic dysfunction-associated fatty liver disease is recognized as the most common cause of chronic liver disease globally with obesity being the prime driver for insulin resistance and hepatic steatosis. Though metabolic and bariatric surgery (MBS) is the most effective treatment option for severe obesity, it carries complication risks and long-term commitment to lifestyle adjustments. In the evolving landscape of obesity management, minimally invasive endoscopic bariatric therapies offer promising weight loss and metabolic benefits with lower complication rates compared to MBS. This editorial provides a comprehensive overview of various endoscopic bariatric techniques used in management of obesity and their effect on metabolic dysfunction-associated fatty liver disease which will help physicians to offer safer alternatives to conventional MBS.

INTRODUCTION

Metabolic dysfunction-associated fatty liver disease (MAFLD) has recently emerged as the most common cause of chronic liver disease affecting around 30% of the global population due to the obesity pandemic[1]. Over the years, hepatic steatosis has undergone a series of nomenclature transformations, from non-alcoholic fatty liver disease (NAFLD) to MAFLD and, more recently, metabolic dysfunction-associated steatotic liver disease. Interestingly, compared to NAFLD, the newer criteria of MAFLD were more inclusive and did not exclude patients with chronic viral hepatitis, excessive alcohol intake, medication-related steatosis, or other chronic liver diseases. The terminology metabolic dysfunction-associated steatotic liver disease has the advantage of removing the stigma associated with the term fatty/non-alcoholic, which is not socially acceptable in many cultures.

It is now identified as the prime reason for end-stage liver disease, liver cancer, and liver-related deaths. MAFLD results from excess fat storage in the liver, a direct consequence of metabolic imbalance due to overconsumption of an energy-rich diet and inadequate energy expenditure from physical inactivity. Therefore, weight loss achieved through creating a negative energy balance is the most important treatment option for managing the disease. Few medications are currently available for the management of obesity, with some promising effects on MAFLD, and many more are in the developmental stage. However, none of these medications are currently approved for the primary treatment of MAFLD. Although a variety of pharmacotherapeutic agents were trialled against MAFLD, with several potential therapeutic agents in the pipeline, only a limited number of them are currently approved against the disease[1-3].

Metabolic and bariatric surgery (MBS) is currently the best treatment option for severe obesity. The negative energy balance from nutrient restriction and/or malabsorption associated with MBS results in massive weight loss in MBS patients and improves several of the adiposity-related metabolic dysfunction/disorders, including MAFLD[4,5]. However, there is inadequate evidence for the newer, minimally invasive, bariatric procedures such as endo-bariatric interventions for managing MAFLD. A basic study by Yu et al[6] in a recent issue of the World Journal of Gastroenterology provides us insight about one of these procedures, called duodenal mucosal ablation (DMA) using irreversible electroporation (IRE) in improving MAFLD in rats. We update the current evidence on endo-bariatric procedures in the potential management of MAFLD in this editorial.

UPPER GASTROINTESTINAL PHYSIOLOGY AND MAFLD

The small intestine has an important role in modulating insulin sensitivity through enhanced hepatic gluconeogenesis and skeletal muscle glucose uptake[7]. The duodenum is vital for nutrient sensing[8]. An exposure to a high-calorie obesogenic diet (high-fat and high-sugar diet) is associated with the development of duodenal villus hyperplasia, characterized by a rise in enterocytes, with resultant increased nutrient absorption, and a fall in the number of enteroendocrine cells, with resultant altered secretion of hormones including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, and cholecystokinin[9]. The nutrient sensing in the duodenum activates the duodenal enteric nervous system that projects directly into the pancreas to regulate the islet cell function[10]. Nutrient sensing following an obesogenic diet decreases insulin secretion and increases glucagon secretion (gut-islet axis) through dysbiosis[11]. Obesogenic diet is associated with an altered duodenal enteric nervous system, leading to duodenal hypercontractility, generating aberrant signals to the hypothalamus (altered gut-brain axis), which in turn causes insulin resistance[12].

Further to villus hyperplasia, various glucose transporters in the duodenum, including sodium-glucose cotransporter-1, and glucose transporter 2 and 5, are increased by many folds in those with obesity and metabolic diseases[13]. The small intestinal gut microbiome (GM) and its metabolites, similar to the more important large intestinal GM, could influence the duodenal nutrient sensing mechanisms. GM metabolites, including short-chain fatty acids and secondary bile acids, contribute to the regulation of the secretion of various incretin hormones[8,14]. Exposure to an obesogenic diet is associated with a reduction in GM metabolites, which affects the incretin homeostasis. This, in turn, results in a reduction of insulin secretion and worsening of insulin resistance[14].

