Duodenal mucosal ablation by irreversible electroporation: Modulating the gut-liver axis in metabolic steatotic liver disease

Abstract

Targeting the gut-liver axis has emerged as a promising strategy in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition that currently represents the most common cause of chronic liver disease worldwide. Within this axis, the duodenum serves not only as a site of nutrient absorption but also as a metabolic sensor capable of influencing systemic and hepatic homeostasis. We have read with great interest the recent study by Yu et al, investigating the effects of duodenal mucosal ablation (DMA) by irreversible electroporation in a rat model of MASLD. The authors reported remarkable reductions in hepatic lipid content, improvements in serum lipid profiles, and both structural and functional changes in the intestinal mucosa, including alterations in enteroendocrine signaling. These results corroborate the pivotal role of the gut-liver axis in the pathogenesis of MASLD and highlight the potential of minimally invasive approaches targeting the proximal intestine. In this letter, we discuss the broader implications of these findings, emphasizing the translational relevance of intestinal modulation strategies in the comprehensive treatment of MASLD.

Key Words: Gut-liver axis; Metabolic dysfunction-associated steatotic liver disease; Duodenal mucosa ablation; Intestinal permeability; Lipids

Core Tip: Duodenal mucosal ablation (DMA) via irreversible electroporation has emerged as a novel strategy to modulate the gut–liver axis in metabolic dysfunction-associated steatotic liver disease (MASLD). In this letter, we analyzed recent preclinical evidence from Yu et al, who reported that DMA leads to reduced hepatic steatosis, improved lipid profiles, and enhanced intestinal barrier integrity. We contextualize these findings within the physiology of the duodenum and explore their translational potential as a minimally invasive therapeutic approach in MASLD.

TO THE EDITOR

The gut-liver axis has emerged as a prominent therapeutic target in the management of metabolic dysfunction-associated steatotic liver disease (MASLD), which is currently recognized as the most prevalent chronic liver disease worldwide[1,2]. The shift in terminology from nonalcoholic fatty liver disease to MASLD emphasizes the role of metabolic dysfunction as a central driver of liver steatosis while recognizing the contributions of other coexisting factors that may influence the development and progression of the disease[3]. One of these factors is the gut-liver axis, the bidirectional communication that is established between the liver and the gut along with its microbiota through hormonal, neural, immune and microbial pathways. This interaction has key functions related to the control of metabolism and the immune system[1]. MASLD has been associated with alterations in this axis, which favor the development of the disease and its progression to more advanced stages. The consumption of diets high in fat, added sugars and ultra-processed foods can alter the gut-liver axis by promoting dysbiosis, increasing intestinal permeability and increasing the translocation of bacterial endotoxins and metabolites into the portal circulation. This translocation, particularly of lipopolysaccharides, contributes to hepatic inflammation, insulin resistance and increased lipid accumulation in hepatocytes, which are key elements in the pathogenesis of MASLD[1].

Among the segments of the gastrointestinal tract, the duodenum plays a central role in coordinating digestion and metabolic signaling (Figure 1). The initial portion of the small intestine serves as the site where chyme from the stomach mixes with bile and pancreatic enzymes, initiating the breakdown and absorption of macronutrients. In addition to its digestive function, the duodenum acts as a nutrient sensor and endocrine center[4,5]. Owing to this anatomical and functional complexity, the duodenum has emerged as a promising target for therapeutic interventions aimed at modulating systemic metabolism. In this context, the study by Yu et al[6] recently published in the World Journal of Gastroenterology explored the effects of duodenal mucosal ablation by irreversible electroporation (IRE) in a rat model of MASLD. These findings support the concept that structural and functional changes in the duodenal mucosa can lead to favorable metabolic outcomes, including reductions in hepatic lipid accumulation and improvements in serum lipid profiles. These results strengthen the rationale for exploring gut-targeted interventions as part of an integrated approach to MASLD management. This letter aims to contextualize these findings within the broader picture of MASLD pathophysiology, highlight the potential role of the duodenum in systemic metabolic regulation and discuss future research directions and clinical translation of gut-targeted strategies.

