MicroRNAs and Bariatric/Metabolic Surgery: Biomarkers, Mediators of Metabolic Remission, or Both?

Abstract

Purpose of Review: Obesity is a growing global health challenge, with severe obesity projected to affect up to 25% of individuals with obesity by 2030. Bariatric surgery remains the most effective treatment, yet the molecular mechanisms underlying its metabolic benefits are not fully understood. This review summarizes current evidence on the role of microRNAs in bariatric/metabolic surgery and evaluates their potential as biomarkers and therapeutic targets. Recent Findings: Bariatric surgery induces significant alterations in circulating and tissue-specific miRNA profiles, particularly those involved in glucose metabolism, inflammation, and adipose tissue remodeling. Among the most frequently reported candidates, miR-122, miR-221, miR-27a, miR-126, miR-144, miR-222, miR-223, miR-375, miR-92a, and miR-155 have been associated with weight loss, improved insulin sensitivity, and diabetes remission. Emerging data suggest that these miRNAs may act not only as biomarkers of metabolic recovery but also as regulators of insulin signaling, inflammatory pathways, and adipocyte function. Summary: Current evidence supports a role for miRNAs in the metabolic adaptations observed after bariatric surgery. Although further validation is required, miRNAs show promise as minimally invasive biomarkers for predicting and monitoring treatment response and may provide insight into the molecular mechanisms underlying obesity remission and improvement of obesity-related comorbidities.

1. Introduction

Bariatric surgery (BS), also known as metabolic surgery, has emerged as an effective treatment for obesity and obesity-related metabolic disorders, such as type 2 diabetes mellitus (DMT2). The mechanisms through which BS exerts its beneficial effects are complex and not yet fully understood. However, accumulating evidence suggests that miRNAs play an important role in these mechanisms, modulating the expression of genes involved in energy homeostasis, inflammation, and insulin resistance.

2. Overview

Obesity is a significant health concern worldwide, which plays a pivotal role in the pathogenesis of many non-communicable diseases such as DMT2, hyperlipidemia, arterial hypertension, cardiovascular diseases, obstructive sleep apnea, chronic kidney disease and carcinogenesis [1]. According to the World Health Organization, more than 2.5 billion people were overweight in 2022, with the prevalence of adult obesity having nearly doubled since 1990 [2,3]. Furthermore, the World Obesity Federation projects that the number of adults living with obesity will exceed 1.1 billion by 2030 if current trends continue [4].

The current obesity-related guidelines endorse BS as a method of choice in particular circumstances because it is the most effective treatment and can alleviate many of the obesity-associated comorbidities when present [5,6,7,8,9,10]. The laparoscopic approach is the preferred treatment method, and there are five most commonly performed types of BS procedures, as follows: sleeve gastrectomy (SG), adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), one anastomosis gastric bypass, and biliopancreatic diversion with or without duodenal switch. SG and AGB reduce food intake and lead to an early feeling of satiety, while others restrict the amount of food intake and induce malabsorption [11,12].

Aside from losing weight, many patients experience improved health following BS. The degree of weight loss after the procedure ranges between 50 and 80% for up to two years, depending on the chosen technique. Notably, compared to weight loss achieved solely through lifestyle changes, BS results not only in decreased body weight but also in remission of type 2 diabetes in as many as 84% of individuals, along with improvement in other obesity-associated comorbidities [13,14,15,16,17,18,19,20,21]. The remission rate of DMT2 following BS varies depending on the specific surgical technique used. According to Courcoulas et al. (2018), 60,2% of patients who underwent RYGB achieved remission of their condition seven years after surgery compared to 20,3% for AGB [22]. In addition, individuals who undergo BS attain higher rates of DMT2 remission compared to those who have similar weight loss using non-surgical techniques [23,24].

One of the most intriguing observations following BS is the rapid improvement in glucose homeostasis and insulin sensitivity, which may occur within days after surgery, often preceding substantial weight loss. This phenomenon suggests that mechanisms beyond simple caloric restriction and weight reduction contribute to metabolic remission. Proposed pathways include alterations in gut hormone secretion, bile acid metabolism, adipose tissue remodeling, inflammatory signaling, and epigenetic regulation. Among the latter, microRNAs (miRNAs) have emerged as promising molecular regulators capable of influencing multiple metabolic pathways simultaneously. Increasing evidence suggests that changes in miRNA expression following BS may not only reflect postoperative metabolic adaptations but may also contribute directly to the mechanisms underlying diabetes remission and long-term metabolic improvement.

