The reduction in body weight is a core symptom of IBD. A total of 11 datasets were used to assess this indicator. A meta-analysis of body weight changes revealed significant heterogeneity (I² = 77.0%, P < 0.05), and a random-effects model was used to conduct meta-analysis on weight change. Analysis of these studies showed that rutin has an effect on weight reduction [SMD: 1.70, P < 0.05; 95% CI(0.84,2.56)] (Figure 3 Forest plot of the effect of rutin on IBD, outcome measure: (a) weight loss. (b) disease activity index).

DAI is an indicator used to measure the activity level of a disease by quantifying its clinical manifestations. Six experiments reported data on DAI. Significant heterogeneity was observed (I² = 87.8%, P < 0.05), and a random-effects model was used for meta-analysis of DAI. Rutin can reduce DAI in mice induced with colitis [SMD: −3.81 P < 0.05; 95% CI(-5.80,-1.82)] (Figure 3 Forest plot of the effect of rutin on IBD, outcome measure: (a) weight loss. (b) disease activity index).

Fluorescein isothiocyanate (FITC) is a fluorescein derivative used to detect intestinal permeability. Four experiments reported FITC levels. Significant heterogeneity was observed (I² = 84.1%, P < 0.05), and a random-effects model was used for meta-analysis of FITC. Rutin can decrease FITC levels in experimental animals induced with colitis [SMD: −3.02, P < 0.05; 95% CI (−5.29, −0.75)](Figure 6 Forest plot of the effect of rutin on IBD, outcome measure: FITC.

Due to significant heterogeneity, subgroup analyses were conducted based on predefined categories: animal gender, modeling method, modeling dosage, and treatment dosage. The results indicated that animal gender was not a primary source of heterogeneity (Figure 7 Subgroup analysis of the effect of rutin on weight loss: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. In eight experiments using DSS-induced colitis, significant heterogeneity was observed. Three experiments utilized other modeling methods, exhibiting non-significant heterogeneity and non-statistically significant conclusions (Figure 7 Subgroup analysis of the effect of rutin on weight loss: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Excluding three experiments that did not involve DSS, subgroup analysis of the modeling dosages in the remaining eight experiments still revealed high heterogeneity (Figure 7 Subgroup analysis of the effect of rutin on weight loss: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Subgroup analysis was conducted based on different rutin doses, except for one experiment without detailed dose data (Power et al., 2016), where six experiments had rutin doses below 40 mg/kg, and 4 experiments had doses above 40 mg/kg, showing significant heterogeneity (Figure 7 Subgroup analysis of the effect of rutin on weight loss: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage., yet rutin reduced weight loss in both subgroups.

Subgroup analysis was conducted based on predefined subgroups: according to different animal genders. Four experiments utilized female animals, while two used males. Both subgroups still exhibited high heterogeneity. Rutin significantly reduced DAI in the female subgroup, whereas the effect was not evident in the male subgroup (Figure 8 Subgroup analysis of the effect of rutin on DAI: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Six studies employed DSS for disease modeling, while one study utilized an alternative approach. Comparative analysis with the overall SMD demonstrated persistent significant heterogeneity (Figure 8 Subgroup analysis of the effect of rutin on DAI: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Regarding the different modeling doses, four experiments utilized DSS doses less than 2.5% (wt/v), showing significant heterogeneity, while two experiments used doses greater than 2.5% (wt/v) with insignificant heterogeneity. Rutin reduced DAI values in both subgroups (Figure 8 Subgroup analysis of the effect of rutin on DAI: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Subgroup analysis based on different doses of rutin showed that, except for one experiment that did not specify the dose, two experiments used rutin doses less than 40 mg/kg, while four experiments used doses greater than 40 mg/kg. Both subgroups exhibited significant heterogeneity. Rutin significantly reduced DAI values in the high-dose subgroup, while the effect was not evident in the low-dose subgroup (Figure 8 Subgroup analysis of the effect of rutin on DAI: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage.

