Herbal and Natural Products for NSAID-Induced Small Intestinal Injury: a systematic review and meta-analysis of randomized controlled trials

Abstract

Objectives

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are widely used medications that frequently cause small intestinal injury (enteropathy). Conventional proton pump inhibitors do not prevent this injury and may exacerbate it through dysbiosis. Herbal medicines and natural products offer potential therapeutic benefits, but synthesized clinical evidence remains limited. Thus, this study will systematically evaluate the efficacy and safety of herbal medicines and natural products for preventing NSAID-induced small intestinal injury.

Methods

MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure will be searched to identify articles published since inception, without restrictions on publication date or language. Randomized controlled trials involving adults aged ≥ 18 years receiving NSAIDs will be included. Two reviewers will independently perform study selection, data extraction, and risk-of-bias assessment using the RoB 2 tool. If appropriate, a meta-analysis will be conducted. The primary outcome will be mucosal injury, objectively assessed using video capsule endoscopy or measures of intestinal permeability. Secondary outcomes will include symptoms and adverse events.

Results

This study will synthesize the current clinical evidence on natural interventions for NSAID-induced enteropathy.

Conclusion

The findings will inform the management of small intestinal injury and guide future research.

INTRODUCTION

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, are among the most widely used medications globally [1, 2]. However, their gastrointestinal (GI) toxicity represents a substantial clinical burden [1, 3, 4]. Approximately 30 million individuals use NSAIDs daily, and usage rates approach 96% among older adults [5, 6]. Consequently, NSAID-related GI complications are among the leading causes of drug-related hospitalization and healthcare utilization [3, 6]. Although clinical research has traditionally focused on upper GI complications, such as gastric and duodenal ulcers, growing evidence underscores the clinical importance of NSAID-induced enteropathy, defined as injury to the small intestine, which is both prevalent and often underrecognized [7-10].

Advances in diagnostic modalities, particularly video capsule endoscopy (VCE), have demonstrated that small intestinal mucosal injury occurs in approximately 60%-80% of NSAID users [11, 12]. Evidence from specific patient populations, such as individuals with rheumatoid arthritis, further supports the high prevalence and clinical significance of these lesions [13]. These injuries can manifest as mucosal erythema, erosions, ulcerations, and, in severe cases, can lead to bleeding or protein loss [10, 14, 15]. Importantly, proton pump inhibitors (PPIs), which are widely used to prevent upper GI injury, do not protect against small intestinal damage and may potentially exacerbate this damage by inducing alterations in the gut microbiota [7, 16-18]. Unlike upper GI injury, NSAID-induced enteropathy remains underrecognized and underdiagnosed and lacks established preventive strategies despite its high prevalence, representing a critical unmet clinical need [18, 19].

The pathogenesis of NSAID-induced enteropathy is complex and multifactorial. In addition to cyclooxygenase inhibition and subsequent prostaglandin depletion, NSAIDs induce mitochondrial dysfunction by uncoupling oxidative phosphorylation, leading to increased production of reactive oxygen species and disruption of epithelial integrity [7, 14, 20, 21]. These processes result in increased intestinal permeability, mucosal inflammation, and ulcer formation. Furthermore, interactions among NSAIDs, bile acids, and the intestinal microbiota via enterohepatic circulation further exacerbate mucosal injury, underscoring the complexity of the underlying disease mechanisms [22].

Given these limitations, there is growing interest in natural products and herbal medicines as potential therapeutic alternatives [6]. Various plant-derived compounds, particularly polyphenols and flavonoids, have demonstrated antioxidant, anti-inflammatory, and cytoprotective effects in experimental models of NSAID-induced GI injury [23, 24]. These agents can reduce oxidative stress, enhance mucosal defense mechanisms (e.g., mucin secretion), and improve intestinal barrier function [23, 24]. Collectively, these properties suggest that natural products and herbal therapies may have promising roles in mitigating NSAID-induced small intestinal injury.

Despite these promising findings, the clinical evidence remains fragmented and inconsistent. Previous systematic reviews have primarily focused on conventional mucoprotective agents or upper GI outcomes [6, 9, 25, 26], with limited attention to small intestinal injury assessed using objective measures. Although a recent comprehensive meta-analysis evaluated the efficacy of various pharmacological agents for small intestinal injury [12], it primarily focused on synthetic drugs, such as misoprostol and rebamipide. Furthermore, prior large-scale network meta-analyses established prevention strategies for general NSAID-associated GI toxicity [26]. However, the potential role of natural products and herbal medicines in protecting the small intestine has not been comprehensively synthesized.

Accordingly, this systematic review and meta-analysis aims to evaluate the efficacy of herbal medicines and natural products in the prevention and treatment of NSAID-induced small intestinal injury. By focusing exclusively on randomized controlled trials (RCTs) and prioritizing objective outcome measures, such as capsule endoscopy findings and validated biomarkers, including measures of intestinal permeability, this study seeks to provide robust, clinically relevant evidence to inform future therapeutic strategies for drug-induced enteropathy.