This review summarizes current evidence regarding miRNA alterations following BS and critically evaluates their role as potential biomarkers of postoperative metabolic outcomes and as mechanistic mediators of metabolic remission. Particular attention is given to miRNAs involved in glucose metabolism, inflammation, and adipose tissue remodeling, as well as their potential future applications as predictive, diagnostic, and therapeutic tools in obesity and metabolic disease.

3. Methods

In this review, the literature search was performed using the PUBMED/MEDLINE, Scopus, and Web of Science databases and included publications available until June 2026. Search terms comprised combinations of miRNA, obesity, BS, metabolic surgery, sleeve gastrectomy, Roux-en-Y gastric bypass, one-anastomosis gastric bypass, adipose tissue, DMT2, weight loss, metabolic remission, and epigenetics. Additional relevant studies were identified through manual screening of the reference lists of eligible articles and recent review papers.

Original studies evaluating circulating tissue-specific miRNA expression in patients undergoing BS were considered for inclusion. Experimental studies investigating the biological role of the individual miRNAs were included when they contributed to the interpretation of clinical findings. Publications not directly related to obesity, BS, or miRNA biology, conference abstracts without a full text, editorials, letters, and duplicate reports were excluded. Only articles published in English were considered.

Due to the fact that this review was designed as a narrative overview rather than a systematic review, no formal assessment of study quality or risk of bias was performed. Particular emphasis was placed on recent publications while retaining landmark studies that established the current understanding of miRNA-mediated regulation in obesity and the metabolic adaptations following BS.

MiRNAs discussed in detail were selected according to their frequency of reporting across the studies summarized in Supplementary Table S1, together with the availability of experimental or clinical evidence supporting their role in glucose homeostasis, insulin signalling, inflammation, adipogenesis, adipose tissue remodelling, or diabetes remission after BS (Supplementary Table S2).

4. MiRNAs in Obesity and Bariatric/Metabolic Surgery

4.1. MiRNAs and Their Association with Obesity and Metabolic Syndrome

MiRNAs are small, endogenous non-coding RNA molecules (approximately 21–23 nucleotides in length) that modulate gene expression post-transcriptionally by binding to messenger RNA (mRNA), leading to its degradation or translational inhibition. In recent years, scientific interest in miRNAs has grown considerably, with around 2600 mature miRNAs identified [25]. Detectable in various body fluids such as blood, serum, plasma, urine, cerebrospinal fluid, and saliva, miRNAs hold promise as non-invasive biomarkers. Notably, a single miRNA can target multiple genes and regulate numerous biological pathways.

Energy homeostasis is meticulously regulated by the endocrine and nervous systems to maintain a balance between caloric intake and energy expenditure [26]. The central nervous system monitors various metabolic parameters (e.g., blood sugar, cholesterol), hormones, and adipokines (such as insulin, leptin, and ghrelin) and adjusts food intake and autonomic nervous system responses accordingly [26]. Inflammatory cytokine synthesis in white adipose tissue can disrupt insulin signaling and contribute to the development of type 2 diabetes and other obesity-related comorbidities [26]. Consequently, maintaining a healthy weight is crucial for balanced homeostasis. It is not surprising that miRNAs have emerged as potential new regulators of adipose tissue (AT) function in obesity [26]. Numerous miRNAs exhibit altered expression in the white adipose tissue of obese individuals compared to their lean counterparts [26]. Visceral adipose tissue is believed to have a more significant metabolic role than white adipose tissue, with some studies indicating differences in miRNA expression between the two types of adipose tissue [27].

Several miRNAs have been identified as promoters of adipogenesis, adipocyte differentiation, lipid metabolism, and insulin signalling. Some miRNAs, including miR-17, miR-21, miR-26b, miR-103, miR-143, miR-181, miR-210, miR-320, miR-375, and miR-378, promote adipocyte differentiation and lipid accumulation, whereas others, such as let-7, miR-15a, miR-22, miR-27a/b, miR-31, miR-33b, miR-93, miR-125a, miR-130, miR-155, miR-193a/b, miR- 221, and miR-222, inhibit adipogenesis or modulate adipose tissue expansion through regulation of key transcriptional networks and metabolic signalling pathways. Recent reviews further highlight that these miRNAs function within complex regulatory networks controlling adipose tissue plasticity, inflammation, cholesterol homeostasis, and systemic metabolic adaptation, rather than acting as isolated regulators [28,29,30,31].