Reducing the duodenal nutrient exposure would decrease nutrient sensing, increase the incretin secretion, decrease the body weight, and enhance the insulin sensitivity, thereby improving metabolic disorders like obesity, type 2 diabetes mellitus (T2DM), and MAFLD. As weight loss of ≥ 5% can decrease hepatic steatosis, ≥ 7% or more weight loss can resolve metabolic dysfunction-associated steatohepatitis, and ≥ 10% or more weight loss can stabilize/regress hepatic fibrosis, anyone with MAFLD should aim for at least ≥ 5%, and if feasible, ≥ 10% of weight loss[15]. Therefore, any small intestine-targeted endoscopic interventions, if able to attain this degree of weight loss, could improve metabolic disorders like MAFLD.

MINIMALLY INVASIVE BARIATRIC PROCEDURES

Various surgical bariatric interventions (MBS) available to improve the metabolic health include Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, adjustable gastric band, sleeve gastrectomy, single anastomosis duodeno-ileal bypass with sleeve gastrectomy, and one anastomosis gastric bypass (or mini gastric bypass)[16]. Various endoscopic bariatric and metabolic therapies (EBMTs) or bariatric endoscopy available to improve the metabolic health include intragastric balloon (IGB), transpyloric shuttle (TPS), endoscopic sleeve gastroplasty (ESG), primary obesity surgery endoluminal (POSE), percutaneous endoscopic aspiration therapy (AT), duodenojejunal bypass liner (DJBL), duodenojejunal bypass sleeve (DJBS), gastroduodenojejunal bypass sleeve (GJBS), SatiSphere, incisionless magnetic anastomosis system (IMAS), magnet system (MS) using a magnetic compression anastomosis device, and duodenal mucosal resurfacing (DMR)[16,17]. The United States Food and Drug Administration (FDA) has approved IGB, TPS, ESG, POSE, as well as AT, whereas DJBL, DJBS, GJBS, SatiSphere, DMR, MS, and IMAS have not received United States FDA approval[18]. EBMTs are minimally invasive procedures that can be used in treatment-naive patients with no prior MBS or in patients who have weight regain following MBS[18]. EBMT can be divided into restrictive (IGB, ESG, POSE, TPS), malabsorptive (DJBL, DJBS, GJBS, SatiSphere, DMR, MS, and IMAS), and gastric aspiration EBMT (AT)[19]. The ESG and POSE fall under the umbrella term endoscopic gastric remodeling.

DMA

DMA is a novel therapy that directly targets the duodenum to reset aberrant enteroendocrine signaling involved in metabolic disorders like T2DM and MAFLD. By ablating the diseased mucosal lining, DMA promotes mucosal regeneration, potentially restoring healthy incretin and bile acid profiles. Unlike other EBMTs, DMA focuses not merely on anatomical restriction or nutrient malabsorption but on reprogramming the metabolic interface of the gut. The DMA techniques entail endoscopic ablation of the defunctioning duodenal mucosa, which is then replaced through the natural healing process with functioning tissue. These endoscopic interventions include techniques such as DMR using circumferential hydrothermal mucosal ablation, duodenal recellularization using electroporation therapy (ReCET), and photodynamic therapy, which uses thermal, electrical, and photodynamic energy, respectively[20]. DMR increases the insulin sensitivity, potentially through increased production of secondary bile acids[21]. The recent experimental study by Yu et al[6] employed IRE as an ablative modality and demonstrated favorable metabolic effects in a rat model of MAFLD.

A systematic review and meta-analysis observed that DMR is associated with a significant glycated hemoglobin (HbA1c) reduction of -0.94%, fasting plasma glucose -15.84 mg/dL, alanine aminotransferase (ALT) -10.82 U/L, and hepatic steatosis, though it was not associated with a statistically significant weight loss[22]. Another systematic review and meta-analysis of 3 randomized controlled trials and 6 uncontrolled trials, seven based on DMR and two based on ReCET, observed that both types of DMA improve the glucose homeostasis by reducing HbA1c and fasting plasma glucose, improved hepatic steatosis, and in combination with GLP-1 based drugs eliminated insulin need in up to 86% patients[20]. DMA thus emerges as a promising, gut-centric therapy with potential applications in patients who are ineligible for surgery or fail to respond adequately to pharmacotherapy. As this approach advances through preclinical and early clinical phases, it warrants rigorous evaluation for long-term safety, durability, and synergy with agents like GLP-1 receptor agonists.

