Duodenal mucosal ablation with irreversible electroporation in non-alcoholic fatty liver disease: Roadmap of the future treatment

Abstract

One of the main causes of liver fibrosis and cancer, non-alcoholic fatty liver disease (NAFLD) is becoming more common every year. The novel work by Yu et al, which evaluates the viability and efficacy of duodenal mucosal ablation (DMA) with irreversible electroporation (IRE) in NAFLD rat models, is examined in this article. When DMA was used with IRE to small rodents, the study found that the duodenum healed successfully two weeks later and had thicker myenterons, narrower and shallower crypts, and slimmer villi than in the sham-control group. When DMA with IRE were used, liver lipid deposition and serum lipid index values decreased; these improvements occurred regardless of food consumption or weight loss. Furthermore, the DMA group's enteroendocrine parameters varied among the various duodenal areas, including claudin and zonula ocludens-1 Levels in the duodenal mucosa. As a result, DMA with IRE in rodents demonstrated no duodenal bleeding or perforation following ablation, providing a promising path for more advanced NAFLD treatment approaches. In order to improve approach outcomes, this paper addresses the implications of extending the study length and animal size, analyzing inflammatory marker studies, and measuring intestinal lipid indexes and endocrine parameters on a weekly basis.

Key Words: Non-alcoholic fatty liver disease; Duodenal mucosal ablation; Irreversible electroporation; Lipid deposition; Endocrine function; Inflammatory markers

Core Tip: The novel work by Yu et al on the feasibility and efficacy of duodenal mucosal ablation (DMA) with irreversible electroporation (IRE) in non-alcoholic fatty liver disease (NAFLD) rodents is thoroughly examined in this article. The duodenum repaired effectively two weeks after DMA with IRE, according to the study in a sophisticated manner. In NAFLD small rats, the detection of liver lipid deposition, serum lipid parameters, and enteroendocrine parameters such claudin and zonula ocludens-1 levels offer new opportunities for side-effects assessment and advanced therapy approaches.

TO THE EDITOR

Every year, the prevalence of non-alcoholic fatty liver disease (NAFLD) rises, and in 2023, it affected around 30% of adults worldwide[1]. Additionally, it is a major contributor to liver fibrosis, which in turn causes primary liver cancer[2]. In NAFLD rat models, the new study by Yu et al[3] offers beneficial and innovative therapy by combining the duodenal mucosal ablation (DMA) and irreversible electroporation (IRE) method.

There are twelve male Sprague Dawley rats in the study. A high-fat (transfat) diet was used for eight weeks to induce the NAFLD rat model. The DMA (n = 6) and non-DMA (sham-control, n = 6) groups were the two groups obtained from the NAFLD group. The DMA with IRE, which included a square-wave pulse generator and an ablation catheter, was used by the authors to implement a sophisticated technique. To assess serum liver function and cholesterol, the researchers used biomedical and histological analyses. Additionally, they measured cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP). The duodenal expression levels of GLP-1, GIP, and CCK were also assessed. This scientific technique made it possible to determine the feasibility and efficacy of DMA with IRE in the NAFLD animal model.

The IRE (a non-thermal ablation technique) induces cell apoptosis, necrosis, and immunogenic cell death[4] and it has been used to treat tumors[5], arrhythmia[6], and chronic obstructive pulmonary disease[7]. The article contains also a significant finding that the duodenal mucosa appeared to have healed macroscopically and histologically, without the occurrence of ulceration, inflammation, fibrosis, or stenosis.

Additionally, two weeks following DMA with IRE, lipid accumulation in the liver decreased and blood lipid parameters significantly improved, which is in line with the findings of a prior study[8] that used hydrothermal therapy. Additionally, the DMA group's serum GLP-1, GIP, and CCK levels were significantly lower than those of the control group, according to Yu et al’s study[3].

As demonstrated by a decrease in serum lipopolysaccharide levels and an increase in zonula occludens-1 and claudin expression in the duodenum, along with decreased liver lipid deposition and improved serum lipid parameters, the authors demonstrated that the duodenal permeability improved following DMA with IRE and these results are consistent with earlier clinical researches[9,10] indicate that DMA with IRE may treat lipid metabolism issues by many processes.

The study of Yu et al[3] has three limitations: (1) Following an invasive operation called a laparotomy, the ablation catheter utilized in this study was inserted into the duodenum; (2) The evaluation of the length of the beneficial effect on liver lipid deposition may have been constrained by the 2-week observation period following DMA; and (3) This study's comparatively small sample size restricts how broadly the results may be applied and raises the possibility of selection bias.

Future studies should measure intestinal lipid indexes and endocrine parameters every week to easily estimate the healing and progress of this technique, as well as inflammatory markers of the liver, duodenum, and ileum tissues, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-10. In order to validate the healing progress of DMA with IRE across many rodent groups, such studies should also be expanded to encompass a longer study period (4–6 weeks) and animal size (8–10 rats/group) by evaluating the serum and organ tissue parameters.

The clinical application of DMA with IRE in NAFLD requires a complicated and time-consuming submucosal saline injection is necessary before to each ablation in order to fully utilize this technique. Additionally, it is important to pay attention to postprocedural gastrointestinal symptoms brought on by the inflammatory response following epithelium necrosis and possible heat injury to deeper tissues[11]. In Yu et al's work[3], the ablation electrode was guided via the pylorus and reached the duodenum during laparotomy, whereas in clinical application of DMA with IRE, the electrode is inserted into the duodenal lumen under endoscopy and this happened due to two reasons: (1) The recently instrument generation 2 catheter ReCET system is the tool utilized for clinical DMA with IRE therapy, and it is not appropriate for rodents; and (2) Compared to clinical application, colonoscopy in rats is comparatively dangerous, costly, and intrusive.

Many methods are utilized to treat metabolic disorders, including metabolic surgery[12], retrievable duodenal-jejunal bypass liners[13], and DMA with IRE. Without the requirement for additional treatments, the DMA with IRE significantly improved the hepatic fat infiltration and metabolic parameters in NAFLD rats fed a high-fat diet. A prior study on using the duodenal-jejunal bypass[14] to alleviate NAFLD also supported this finding. Using the DMA with IRE method could lead modified therapeutic procedures and aid in the development of more accurate and advanced technical methods. The results of the study have important implications for modified and advanced NAFLD Therapy. According to the study's findings, NAFLD is characterized by elevated intestinal permeability and persistent low-grade endotoxemia[15], while DMA with IRE may be a suitable therapy option for NAFLD by improving intestinal permeability[16]. By decreasing hepatic lipid accumulation and improving serum lipid markers in NAFLD, this DMA with IRE technique could effectively treat the disease without any side-effects.

CONCLUSION

The intestinal endocrine system, including serum GLP-1, GIP, and CCK levels were decreased, hepatic lipid deposition was declined, and the duodenal wall structure was improved by DMA with IRE. In order to easily estimate the post-operative progress and healing, future research should focus on a larger study period (4–6 weeks) and animal size (8–10 rats/group), as well as inflammatory markers of the liver, duodenum, and ileum tissues, such as TNF-α, IL-1β, IL-6, and IL-10. The potential of clinical application of DMA with IRE in NAFLD is easier than that in experimental animals due to the recently instrument used is not suitable for rats and colonoscopy is safe, cheap, and sensitive in humans than rats. Additionally, intestinal lipid indexes and endocrine parameters should be assessed weekly. Future improvements in patient care through more accurate and advanced therapeutic methods in NAFLD therapy may be possible due to the safety and efficacy of DMA with IRE method