Figure 1 Duodenal lipid absorption and gut-derived signals involved in metabolic dysfunction-associated steatotic liver disease pathophysiology. Lipid absorption in the duodenum begins with emulsification of dietary fats by bile salts, followed by enzymatic hydrolysis into monoglycerides and free fatty acids. These products are incorporated into micelles, absorbed by enterocytes, re-esterified and packaged into chylomicrons for transport through the lymphatic system. In parallel, luminal nutrients stimulate enteroendocrine cells to secrete hormones such as cholecystokinin, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, which regulate insulin secretion, bile release and gastric motility. In the context of metabolic dysfunction-associated steatotic liver disease (MASLD), altered intestinal permeability and microbial dysbiosis may lead to increased translocation of microbial metabolites and toxins, such as lipopolysaccharides, into the portal circulation, contributing to hepatic inflammation and metabolic dysfunction. The dashed lines indicate pathological processes specifically associated with MASLD and do not reflect normal physiology. CCK: Cholecystokinin; GIP: Glucose-dependent insulinotropic polypeptide; GLP-1: Glucagon-like peptide-1; GLUT-2: Glucose transporter-5; LDL-R: Low-density lipoprotein receptor; LPS: Lipopolysaccharides; SGLT-1: Sodium-glucose cotransporter 1; TLR: Toll-like receptor; VLDL: Very low-density lipoproteins.

THE DUODENUM: A METABOLIC GATEKEEPER

As a key interface between the gastrointestinal tract and systemic metabolism, the duodenum plays a crucial role in initiating nutrient absorption. Its structural and functional properties are perfectly adapted to ensure efficient absorption of carbohydrates, proteins, fats and micronutrients. For example, lipid absorption begins in the duodenum with emulsification of dietary fats by bile salts, followed by enzymatic hydrolysis into monoglycerides and fatty acids by pancreatic lipase, which are subsequently incorporated into micelles. These micelles facilitate the transport of lipids through the intestinal epithelium for absorption[4]. In addition to its absorptive functions, the duodenum acts as a sophisticated metabolic sensor and endocrine organ. Enteroendocrine cells spread throughout the mucosa sense luminal nutrients and secrete a wide range of hormones, such as cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)[5]. These hormones coordinate digestive processes by modulating pancreatic enzyme secretion, gallbladder contraction and gastric emptying while exerting systemic effects such as stimulating insulin secretion, inhibiting glucagon release, delaying gastric emptying and promoting satiety[5]. Through these mechanisms, the duodenum not only regulates local digestive processes but also significantly influences the energy balance and metabolic homeostasis of the entire organism.

As part of the gut-liver axis, the duodenum plays a critical role in modulating the quality and quantity of nutrients, bile acids and microbial metabolites that reach the liver via the portal circulation. There is increasing evidence that impaired intestinal barrier function plays a key role in the pathogenesis of MASLD. Specifically, increased duodenal permeability has been observed in patients with MASLD, which is correlated with the severity of liver steatosis. This phenomenon is driven by altered tight junction proteins, such as zonula occludens-1 (ZO-1), which compromises the mucosal barrier[7,8]. This compromised barrier function facilitates the translocation of microbial products, such as lipopolysaccharides, into the portal circulation, where they can activate the hepatic immune response and promote inflammation. Recent studies have explored how the duodenal mucosa-associated microbiota contributes to this process. In patients with chronic liver disease, Raj et al[9] reported that duodenal microbial dysbiosis is characterized by reduced alpha diversity and an overrepresentation of Streptococcus species, along with a lower abundance of potentially beneficial genera such as Veillonella, Porphyromonas and Actinomyces. Importantly, microbial diversity was inversely correlated with both intestinal permeability and serum alanine aminotransferase (ALT) levels, suggesting a direct relationship between dysbiosis, mucosal dysfunction and liver inflammation[9]. Furthermore, Ren et al[10] recently described distinctive microbial alterations in the duodenal mucosa of patients with MASLD, identifying an increased relative abundance of genera such as Serratia and Aggregatibacter and a predicted enrichment in metabolic pathways related to amino acid and carboxylate degradation. Although overall diversity was not significantly different from that of the controls, these compositional and functional changes may reflect early metabolic alterations at the intestinal interface that influence nutrient absorption, barrier function, and subsequent liver injury[10]. A recent systematic review and meta-analysis by Gudan et al[11] reported that the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with MASLD, including simple steatosis, steatohepatitis, fibrosis, and cirrhosis, reached approximately 35%, with even higher rates observed in patients with steatohepatitis (up to 41%). The presence of SIBO has been associated with bile acid deconjugation, impaired fat absorption, vitamin deficiencies, overproduction of ammonia, and increased translocation of bacterial antigens. These mechanisms can further exacerbate hepatic steatosis, inflammation and fibrosis, reinforcing the importance of the duodenum and its microbial environment in the gut-liver axis[1].