OTHER EBMTS

IGB

In IGB, as many as three silicone balloons may be inserted into the stomach for about six months, aiming to decrease the available volume of the stomach and modify gastric motility[16]. The IGB can be inserted endoscopically (Orbera, ReShape Duo, Spatz3, and Heliosphere) or swallowed (Obalon and Elipse); can be fluid-filled (Orbera, ReShape Duo, Spatz3, and Elipse) or gas-filled (Obalon and Heliosphere); FDA approved (Orbera, ReShape Duo, Obalon, and Spatz3) or not (Elipse and Heliosphere)[23]. A recent systematic review and meta-analysis observed that IGB improves steatosis in 79.2%, NAFLD activity score (NAS) in 83.5%, homeostatic model assessment of insulin resistance (HOMA-IR) in 64.5%, and liver volume in computed tomography in 93.9% of patients[24].

TPS

TPS comprises a big and a small silicon-filled bulb connected by a silicone tether. The big bulb is placed endoscopically in the stomach. However, the small bulb moves in and out of the stomach through the pylorus, causing an intermittent gastric outlet obstruction[16]. In a randomized double-blinded sham-controlled study with TPS endoscopically placed for one year, the mean total body weight loss (TBWL) achieved after 12 months of TPS was 9.5% in the treatment arm in comparison to 2.8% in the sham arm[25]. Nearly 67% in the treatment arm achieved ≥ 5% TBWL in comparison to only 29.3% in the sham arm[25].

ESG

In ESG, using an endoscopic suturing device, many sutures are placed along the greater curvature to make a tubular gastric sleeve, which results in altered gastric storage capacity and motility[16]. ESG is associated with marked improvement of obesity and its adverse metabolic consequences. Another systematic review and meta-analysis observed that ESG after 12 months, is associated with statistically significant reductions in TBWL (17.28%), excess body weight loss (EBWL, 47.97%), body mass index (6.31 kg/m²), hepatic steatosis index (4.85), NAFLD fibrosis score (0.5), ALT (6.32 U/L), and HbA1c (0.51%)[26].

POSE

In POSE, using an endoscopic plication device, many full-thickness plications are placed in the gastric fundus and body to make a stomach with lowered volume with altered motility[16]. In a systematic review and meta-analysis, POSE at 3-6 months is associated with 13.45% TBWL and 42.62% EBWL, and at 12-15 months with 12.68% TBWL and 48.86% EBWL[27]. Naturally, these physiological improvements in adiposity-related parameters are expected to improve MAFLD and its adverse outcomes in patients.

Percutaneous endoscopic AT

It is placed endoscopically like a percutaneous endoscopic gastrostomy tube, and it has an aspiration catheter and an external device that allows drainage of nearly one-third of gastric contents 30 minutes after a meal[16]. This results in a reduction of total energy absorption from the small intestine and facilitates creating an effective negative energy balance in the individual. In addition to weight loss, AT is associated with improvement in comorbidities including systolic/diastolic blood pressure, HbA1c, triglyceride, ALT, and aspartate aminotransferase[28]. Therefore, this method can be an effective therapeutic strategy for patients with MAFLD.

Endoluminal bypass liners

The endoluminal bypass liners, including DJBL, DJBS, GJBS, and SatiSphere, act as a physical barrier preventing contact between the chyme and the upper gastrointestinal mucosa. Their use also decreases the production of various anti-incretins, including dopamine, ghrelin, enterostatin, and oxyntomodulin, and increases the output of incretins as well as conjugated bile acids, and favorably alters the GM[28,29]. The DJBL is a 60 cm long flexible fluoropolymer-coated tube that is endoscopically placed in the duodenum for 12 months, anchored to the duodenal bulb, to bypass the absorption of food from the proximal part of the duodenum[30]. The DJBS is similar to the above but with some minor changes in the material, delivery/anchoring systems, and the duration of treatment (3 months). In contrast, GJBS is a 120 cm long fluoropolymer-coated tube that is anchored to the gastroesophageal junction for 12 months. SatiSphere is made of nitinol wire with two pigtail ends, with several spheres of polyethylene terephthalate placed using an endoscopy in the duodenum for 3 months[31]. An observational study showed that DJBS is associated with a significant reduction in hepatic stiffness by 5.1 kPa in patients with pre-existing liver fibrosis[32]. The endoluminal bypass liners need to be removed in 3-12 months, as earlier trials showed liver abscess from the liner devices[29]. Moreover, they are at risk of causing gastrointestinal bleeding and pancreatitis.