A substantial body of scientific evidence highlights the clinical advantages of BS beyond weight reduction and diabetes remission. However, the underlying mechanisms responsible for the sustained weight loss and amelioration of obesity-related conditions remain inadequately explored [23,32,33,34,35,36]. Collectively, numerous miRNAs have been reported to change following BS [37,38], reflecting the growing interest in miRNA expression patterns before and after surgery and their involvement in key biological pathways.

4.2. MiRNAs Associated with Glucose Metabolism and Diabetes Remission

Several miRNAs reported after BS appear to be closely linked to glucose metabolism, insulin sensitivity, and diabetes remission. Because numerous miRNAs have been investigated following bariatric surgery, we focused on those most consistently reported and supported by experimental or clinical evidence. The frequency analysis used to guide this selection is presented in Supplementary Table S2. Principal clinical studies are summarized in

Table 1. Clinical studies evaluating miRNA alterations following bariatric surgery, organized according to their principal biological focus.

Glucose Metabolism, Insulin Sensitivity, and Diabetes Remission
Study	Population/Surgery	Biological Specimen	Principal Finding	Representative miRNAs
Lirun et al. (2015) [39]	T2DM patients undergoing RYGB	Serum	Distinct postoperative miRNA changes according to BMI	let-7 family, miR-24, miR-320, miR-1281, miR-19b, mir-23a
Rega-Kaun et al. (2019) [40]	With/Without T2DM/RYGB	Serum	Improvement in glucose metabolism and insulin secretion	miR-122, miR-130b, miR-132, miR-375
Zhu et al. (2017) [41]	With/Without T2DM/RYGB	Venous blood	Improved glucose homeostasis	miR-122, miR-320
Wang et al. (2018) [42]	T2DM patients/NA	Peripheral blood	Improved insulin sensitivity through SIRT1 regulation	miR-448
Lu et al. (2023) [43]	Patients with and without T2DM	Serum	Distinct miRNA signatures according to diabetic status	Multiple miRNAs
Martínez et al. (2026) [44]	Obese/RYGB	Plasma	Prediction of persistent T2DM	miR-144
Inflammation and Immune Regulation
Study	Population/Surgery	Biological Specimen	Principal Finding	Representative miRNAs
Ortega et al. (2015a) [45]	Bariatric surgery	SAT	Reduced inflammatory activity	miR-130b, miR-155, miR-221
Ortega et al. (2015b) [46]	RYGB	SAT	Postoperative reduction in inflammatory signalling	miR-146a, miR-146b, miR-155, miR-221, miR-222, miR-223
Hulsmans et al. (2012) [47]	RYGB	Blood sample	Normalization of obesity-associated inflammatory miRNAs	miR-181 family
Macartney-Coxson et al. (2020) [48]	Gastric bypass	SAT/VAT	NLRP3 inflammasome-related remodeling	miR-24, miR-221, miR-223; miR-22; miR-27a
Ho et al. (2021) [49]	T2DM vs. statin-treated patients/RYGB	Serum	Changes in inflammation related HDL miRNAs	miR-24, miR-222, miR-223; miR-126
Liu et al. (2023) [50]	SG	PBMCs	Immune pathway modulation	Multiple miRNAs
Adipose Tissue, Lipid Metabolism, and Tissue Remodelling
Study	Population/Surgery	Biological Specimen	Principal Finding	Representative miRNAs
Alkandari et al. (2018) [51]	With and without T2DM/RYGB	Plasma	Longitudinal metabolic remodeling	miR-27a, miR-33a, miR-125b, miR-320; miR-192
Alkandari et al. (2019) [52]	With and Without T2DM/RYGB and SG	Urine	Tissue remodeling and fibrosis	miR-192, miR-200a, miR-200b
Kurylowicz et al. (2017) [53]	Bariatric surgery	SAT and VAT	Adipogenesis and adipose tissue remodeling	miR-23a, miR-27a, miR-146b, miR-200a, miR-200b; miR-144; miR-223; miR-22
Blum et al. (2017) [54]	SG	Serum	Endothelial recovery	miR-21, miR-22, miR-122
Sangiao-Alvarellos et al. (2020) [55]	SG and RYGB	Serum	Longitudinal metabolic adaptation	miR-122, miR-192, miR-210, miR-221, miR-222
Carmona-Maurici et al. (2024) [56]	Bariatric surgery	Plasma	Cardiovascular and metabolic adaptation	miR-126, miR-144, miR-375
Prediction of Bariatric Surgery Outcomes
Study	Population/Surgery	Biological Specimen	Principal Finding	Representative miRNAs
Nuñez-López et al. (2017) [57]	RYGB ± exercise	Plasma	Metabolic response to exercise and insulin	miR-17; miR-15a; miR-106b; miR-135b
Cereijo et al. (2019) [58]	With and without T2DM/RYGB and SG	Serum	Prediction of glycaemic improvement and BS success	miR-92a
Hubal et al. (2017) [59]	Gastric bypass	Plasma/Serum exosomes	Improvement in insulin signalling	miR-122, miR-126, miR-155
Bae et al. (2019) [60]	RYGB and SG	Serum exosomes	Surgery-responsive exosomal miRNAs	9 surgery-responsive
Lu et al. (2023) [43]	With and without T2DM/SG and RYGB	Serum	Procedure-specific miRNA signatures	Multiple miRNAs
Doyon et al. (2020) [61]	High vs. low weight loss/RYGB and SG	Serum	Differential weight loss-associated miRNAs	miR-27a, miR-126, miR-375
Mela et al. (2023) [62]	RYGB/BPD, SG	Serum	Quality of life and weight loss response	miR-19b
Mela et al. (2025) [63]	Bariatric surgery	Serum	Prediction of long-term %EWL	miR-222 and miR-365b
Zhao et al. (2026) [64]	High vs. low responders	Blood	Predictive circulating miRNA signature	miR-1914-3p, miR-664b-5p, miR-370-3p
Yeh et al. (2022) [65]	RYGB and SG	Serum	Prediction of treatment response	miR-31, miR-181a, miR-328