Subgroup analysis was conducted based on predefined subgroups: according to different animal genders. Seven experiments utilized female animals, while two used males. Both subgroups still exhibited high heterogeneity. Rutin reduced MPO levels in both subgroups (Figure 9 Subgroup analysis of the effect of rutin on MPO: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Subgroup analysis was conducted based on different modeling methods. Both subgroups still exhibited high heterogeneity. Rutin was more effective in reducing MPO levels in the subgroup that used DSS for modeling (Figure 9 Subgroup analysis of the effect of rutin on MPO: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Subgroup analysis was conducted based on different modeling doses. Except for four experiments that did not utilize DSS for modeling, two experiments used DSS doses less than 2.5% (wt/v) with insignificant heterogeneity, while three experiments used doses greater than 2.5% (wt/v) with significant heterogeneity. Rutin reduced MPO levels in each subgroup (Figure 9 Subgroup analysis of the effect of rutin on MPO: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Subgroup analysis was conducted based on different rutin doses. Except for one experiment that did not specify the rutin dose, six experiments used rutin doses less than 40 mg/kg, and two experiments used doses greater than 40 mg/kg. Significant heterogeneity was observed exclusively in the low-dose rutin subgroup. Rutin reduced MPO levels in both groups (Figure 9 Subgroup analysis of the effect of rutin on MPO: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage.

Subgroup analysis was conducted based on predefined subgroups

According to different animal genders. Six experiments utilized female animals, while three used males. Both subgroups still exhibited high heterogeneity (Figure 10 Subgroup analysis of the effect of rutin on TNF-α: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Rutin reduced TNF-α levels in both subgroups. Subgroup analysis was conducted based on different modeling methods. Only one experiment did not use DSS for modeling, and in the experiments with DSS for modeling, heterogeneity remained high (Figure 10 Subgroup analysis of the effect of rutin on TNF-α: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Subgroup analysis was conducted based on different modeling doses. Except for one experiments that did not utilize DSS for modeling, two experiments used DSS doses less than 2.5% (wt/v), five experiments used doses greater than 2.5% (wt/v) with significant heterogeneity (Figure 10 Subgroup analysis of the effect of rutin on TNF-α: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage. Rutin can reduce the content of TNF-α in both subgroups, but only the group with the high dosage for model establishment shows significant significance. Subgroup analysis was conducted based on different rutin doses. Except for one experiment that did not specify the rutin dose, four experiments used rutin doses less than 40 mg/kg did not show significant heterogeneity, and four experiments used doses greater than 40 mg/kg exhibited significant heterogeneity. Rutin reduced TNF-α levels in both groups (Figure 10 Subgroup analysis of the effect of rutin on TNF-α: (a) animal gender (b) modeling method (c) modeling dosage (d) treatment dosage.

Through real-time quantitative PCR analysis, rutin significantly reduces the expression levels of crucial inflammatory cytokines, including interferon-gamma (IFNγ), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), decreasing the production of pro-inflammatory factors by over 80%. These factors play a critical role in inflammatory bowel diseases, and their reduction contributes to alleviating intestinal inflammation (Mascaraque et al., 2014; Wu et al., 2023). Moreover, rutin effectively suppresses the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in colonic tissues, as well as decrease the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Rutin also significantly decreases the activity of MPO in dss-induced acute colitis mice (Marín et al., 2013). At the biochemical level, the rutin metabolites 3,4-dihydroxyphenylacetic acid (DHPAA) and 3,4-dihydroxytoluene (DHT) possess vicinal hydroxyl groups. These hydroxyl groups undergo condensation reactions with carbonyl groups in reactive carbonyl species (RCS), such as glyoxal and methylglyoxal, forming stable adducts. This reaction depletes reactive carbonyl species (RCS), thereby limiting their capacity to participate in glycation reactions with amino acid residues in proteins. Consequently, it inhibits the formation of advanced glycation end-products (AGEs) and suppresses inflammation (Pashikanti et al., 2010).

The NF-κB signaling pathway is a crucial mediator in the development and progression of inflammatory bowel disease (IBD). This pathway plays a pivotal role in regulating the immune response to infection and inflammation. In response to inflammatory stimuli, NF-κB is activated by phosphorylation of its inhibitor, IκB, leading to IκB degradation and allowing NF-κB to translocate to the nucleus. Within the nucleus, NF-κB binds to specific DNA sequences, triggering the transcription and translation of various pro-inflammatory cytokines and mediators, such as TNF-α, IL-1β, and IL-6, which play crucial roles in the inflammatory processes of IBD (Liu et al., 2022). Through Western blot analysis, the study found that rutin can directly inhibit the binding of p65 to DNA (Kim et al., 2005) and alter the cytoplasmic ratio of p-IκBα and IκBα. Additionally, rutin significantly inhibits the activation of MAPKs-NF-κB, PI3K-Akt, MK2, and GSK3ß. It prevents various oxidative inflammatory signaling cascades and kinases, such as p38/MK2 and PI3K/Akt/GSK3β/MAPKs, from activating the classical inflammatory transcription factor NF-κB to exacerbate the inflammatory response. This suggests that rutin may alleviate DSS-induced colitis by influencing the NF-κB signaling pathway (Sharma et al., 2021; Liu et al., 2022).