IMAS

The IMAS involves the creation of a permanent lateral jejuno-ileostomy using two octagonal magnets, one placed in the proximal jejunum using enteroscopy and the other placed in the terminal ileum using a colonoscopy, resulting in tissue necrosis without surgical incision, with the magnets expelled in stool within two weeks[16]. IMAS causes diversion of nutrients and bile acid, causing malabsorption and weight loss. Further progress in research in this area is currently halted due to the practical difficulties involved in having a simultaneous enteroscopy and colonoscopy in placing the magnets.

MS using magnetic compression assistance device involves creation of a permanent lateral duodeno-ileostomy using two linear MS magnets, both delivered endoscopically, proximal one to the duodenum and the distal one to the ileum, under laparoscopic guidance[33]. The procedure is simpler and better tolerated than single anastomosis duodeno-ileal bypass with sleeve gastrectomy. Notably, the magnets are expelled naturally in the stool without any complications.

COMPARISON OF VARIOUS EBMTS

A systematic review and meta-analysis of 18 studies, 14 involving IGBs, two involving ESGs, and two involving ATs, observed a 14.5% TBWL at 6 months with a reduction in hepatic fibrosis (0.7)[34]. This is associated with significant reductions in ALT (-9.0 U/L), hepatic steatosis (standardized mean difference, -1.0), NAS (-2.5), waist circumference (-4.5 inches), HOMA-IR (-1.8), and HbA1c (-0.2)[34]. A systematic review and meta-analysis of 33 studies comprising of 19 studies involving IGBs, eight studies involving endoluminal bypass liners, three studies involving ESGs, two studies involving ATs, and one study involving POSE, observed statistically significant reduction in NAFLD fibrosis score (mean difference, -0.58), and statically non-significant reduction in hepatic stiffness (transient elastography, -6.39 kPa) and fibrosis-4 (-0.028)[35]. The meta-analysis also showed a significant reduction in hepatic steatosis (-53.76 dB/m) and NAS (-3), a reduction in HOMA-IR, ALT (-12.44 U/L), aspartate aminotransferase (-7.88 U/L), gamma-glutamyl transferase (-12.07 U/L), body weight, cholesterol, and triglyceride levels.

Another systematic review and meta-analysis of 22 studies compared the TBWL and EBWL observed following various EBMTs, including AT, IGB, POSE, and DJBL[36]. The TBWL achieved was 10.4% for AT, 5.3% for fluid-filled IGB, 4.9% for POSE, and 4.5% for DJBL. The EBWL achieved was 27.3% for AT, 22.4% for fluid-filled IGB, 15.3% for POSE, and 13% for DJBL. Six months after the removal of fluid-filled IGBs, the extent of TBWL and EBWL decreases, indicating the need for sustainable lifestyle changes. The TBWL and EBWL achieved by gas-filled IGB and botulinum toxin were not statistically significant[36].

EXPERIMENTAL STUDY ON DMA USING IRE

The experimental study by Yu et al[6] in the recent issue of the World Journal of Gastroenterology on DMA using IRE, when experimented on rats, has shown fewer complications, including bleeding, perforation, or stenosis, compared to various metabolic surgeries. The DMA using IRE not only improved the lipid parameters and ALT within 2 weeks of the procedure, but also reduced hepatic fat deposition, even though the weight and food intake did not change significantly.

GUT-LIVER AXIS MECHANISM IN MAFLD AND THE ROLE OF DMA

The gut-liver axis encompasses bidirectional communication between the intestine and liver via the portal circulation, involving nutrient signaling, microbial metabolites, enteroendocrine hormones, and inflammatory mediators like lipopolysaccharide (LPS). In MAFLD, increased intestinal permeability and dysbiosis lead to elevated LPS translocation into the liver, triggering low-grade inflammation, hepatic insulin resistance, and lipid accumulation. Yu et al[6] demonstrated that DMA using IRE reduced serum LPS levels and increased duodenal expression of tight junction proteins such as claudin-1 and zonula occludens-1, suggesting restoration of mucosal barrier integrity, indicating that DMA can achieve a reduction in intestinal permeability and metabolic endotoxemia.