, while detailed study characteristics and complete miRNA profiles are provided in Supplementary Table S1.

miR-122 is one of the most frequently reported miRNAs in this field. Liao et al. demonstrated that human visceral and subcutaneous adipose tissues show the greatest difference in miR-122 expression levels. Moreover, the ratio of miR-122 abundance between visceral and subcutaneous fat was found to correlate with the percentage of excess body weight loss at both 6 months and 1 year following BS [66]. In accordance, Nunez Lopez et al. found statistically significant change (>1.5 fold) in the expression of miR-122 [57] 1–3 months following RYGB.

Blum et al. also reported postoperative upregulation of miR-122 after sleeve gastrectomy and suggested that the miR-122/miR-451 ratio may reflect endothelial function in patients with obesity [54]. To the contrary, Alvarellos et al. observed a decrease in circulating liver-associated miR-122 after metabolic surgery, while Rega-Kaun et al. reported downregulation of miR-122 after gastric bypass. These apparently divergent findings may reflect differences in sample source, surgical technique, follow-up interval, and metabolic status of the studied populations [40,55].

miR-126 is primarily expressed in endothelial cells and contributes to vascular and metabolic regulation. Increased circulating and HDL-associated miR-126 levels have been observed following bariatric surgery and coincide with improvements in cardiometabolic status [49]. A recent meta analysis also identified miR-126 as one of the few miRNAs consistently increased after weight loss interventions [67], whereas reduced expression has been reported in severely obese patients with subclinical atherosclerosis [56].

miR-375 is primarily relevant in the context of pancreatic function and diabetes remission. Rega-Kaun et al. reported postoperative upregulation of miR-375 after gastric bypass, in parallel with downregulation of miR-122, miR-130, and miR-132 [40]. These miRNAs were associated with improved pancreatic function, insulin sensitivity, and hepatic injury. Doyon et al. also identified miR-375 among the differentially expressed miRNAs distinguishing high-weight-loss from low-weight-loss bariatric patients, linking it to obesity, type 2 diabetes, adipocyte proliferation and differentiation, and insulin sensitivity [61].

miR-92a also appears to be related to impaired carbohydrate metabolism. Lirun et al. reported downregulation of miR-92a after RYGB in both BMI groups of patients with type 2 diabetes [39]. Cereijo et al. found that miR-92a was elevated at baseline in patients with obesity and abnormal glucose metabolism and significantly decreased after BS. Its expression correlated with HbA1c, insulin levels, and HOMA-IR, supporting its potential role as a biomarker of glycemic improvement after surgery [58].

miR-320 has been repeatedly associated with insulin signaling and glucose metabolism. Lirun et al. observed upregulation of miR-320a/b/c after RYGB in the both BMI groups [39], whereas Zhu et al. selected miR-320a for validation in patients with type 2 diabetes after BS and reported postoperative downregulation in most patients [41]. Atkin et al. also identified miR-320c among the miRNAs significantly altered 21 days after RYGB in patients with obesity and type 2 diabetes [68]. Taken together, these findings suggest that miR-320 family members may be involved in the early and late molecular responses related to insulin signaling, although the direction of change remains inconsistent across studies.