In addition to alterations in microbial composition and permeability, functional changes in nutrient transport at the duodenal level that may contribute to liver injury have also been observed. Fiorentino et al[12] demonstrated that individuals with MASLD have increased expression of sodium-glucose cotransporter 1 (SGLT-1) in duodenal mucosal biopsies, independent of body mass index and glucose tolerance status. This increase was associated with increased postload glucose concentrations, a marker of early postprandial hyperglycemia implicated in the pathogenesis of metabolic disease. Furthermore, among individuals with MASLD, elevated SGLT-1 Levels are correlated with an increased likelihood of advanced fibrosis, as estimated by noninvasive scoring systems[12]. Similarly, De Vito et al[13] reported that the expression of the fructose-specific transporter glucose transporter-5 (GLUT-5) is significantly elevated in the duodenum of patients with MASLD, independent of adiposity and glycemic status. Higher duodenal GLUT-5 Levels are positively associated with insulin resistance, serum uric acid concentrations and increased MASLD fibrosis scores, suggesting a role for intestinal fructose absorption in promoting hepatic lipogenesis, oxidative stress and fibrosis progression.

Collectively, the convergence of microbial dysbiosis, impaired barrier function, and altered nutrient transport at the duodenum illustrates the multifaceted role of this intestinal segment in the pathogenesis of MASLD. This growing body of evidence supports the rationale for targeting the duodenum in novel therapeutic strategies aimed at restoring the gut-liver balance and interrupting the progression of MASLD[14].

PRECLINICAL INSIGHTS INTO DUODENAL MODULATION IN MASLD

Yu et al[6] explored the feasibility and metabolic effects of duodenal mucosal ablation (DMA) by IRE in a rat model of MASLD. To induce hepatic steatosis, male Sprague-Dawley rats were fed a high-fat diet for eight weeks. Once hepatic steatosis was confirmed, the animals were randomly assigned to either a DMA procedure using IRE or a simulated procedure. The IRE protocol was applied to a 5 cm segment of the duodenum via a custom-made catheter delivering pulsed electric fields at 250 V/cm. Two weeks after surgery, the duodenum showed complete mucosal healing with no signs of perforation, hemorrhage or stenosis. Histologically, the DMA group presented slimmer villi (villus length: 845 ± 74 μm vs 561 ± 104 μm; villus thickness: 133 ± 32 μm vs 200 ± 110 μm; P < 0.05), thicker mucosal and muscular layers and narrower and shallower crypts (crypt depth: 220 ± 52 μm vs 236 ± 51 μm; crypt width: 38 ± 6 μm vs 49 ± 5 μm; P < 0.05), indicating satisfactory mucosal remodeling.

Histologically, the simulated group showed marked hepatic lipid deposition, characterized by lipid droplets of various sizes, altered hepatocyte architecture and general disorganization of liver tissue. In contrast, the DMA group exhibited significant histological improvement, with a more preserved hepatocyte structure and less lipid accumulation, which were accompanied by improvements in the serum lipid profile. Total cholesterol and low-density lipoprotein-cholesterol were significantly lower in the DMA group than in the simulated group (2.08 mmol/L vs 4.22 mmol/L and 1.05 mmol/L vs 4.07 mmol/L, P < 0.01, respectively), whereas high-density lipoprotein cholesterol, triglycerides and free fatty acids increased (3.26 2.06 mmol/L vs 2.06 mmol/L, 1.76 mmol/L vs 1.22 mmol/L, 1.03 mmol/L vs 0.32 mmol/L, P < 0.05, respectively). These metabolic improvements occurred independently of changes in weight or food intake. In addition to hepatic parameters, DMA also influences intestinal hormonal dynamics and intestinal physiology. Although the circulating levels of GLP-1, GIP and CCK were lower in the DMA group than in the simulated group (810 pmol/L vs 11.39 pmol/L, 366.70 pg/mL vs 409.10 pg/mL, and 258.01 pg/mL vs 271.70 pg/mL, P < 0.05, respectively), immunofluorescence analysis revealed that their expression levels and fluorescence intensities in the duodenal mucosa were significantly increased, suggesting a local increase in enteroendocrine signaling despite lower systemic concentrations. In parallel, intestinal barrier function also improved after DMA. The serum levels of lipopolysaccharide were significantly lower in the DMA group than in the simulated group (646 vs 605.40, P < 0.01). This increase was accompanied by an increase in the tight junction proteins ZO-1 and claudin in the duodenal mucosa, indicating increased epithelial integrity and decreased intestinal permeability.

These results support the concept that the duodenum is a metabolically active and hormonally dynamic organ with the capacity to influence extraintestinal targets such as the liver. By modifying the duodenal architecture and function, the intervention appeared to influence several key elements involved in the pathogenesis of MASLD, such as lipid manipulation, hormonal signaling, and gut-liver immune communication. While further studies are needed to assess long-term outcomes and translational applicability, these findings provide a solid experimental basis for considering duodenal modulation as a potential strategy to address the complex metabolic alterations associated with MASLD.