Further, Yu et al[6] observed downregulation of serum GLP-1, glucose-dependent insulinotropic polypeptide, and cholecystokinin despite increased local expression in duodenal tissue, indicating a possible rebalancing of enteroendocrine feedback loops. These hormones modulate pancreatic secretion, hepatic glucose metabolism, and appetite regulation, and their dysregulation is commonly seen in MAFLD and T2DM. DMA seems to restore this hormonal axis by altering the density and activity of enteroendocrine cells, potentially resetting the gut-pancreas-liver signaling to a healthier state.

Histological analysis revealed reduced hepatocyte ballooning and macrovesicular steatosis in the treated group. Importantly, the IRE method preserved submucosal architecture, minimizing the risk of fibrosis or strictures, a limitation often associated with prior ablation techniques such as DMR and ReCET. Compared to thermal-based DMR, IRE offered better precision while avoiding the deeper muscularis damage reported with some ReCET protocols. These findings suggest that IRE may deliver safer and more physiologically targeted duodenal reconditioning, laying the foundation for its clinical translation. Notably, these changes occurred without significant alterations in body weight or food intake, underscoring the weight-independent benefits of duodenal reconditioning. Compared to earlier ablation techniques such as thermal and hydrothermal methods, IRE produced fewer complications and preserved tissue architecture, enhancing its translational potential.

TRANSLATIONAL GAP

Despite these promising findings, several key translational gaps must be addressed before DMA can be applied clinically. The rat duodenum differs from that of humans in wall thickness, mucosal architecture, and immune reactivity, differences that may influence tissue response, ablation depth, and healing outcomes. In Yu et al’s study, the procedure was performed using laparotomy to ensure precise catheter placement[6]. The highly invasive nature of the procedure is a limitation, as the standard ablation catheter used for the ReCET was not suitable for small animals due to the narrow lumen and thin walls. In contrast, future human applications aim to utilize minimally invasive endoscopic catheters to deliver controlled mucosal ablation, improving feasibility and patient comfort. However, long-term safety data in humans remain limited. To address this, phase I clinical trials are planned using an endoscopic catheter-based DMA approach, with a proposed follow-up period of 6-12 months to evaluate both metabolic efficacy and adverse events. These trials will be crucial to determine the translational viability and clinical integration of DMA into the MAFLD treatment paradigm. The study’s other limitations included a small sample size (20-rat randomized clinical trial), a short observation period of two weeks, and the comparison of the study outcomes to the historical techniques. Small sample size limits the generalizability and increases the risk of selection bias. Short observation period limits the evaluation of effects on weight, food intake, and hepatic fat deposition. Future studies with larger sample sizes, longer observation periods, and non-invasive techniques in ablation catheter placement are needed[6].

Future directions

Combination of EBMT with an injectable GLP-1 receptor agonist is a promising strategy in the management of obesity, T2DM, and MAFLD. Empirical evidence supports this synergy: A 2024 study by Jirapinyo et al[37] demonstrated that combining ESG with semaglutide in a cohort of patients with MAFLD and compensated advanced liver disease, combination therapy led to significantly higher TBWL (18.2% vs 9.6%, P = 0.004), greater ALT reduction (55% vs 29%, P = 0.008), improved NAFLD fibrosis score (181% vs 30%, P = 0.04), and a larger decrease in liver stiffness (54% vs 14%, P = 0.05) compared to endoscopic gastric remodeling alone. These findings underline the potential of combined endoscopic and pharmacological approaches in the treatment of metabolic liver disease.

This highlights the potential of integrated therapies to maximize metabolic benefits and reduce disease progression in MAFLD. Interventions should be initiated within 6 months of each other, as prolonged GLP-1 receptor agonist therapy before initiation of EBMT results in suboptimal treatment response, indicating the need for early referral[38]. Similarly, a combination of small intestine-directed and stomach-directed EBMTs is another promising approach in managing people with obesity and MAFLD. Repeated placement of one of the small intestine-directed EBMTs or switching between various EBMTs could provide longer-term weight loss benefits. A mucin-complexing polymer, GLY-200, administered orally, known as polymeric duodenal exclusion therapy, could bind to the duodenal mucosa to enhance the duodenal mucosal barrier function[39]. This can be another effective and non-invasive malabsorptive therapy in addressing obesity and MAFLD. Figure 1 illustrates various EBMTs currently available. These endoscopic therapies are designed to mimic the metabolic benefits of bariatric surgery by altering nutrient sensing, gut hormone secretion, and the gut-liver axis, without permanent anatomical changes. Table 1 summarizes the salient features of different EBMTs currently available[25,40-49].