Recent studies have provided additional insight into the relationship between miRNAs and postoperative metabolic improvement. Lu et al. demonstrated that patients with obesity and DMT2 exhibit a distinct pattern of miRNA alterations after BS compared with individuals without diabetes [43]. The affected miRNAs were linked to pathways involved in insulin secretion, lipid metabolism, PI3K/Akt signaling, and inflammatory regulation, suggesting that diabetes remission may be accompanied by specific molecular changes rather than representing only a consequence of weight loss [43].

Overall, current evidence supports miR-122, miR-126, miR-375, miR-92a, and miR-320 as candidate biomarkers of metabolic improvement after BS, particularly in relation to insulin sensitivity, glucose homeostasis, and diabetes remission. However, the heterogeneity of study design, biological samples, surgical techniques, and follow-up intervals prevents definitive conclusions regarding their causal role.

4.3. MiRNAs Associated with Inflammation

Inflammation is a central component of obesity-related metabolic dysfunction and may contribute to insulin resistance, adipose tissue dysfunction, and cardiovascular risk. Several miRNAs discussed in the available literature, particularly miR-21, miR-155, miR-146a, miR-221, miR-222 and miR-223, appear to be related to inflammatory signaling after BS. Relevant studies are summarized in Table 1.

Blum et al. reported postoperative downregulation of miR-21 after sleeve gastrectomy [54]. Although this study primarily focused on circulating miRNA changes and endothelial function, miR-21 is commonly considered relevant to inflammatory and adipose tissue-related pathways [54]. Its postoperative reduction may therefore reflect a broader shift in the inflammatory phenotype after weight loss surgery.

miR-155 has been repeatedly linked to inflammation and adipose tissue dysfunction. Ortega et al. reported postoperative downregulation of miR-155 in subcutaneous adipose tissue two years after RYGB, together with other miRNAs associated with cell proliferation, lipid metabolism, and inflammatory changes [45,46].

miR-146a and miR-223 are also relevant to the inflammatory profile of adipose tissue. Ortega et al. reported decreased levels of miR-146a, miR-146b, miR-155, miR-221, miR-222, miR-223, and related miRNAs after surgery-induced weight loss [45]. These miRNAs were associated with adipose tissue dysfunction, oxidative stress, apoptosis, inflammatory events, insulin resistance, and type 2 diabetes development. Kurylowicz et al. also demonstrated substantial postoperative changes in adipose tissue miRNA expression, including miRNAs involved in inflammation, immune response, lipid metabolism, and insulin signaling [53,69].

Based on the frequency analysis of the studies included in this review (Supplementary Table S1), miR-221 and miR-222 were among the most consistently reported miRNAs following bariatric surgery. Both have been associated with adipose tissue function, inflammatory responses, and insulin resistance, suggesting a potential role in the metabolic adaptations that occur after bariatric surgery. Changes in the expression of miR-221 and miR-222 have been described in both adipose tissue and circulating samples following surgery, although the reported patterns were not uniform across studies and appeared to depend on the biological specimen, surgical procedure, and timing of sample collection [45,46,49,55,57]. Collectively, these studies suggest that miR-221 and miR-222 are more likely to reflect adipose tissue remodelling during postoperative metabolic recovery than to serve as robust biomarkers of bariatric surgery outcomes. Additional well designed prospective studies are needed to better define their biological and clinical relevance.

Additional support for an inflammatory mechanism comes from Macartney-Coxson et al., who reported increased NLRP3 inflammasome protein in the omentum after gastric bypass [48]. Although this finding does not establish a direct causal role for a specific miRNA, it supports the concept that BS is associated with remodeling of inflammatory pathways in adipose tissue.

Overall, miR-21, miR-155, miR-146a, miR-221, miR-222, and miR-223 appear to represent a group of inflammation-related miRNAs that may reflect postoperative changes in adipose tissue inflammation and immune signaling. Based on the available evidence, they are better considered potential mediators of inflammatory remodeling rather than fully validated clinical biomarkers.

4.4. MiRNAs Associated with Adipogenesis and Weight Loss

Several miRNAs reported after BS are linked to adipogenesis, adipocyte differentiation, lipid metabolism, and weight loss response. Among these, miR-27a, miR-378, and miR-130b are supported by postoperative BS data, whereas miR-143 is relevant to adipogenesis but is less directly supported by the BS studies summarized in the present manuscript. Relevant studies are summarized in Table 1.