The gut microbiota plays a fundamental role in maintaining intestinal health and is crucial in the pathophysiology of inflammatory bowel disease (IBD). One of the primary functions of the gut microbiota is to support the integrity of the epithelial barrier. When the epithelial barrier is compromised, endotoxins (such as lipopolysaccharides) are more likely to translocate into colonic tissues. Once endotoxins enter the colonic tissues, they activate immune cells such as Kupffer cells (liver macrophages) and neutrophils. This activation stimulates the NF-κB signaling pathway, leading to a significant increase in the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) (Liu et al., 2022).

Some studies have found through high-throughput sequencing of 16S rRNA that rutin can restore the decreased abundance of gut microbiota caused by IBD (such as Faecalibaculum rodentium and Turicibacter) and reduce the abundance of potentially disease-associated bacteria (such as Romboutsia and the Escherichia-Shigella group). The enrichment of Escherichia-Shigella is a potential characteristic of IBD patients and an initiator of IBD pathogenesis, including the stimulation of mucin degradation by proteases, adhesion and invasion of intestinal epithelial cells, and promotion of the secretion of pro-inflammatory cytokines and chemokines (Liu et al., 2022) (Mazzarella et al., 2017). Additionally, rutin can be metabolized by gut microbiota into microbial-derived metabolites with anti-inflammatory, antioxidant, and colonic barrier-protective properties, which may contribute to the production of SCFAs in colitis mice (Power et al., 2016; Liu et al., 2022).

Rutin can regulate tight junction proteins, mucin secretion proteins, epithelial cell proliferation, and apoptosis, which contribute to maintaining the integrity of the intestinal barrier (Sharma et al., 2021). During the recovery phase of colitis, rutin significantly enhances the restoration of colonic crypts and goblet cells while reducing the activity of colonic myeloperoxidase (MPO). (Power et al., 2016).

Rutin has immunomodulatory potential and can suppress the exacerbation of inflammation in adaptive immune responses by influencing Treg cells in the spleen, thus alleviating inflammation (Sharma et al., 2021).

High intestinal permeability is a primary characteristic of leaky gut syndrome, which allows food antigens, symbiotic or pathogenic bacteria, and bacterial components to enter the lamina propria and subsequently the bloodstream, triggering systemic inflammation described in various disease conditions (Vanuytsel et al., 2021). In scientific experiments, intestinal permeability is typically assessed using fluorescent dextrans such as fluorescein isothiocyanate (FITC)-labeled dextran and tetramethylrhodamine B isothiocyanate (TRITC)-labeled dextran (Woting and Blaut, 2018). The two included articles demonstrated that rutin can improve intestinal permeability in mouse models of IBD (Liu et al., 2022; Wu et al., 2023).

Among the included studies, dexamethasone (DEX) markedly reduced reactive oxygen species (ROS) levels to 1.1-fold, whereas rutin exhibited a more modest reduction (2.8-fold) (Wu et al., 2023). In contrast, comparative analyses between sulfasalazine (SASP) and rutin revealed comparable efficacy in mitigating weight loss, lowering disease activity index (DAI), and controlling inflammatory cytokines (e.g., TNF-α, IL-6) (Marín et al., 2013; Liu et al., 2022). Findings indicated that rutin achieved effects equivalent to 5-aminosalicylic acid (5-ASA) in improving DAI, colon length, and histopathological damage, with superior performance in specific metrics such as suppressing immunoglobulin levels (Sharma et al., 2021). Furthermore, rutin demonstrated anti-inflammatory potency comparable to budesonide in reducing pro-inflammatory cytokine secretion, while outperforming budesonide in attenuating weight loss and mortality rates (Mascaraque et al., 2014; Mascaraque et al., 2015).

Studies have demonstrated that rutin alleviates streptozotocin (STZ)-induced inflammation and mitigates sporadic Alzheimer’s-type dementia by modulating pro-inflammatory mediators such as cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) (Javed et al., 2012; Sun et al., 2021)

Additionally, rutin exerts therapeutic benefits in diabetes management by reducing intestinal carbohydrate absorption, stimulating insulin secretion from pancreatic β-cells, preventing degeneration of Langerhans islets, enhancing tissue glucose uptake, and suppressing hepatic gluconeogenesis (Ghorbani, 2017). These mechanisms collectively contribute to its efficacy in treating diabetes and associated complications. Furthermore, emerging evidence suggests rutin’s potential in addressing obesity and acute lung injury through its anti-inflammatory and metabolic regulatory properties (Yuan et al., 2017; Yeh et al., 2014).