Figure 1 Various endoscopic bariatric and metabolic therapies currently available. DJBL: Duodenojejunal bypass liner; DJBS: Duodenojejunal bypass sleeve; IRE: Irreversible electroporation; ReCET: Recellularization using electroporation therapy.

Table 1 Comparison between various available endoscopic bariatric and metabolic therapies.

Therapy	Mechanism	Benefit	Risk	TBWL	Metabolic effects	Quantitative risk data	Study period	Ref.
Intragastric balloon	Space-occupying balloon induces satiety	Minimally invasive, well-studied	Gastrointestinal symptoms, risk of deflation or migration	8%-15%	Improved insulin sensitivity, reduced liver fat	Overall complication rate: 5%-22%, balloon rupture: 0.7%, severe complication: 0.17%	12 months	[40,41]
Transpyloric shuttle	Delays gastric emptying via the anchoring bulb-pair device	Targets appetite and satiety, reversible	Gastric ulceration, device migration, and limited long-term data	9.5%-14.5%	Improved glycemic control and improved lipid profile	Device-related adverse events: 2.8%	12 months	[25]
Endoscopic sleeve gastroplasty	Endoscopic suturing to reduce gastric volume	Durable, anatomy-preserving, repeatable	Requires expertise, rare bleeding/perforation risk	16%-20%	Improved HbA1c, transaminitis, insulin resistance	Serious adverse events: 2.2%, perforation: 0.1%-0.4%	3 months	[42,43]
Aspiration therapy	Removes part of ingested food via PEG tube	Effective long-term behavioral modification	Requires an external device, social stigma, and risk of electrolyte imbalance	18%-20%	Improved glycemic control and improved lipid profile	No severe adverse events; buried bumper syndrome: 3.3%	12 months; 4 years	[44,45]
Endoluminal bypass liner	Endoscopic liner bypasses the duodenum and proximal jejunum	Mimics gastric bypass, no surgery, improves metabolic markers	Gastrointestinal symptoms, risk of hepatic abscess, and early removal	10%-15%	Improved HbA1c, hepatic steatosis, and insulin resistance	Perforation: < 1%; overall serious adverse events: 3%-5%	26 weeks; 3 months	[46,47]
Duodenal mucosal ablation	Thermal or electrical ablation of the duodenal mucosa to reset signaling	Restores metabolic function, with no permanent implant	Experimental, safety/durability still under evaluation	7%-10%	Reduced fasting glucose, improved insulin sensitivity, and liver steatosis	Adverse event: At least one adverse event in 52% (81% mild)	12 months	[48]
Incisionless magnetic anastomosis system	Creates jejuno-ileal bypass using self-assembling magnets	Incisionless, mimics surgical bypass, promotes malabsorption	Still under evaluation, may cause malabsorption and diarrhoea	14%-18%	Improved glycemic control and potential GLP-1 elevation	Perforation: 10%	12 months	[49]

TBWL: Total body weight loss; PEG: Percutaneous endoscopic gastrostomy; HbA1c: Glycated hemoglobin; GLP-1: Glucagon-like peptide-1.

CONCLUSION

A rapid rise in the MAFLD prevalence parallels the global obesity pandemic. Obesity serves as the major contributor to MAFLD, triggering insulin resistance, hepatic steatosis and systemic inflammation. Standard interventions, including lifestyle management and pharmacotherapy, rarely achieve sustained and metabolically optimal weight loss outcomes in patients with moderate to severe obesity. MBS is the most effective option for long-term weight reduction and resolution of obesity associated co-morbidities. However, it is associated with surgical risks, post-operative complications, and limited accessibility.

EBMTs are upcoming, minimally invasive alternatives that offer a spectrum of options tailored to different patient profiles. Among EBMTs, DMA has gained attention as a promising approach targeting the duodenum, a critical regulator of nutrient sensing and entero-endocrine hormone secretion. DMA and other EBMTs such as IGBs, ESG, and AT have demonstrated varying degrees of efficacy in promoting weight loss, improving insulin sensitivity and reducing hepatic inflammation and steatosis. DMA, especially using emerging techniques like IRE, holds promise in MAFLD due to its dual benefit of metabolic improvement and a favorable safety profile in early animal studies. Endoscopic interventions like DMA represent a paradigm shift in the management of MAFLD, offering scalable and less invasive alternatives to conventional surgery. Further clinical trials are needed to confirm their long-term efficacy and safety before widespread adoption.

ACKNOWLEDGEMENTS

We are thankful to Annlyn Vinu Thomas for providing us the audio clip for the core tip of this article.