Doyon et al. identified miR-27a-3p among seven differentially expressed miRNAs distinguishing high-weight-loss from low-weight-loss bariatric patients [61]. These miRNAs were linked to obesity, fatty acid synthesis, type 2 diabetes, adipocyte proliferation and differentiation, and insulin sensitivity [61]. Alkandari et al. also reported statistically significant postoperative changes in miR-27a-3p six months after RYGB, linking these alterations to insulin/IGF-1 signaling, PI3 kinase, and cadherin signaling pathways. These data support miR-27a as a candidate miRNA involved in both adipose tissue remodeling and metabolic recovery [51].

miR-378 is another relevant candidate in the context of adipogenesis and lipid metabolism. Alkandari et al. found that miR-378a-3p was significantly altered six months after RYGB. In the same study, the altered miRNAs were related to insulin/IGF-1 signaling and other metabolic pathways [51]. Bae et al. also reported postoperative downregulation of several miR-378 family members, including miR-378c, miR-378d, and miR-378g, among surgery-responsive miRNAs that were elevated before surgery and decreased after bariatric intervention [60].

miR-130b is supported by data from Rega-Kaun et al., who reported downregulation of miR-130b-3p after gastric bypass [40]. This miRNA was analyzed together with miR-122, miR-132, and miR-375, which were associated with pancreatic function, insulin sensitivity, and hepatic injury [40]. Although the available data do not fully define the mechanistic role of miR-130b after BS, its postoperative modulation suggests a possible relationship with metabolic and adipose tissue remodeling.

miR-143 is well recognized in the broader literature on adipogenesis and obesity; however, in the text summarized here, it is mainly discussed in the general context of adipogenic and atherogenic processes rather than as a repeatedly reported postoperative miRNA after BS. Therefore, it may be mentioned as biologically relevant to adipogenesis, but it should not be presented as one of the strongest BS-associated candidates unless additional supporting studies are included.

Overall, miR-27a, miR-378, and miR-130b appear to be the most defensible candidates from the current manuscript for discussion in relation to adipogenesis, adipose tissue remodeling, and weight loss response after BS. miR-143 may be retained as background biological context but should be interpreted cautiously.

4.5. MiRNAs as Predictors of BS Success

A clinically important question is whether perioperative miRNA profiles can predict the success of bariatric/metabolic surgery, including weight loss, diabetes remission, and broader metabolic improvement. The available studies suggest several candidate miRNAs, including miR-122, miR-30c-5p, miR-590-5p, miR-26a-5p, miR-106b-5p, and miR-210-3p. Relevant studies are summarized in Table 1.

miR-122 is the most consistent candidate biomarker in the available literature. Liao et al. showed that the ratio of miR-122 expression between visceral and subcutaneous adipose tissue correlated with excess body weight loss at both 6 months and 1 year after BS [66]. Blum et al. further suggested that the miR-122/miR-451 ratio could serve as an indicator of endothelial function in patients with obesity [54]. Alvarellos et al. also reported postoperative changes in circulating liver-associated miR-122 after metabolic surgery [55]. These data support miR-122 as a potential biomarker of both weight loss response and metabolic improvement.

Doyon et al. identified miR-30c-5p and miR-590-5p among seven differentially expressed miRNAs separating high-weight-loss from low-weight-loss bariatric patients [61]. The authors suggested that a combination of miR-30c-5p and miR-590-5p may discriminate between high and low responders [61]. These findings are directly relevant to the potential use of miRNAs as predictors of BS success.

miR-210 is also supported by Alvarellos et al., who found that miR-210 was upregulated in patients with obesity compared with lean controls and decreased after metabolic surgery [55]. This reinforces its potential relevance as part of the metabolic recovery signature following BS.

Evidence from recent studies suggests that miRNAs may provide useful information regarding the variability in patient response to BS. Lu et al. observed distinct early postoperative miRNA changes following SG and RYGB, some of which were associated with short-term weight loss outcomes [70]. Conversely, Mela et al. reported that circulating miR-19b, miR-365b-5p and miR-222-5p were associated with long-term weight loss success, supporting the notion that specific miRNA profiles may reflect different phases of the postoperative metabolic response [62,63].

Taken together, miR-122, miR-30c-5p, miR-590-5p, miR-26a-5p, miR-106b-5p, and miR-210-3p represent the strongest candidates in the present manuscript for future evaluation as predictors of BS outcomes. However, none of these markers can currently be considered clinically validated. Prospective studies with standardized sampling, defined surgical procedures, homogeneous metabolic phenotyping, and long-term follow-up are required before miRNA-based prediction can be implemented in clinical decision-making.