PHYSIOLOGICAL INSIGHTS AND TRANSLATIONAL PERSPECTIVES

Previous studies have proposed the proximal small intestine as a promising target for improving metabolic regulation, particularly in the context of type 2 diabetes and obesity, through surgical interventions such as duodenal bypass or exclusion, which have demonstrated benefits in glycemic control, insulin sensitivity and lipid metabolism[15-17]. These findings support the concept that modifying nutrient exposure in the duodenum can trigger a cascade of hormonal, neural, and metabolic responses that extend beyond the gastrointestinal tract. In this context, the study by Yu et al[6] offers a novel and minimally invasive approach to modulate duodenal function without the need for anatomic bypass or resection. By applying IRE to the duodenal mucosa, the authors were able to reproduce several of the metabolic benefits previously attributed to bariatric procedures, such as reduced hepatic lipid accumulation, improved serum lipid profiles and a reduced inflammatory response[18].

Although these findings are promising, several key steps remain to translate this strategy to clinical application. Encouragingly, initial clinical experience with endoscopic approaches such as duodenal mucosal resurfacing (DMR) has demonstrated favorable short-term results. A systematic review and meta-analysis by de Oliveira et al[19] that included 127 patients from four studies reported significant improvements in glycemic and hepatic parameters after DMR. Three and six months after the procedure, glycated hemoglobin levels decreased by 1.72% and 0.94%, respectively, and fasting plasma glucose was reduced by 15.8 mg/dL. These benefits occurred with minimal weight loss, highlighting weight-independent metabolic effects. In addition, ALT levels decreased by more than 10 U/L, and hepatic steatosis measured by magnetic resonance imaging-derived proton-density-fat fractions was reduced by 6.6%, a magnitude comparable to that observed with pharmacological interventions over similar periods[19]. These results are consistent with previous prospective findings by van Baar et al[20] and Papaefthymiou et al[21] and reinforce the safety and feasibility of duodenal endoscopic techniques. Nevertheless, to move toward broader clinical application, future trials should address long-term durability, histologic outcomes, and mechanistic pathways, particularly in populations with varying degrees of liver fibrosis and metabolic risk profiles[22]. In addition, standardization of procedural parameters, such as ablation depth, treated segment length and energy delivery parameters, is critical to ensure reproducibility and safety across centers. The variability of technical approaches among studies, including those using radiofrequency, thermal or photochemical ablation, further underscores the need for comparative trials to determine the optimal modality[22]. Most clinical trials to date have focused on individuals with type 2 diabetes, and hepatic metabolic disease is often considered a secondary outcome. Although promising reductions in hepatic steatosis and liver enzymes have been reported, these outcomes are not always the primary endpoints, and histologic data remain limited. Therefore, specific studies are needed in patients with MASLD, especially those without overt diabetes, to define the direct hepatic benefits of duodenal interventions and their potential role in arresting or reversing disease progression.

In parallel, a better understanding of the underlying mechanisms is essential to guide the optimization and personalization of these interventions. While improvements in lipid metabolism, intestinal hormone signaling, and intestinal permeability have been documented, it remains unclear which of these pathways plays a dominant role, whether they act synergistically, and how they influence baseline metabolic status or disease severity. For example, the paradoxical finding of lower circulating incretin levels despite the increased number of hormone-producing cells observed by Yu et al[6] suggests that local mucosal remodeling does not always translate into systemic hormonal changes, possibly due to altered nutrient contact or feedback mechanisms yet to be defined.

To successfully translate this therapy into clinical practice, future research should prioritize well-designed prospective trials focused specifically on MASLD populations, with liver-specific outcomes, such as histologic changes, fibrosis progression, and image-based quantification of steatosis, as primary end points. These studies should incorporate long-term follow-up to assess the durability of hepatic and metabolic improvements. Mechanistic substudies employing transcriptomics, metabolomics and microbiome analyses will be essential to unravel the pathways driving therapeutic response and identify reliable biomarkers of efficacy. In parallel, comparative studies of different ablation modalities, such as IRE and thermal, radiofrequency or photochemical techniques, are needed to determine the most effective and safe approach. Given the heterogeneity of MASLD, stratifying patients by metabolic phenotype could allow a more personalized application of DMA therapies. Finally, evaluation of patient-reported outcomes, tolerability of the procedure and health system feasibility will be critical to support real-world implementation and long-term integration into MASLD treatment algorithms.

CONCLUSION

The findings of Yu et al[6] highlights the duodenum as a promising target in the treatment of MASLD. Ablation of the duodenal mucosa improved liver fat, metabolic markers, and intestinal barrier function in a preclinical model, supporting its translational potential. Going forward, focused clinical trials in MASLD populations will be essential to define its long-term efficacy, safety and place in therapy.