Overall, the available literature suggests that miRNAs occupy a dual role in the context of BS, acting both as measurable indicators of metabolic response and as potential regulators of the biological processes underlying metabolic remission. A synthesis of the most consistently reported miRNAs and their proposed roles as biomarkers, mediators, or both is presented in

Table 2. Proposed roles of the most frequently reported miRNAs following bariatric/metabolic surgery.

miRNA	Main Biological Process	Potential Biomarker	Potential Mediator
miR-122	Glucose metabolism, insulin resistance, hepatic metabolism	Yes (associated with excess weight loss and metabolic improvement)	Yes
miR-221	Inflammation, adipose tissue remodeling	Possible	Yes
miR-27a	Adipogenesis, insulin signalling	Possible	Yes
miR-126	Glucose metabolism	Possible	Yes
miR-144	Glucose metabolism, adipose tissue remodeling, and cardiometabolic adaptation	Yes (preoperative miR-144-3p associated with persistent T2DM after RYGB)	Yes
miR-222	Inflammation, immune regulation	Possible	Yes
miR-223	Inflammation, metabolic regulation	Possible	Yes
miR-375	β-cell function, glucose homeostasis	Yes (associated with diabetes remission and metabolic improvement)	Yes
miR-320	Insulin signalling, glucose metabolism	Possible	Yes
miR-21	Inflammation, adipose tissue function	Possible	Yes
miR-155	Inflammation, adipogenesis	Possible	Yes
miR-146a	Inflammatory signalling	Possible	Yes
miR-378	Adipogenesis, lipid metabolism	Possible	Yes
miR-130b	Adipocyte differentiation, metabolic regulation	Possible	Yes
miR-92a	Glucose metabolism, insulin sensitivity	Yes (associated with HbA1c, insulin levels and HOMA-IR)	Possible

.

5. Discussion

Collectively, the available evidence indicates that although numerous miRNAs have been associated with bariatric surgery, only a relatively small group has been reported consistently across independent clinical studies and therefore represents the most robust candidates for further investigation. The present review highlights the growing evidence that miRNAs may represent an important molecular link between BS and postoperative metabolic improvement. Although numerous miRNAs have been reported to change following bariatric procedures, the available literature suggests that only a limited number of candidates have been consistently associated with clinically meaningful outcomes such as weight loss, improved insulin sensitivity, and diabetes remission. Supplementary Table S2 summarizes the frequency of individual miRNAs reported across the included clinical studies and provides the rationale for selecting the miRNAs discussed in the following sections. Among these, miR-122, miR-375, miR-92a, and members of the miR-320 family emerge as the most promising candidates related to glucose metabolism, while miR-21, miR-155, miR-146a, and miR-221, miR-222 and miR-223 appear to be more closely connected to inflammatory remodeling and adipose tissue dysfunction. In parallel, miR-27a, miR-378, and miR-130 have been implicated in adipogenesis, lipid metabolism, and postoperative weight loss response.

One of the central questions addressed by this review is whether miRNAs should be regarded primarily as biomarkers of metabolic recovery or as active mediators of metabolic remission. Current evidence suggests that these roles are not mutually exclusive. Several miRNAs fulfil key characteristics of biomarkers because their expression correlates with clinically relevant outcomes. For example, miR-122 has been associated with excess weight loss, endothelial function, and metabolic improvement after BS, while miR-92a has been linked to HbA1c, insulin levels, and HOMA-IR [39,54,55,57,58,66]. Similarly, miR-26a-5p, miR-106b-5p, and miR-210-3p have been associated with diabetes remission following gastric bypass [71]. These observations support the concept that selected miRNAs may serve as measurable indicators of postoperative metabolic response.

At the same time, accumulating evidence suggests that several miRNAs participate in biological pathways directly involved in metabolic recovery. Many of the miRNAs identified after BS regulate insulin signaling, glucose homeostasis, adipocyte differentiation, inflammatory signaling, and lipid metabolism. For example, miR-375 is strongly linked to pancreatic β-cell function, whereas miR-320 family members influence insulin signaling pathways [40,61]. Similarly, miR-21, miR-221, miR-222, miR-155, miR-146a, and miR-223 are associated with inflammatory responses and adipose tissue dysfunction, processes that are increasingly recognized as central contributors to obesity-associated insulin resistance [45,46,53,54,69]. Consequently, these molecules may represent not only markers of metabolic improvement but also potential mediators of the molecular adaptations that occur after BS.

A recurring challenge throughout the literature is the considerable heterogeneity between studies. Differences exist in patient selection, prevalence of type 2 diabetes, baseline metabolic status, type of bariatric procedure, duration of follow-up, and biological material analyzed. Studies have evaluated miRNA expression in serum, plasma, urine, visceral adipose tissue, subcutaneous adipose tissue, liver-associated circulating fractions, and peripheral blood cells. Furthermore, the timing of sample collection ranges from several weeks to multiple years after surgery. Such variability likely contributes to the inconsistent direction of change reported for certain miRNAs, particularly miR-122 and members of the miR-320 family. Consequently, direct comparison between studies remains challenging and may explain why some findings have not been consistently replicated.

Another important consideration is the distinction between weight loss and metabolic remission. BS frequently improves glucose homeostasis and insulin sensitivity before substantial weight reduction has occurred, suggesting that mechanisms beyond simple weight loss contribute to postoperative metabolic recovery. Several miRNAs reviewed here appear to be more strongly associated with glycemic improvement than with weight loss itself. For example, miR-92a correlates with markers of carbohydrate metabolism, whereas miR-26a-5p, miR-106b-5p, and miR-210-3p have been associated with diabetes remission [71]. In contrast, miR-122 and miR-30c-5p may better reflect overall metabolic response and weight loss success [54,55,57,61,66]. These observations raise the possibility that distinct miRNA signatures may characterize different aspects of postoperative recovery.

From a clinical perspective, miRNAs hold considerable promise as minimally invasive biomarkers. Their stability in biological fluids and their association with key metabolic pathways make them attractive candidates for predicting surgical outcomes, identifying patients likely to achieve diabetes remission, and monitoring postoperative metabolic adaptation. The findings of Doyon et al., demonstrating differential expression of miR-30c-5p and miR-590-5p between high and low weight loss responders, illustrate the potential utility of miRNA-based prediction models [61]. Nevertheless, the current evidence remains insufficient to support routine clinical implementation. Most available studies involve relatively small cohorts, use different analytical platforms, and lack external validation. Furthermore, mechanistic studies establishing causality remain limited.

Interest in the role of miRNAs in metabolic BS has grown considerably over the past decade. A systematic review identified more than 500 unique miRNAs reported across published studies, but also emphasized the marked variability in study design, sample source, and analytical techniques [72]. While early investigations largely focused on describing postoperative changes in miRNA expression, more recent studies have explored their potential clinical relevance. Differences in miRNA profiles have been linked to the type of bariatric procedure performed, diabetic status, cardiovascular risk, and the degree of long-term weight loss achieved. These observations suggest that miRNAs may have value not only as indicators of metabolic improvement but also as potential tools for identifying distinct patient phenotypes.

Two recent studies further illustrate the distinct contexts in which tissue-specific and circulating miRNAs may be relevant to BS. A recent liver-tissue study by Rodríguez et al. identified higher miR-128-3p expression and lower miR-223-3p expression in patients with obesity undergoing BS. These changes were not related to the severity of the histological liver findings, suggesting that they may reflect the underlying metabolic dysfunction associated with obesity. Both miRNAs may therefore have potential as biomarkers or therapeutic targets, although the cross sectional design does not allow conclusions regarding postoperative changes [73]. By contrast, Zhao et al. used preoperative small RNA sequencing to identify miR-1914-3p, miR-664b-5p, and miR-370-3p as differentially expressed between patients with high and low weight loss one year after bariatric surgery [64]. These studies highlight two distinct applications of miRNA profiling: tissue-specific signatures may characterize underlying metabolic dysfunction, whereas circulating preoperative signatures may contribute to predicting postoperative treatment response. Both approaches require longitudinal validation in larger independent cohorts.

Future research should focus on the development of standardized protocols for sample collection, miRNA quantification, and data analysis. Large prospective multicenter studies with longitudinal follow-up are required to validate candidate biomarkers and determine their reproducibility across different patient populations and surgical techniques. Integration of miRNA signatures with established clinical, biochemical, and anthropometric predictors may further improve the prediction of weight loss and diabetes remission after BS. Finally, mechanistic studies investigating the direct effects of miRNA modulation on insulin signaling, inflammation, and adipose tissue remodeling may clarify whether these molecules represent merely markers of metabolic improvement or genuine therapeutic targets.

6. Conclusions

Taken together, current evidence suggests that miRNAs occupy a unique position at the interface between biomarker discovery and mechanistic understanding of metabolic remission following BS. While several miRNAs show promise as predictors of postoperative outcomes, others appear to participate directly in the biological pathways underlying metabolic recovery. Future studies will determine whether these molecules can ultimately be translated into clinically useful biomarkers, therapeutic targets, or both.