MATERIALS AND METHODS

1. Study design and registration

This systematic review and meta-analysis protocol will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement [27]. The protocol has been registered in the International Prospective Register of Systematic Reviews (CRD420261355613). Any subsequent amendments to the protocol will be documented in the final manuscript.

2. Eligibility criteria

1) Types of studies

Only RCTs investigating the protective or therapeutic effects of herbal and natural products on NSAID-induced small intestinal injury (enteropathy) will be included. Both parallel-group and crossover trials conducted in humans will be considered eligible. Nonrandomized clinical trials, observational studies, and preclinical studies (animal or in vitro) will be excluded.

2) Types of participants

Studies involving adults (≥ 18 years) receiving NSAIDs will be included. Eligible populations will include both healthy volunteers (as experimental models of acute injury) and patients with chronic conditions (e.g., rheumatoid arthritis and osteoarthritis). Studies will be eligible regardless of whether the intervention is used to prevent NSAID-induced injury or to treat established small intestinal injury. The clinical purpose of each study will be classified as prevention or treatment during data extraction.

3) Types of interventions

Eligible interventions must be classified as nonpharmacological or complementary therapies and administered orally. They may be used either as monotherapy or in combination with conventional treatments (e.g., PPIs). Given the anticipated heterogeneity of the interventions, synthesis will be structured according to prespecified intervention categories, including microbial agents such as probiotics and synbiotics; defined natural-origin compounds or functional components, such as plant-derived compounds, mineral complexes, amino acid derivatives, functional food proteins, and dietary fibers; and compound preparations containing multiple active components. Meta-analysis will be performed only when studies are sufficiently comparable within the same intervention category, clinical purpose, and outcome domain.

4) Types of outcome measures

Regarding the primary outcome, the objective assessment of small intestinal injury will be analyzed as two distinct outcome domains: morphological mucosal injury assessed by VCE findings (e.g., changes in the number of erosions or ulcers and validated scoring systems such as the Lewis score) and functional measures of intestinal permeability (e.g., the lactulose–mannitol ratio). These outcome domains will not be combined in a single meta-analysis.

Secondary outcomes will include clinical symptoms related to GI distress and the incidence and types of treatment-emergent adverse events.

3. Information sources and search strategy

A comprehensive literature search will be conducted using PubMed (including MEDLINE), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the China National Knowledge Infrastructure (CNKI) to identify articles published since inception. The inclusion of CNKI is intended to ensure a comprehensive synthesis of evidence regarding herbal medicines and natural products by capturing relevant clinical trials published in East Asian journals that might not be indexed in Western databases. No restrictions on publication date or language will be applied to minimize selection bias. Additional studies will be identified through manual screening of the reference lists of all included articles. Representative search strategies for PubMed and CNKI are presented in Table 1.

Table 1.

Search strategy

No.	Search strategy for PubMed, Embase, and CENTRAL
#1	NSAIDs OR “nonsteroidal anti-inflammatory drugs” OR aspirin OR indomethacin OR diclofenac OR naproxen OR ibuprofen
#2	“small intestine” OR “small bowel” OR jejunum OR ileum
#3	enteropathy OR “mucosal injury” OR “intestinal injury” OR “capsule endoscopy” OR “intestinal permeability”
#4	“herbal medicine” OR “plant extract” OR “natural product” OR phytochemical OR botanical OR probiotic* OR synbiotic*
#5	“randomized controlled trial” OR randomized OR placebo
#6	#1 AND #2 AND #3 AND #4 AND #5
No.	Search strategy for CNKI
#1	非甾体抗炎药 OR NSAIDs OR 阿司匹林 OR 吲哚美辛 OR 双氯芬酸
#2	小肠损伤 OR 小肠黏膜损伤 OR 小肠溃疡 OR 肠道通透性 OR 胶囊内镜
#3	#1 AND #2

An asterisk (*) indicates truncation. Search syntax will be adapted according to the requirements of each database. For CNKI, a broad Chinese-language search strategy will be applied using NSAID-related and small-intestinal-injury-related terms. Eligibility for herbal medicines, natural products, functional foods, probiotics, or related interventions will be determined during title/abstract and full-text screening.

4. Study selection process and data handling

Study identification and screening will follow a predefined workflow. Prior to formal screening, a pilot calibration exercise will be conducted using a subset of records to ensure consistent application of the eligibility criteria. Screening will then proceed in two phases: title and abstract review followed by full-text review. Any discrepancies arising during the process will be resolved through discussion or, if necessary, consultation with a third reviewer. The study selection process will be illustrated using a PRISMA flow diagram (Fig. 1).

Figure 1.

PRISMA flowchart.

Relevant study information will be systematically extracted using a predefined data collection framework. Extracted variables include study characteristics (author, publication year, and country), participant characteristics (sample size, age, and underlying conditions), intervention and comparator details (including NSAID exposure and characteristics of herbal medicines or natural products), and outcome measures related to small intestinal injury, such as capsule endoscopy findings and intestinal permeability indices. Data extraction will be performed independently by two reviewers to enhance accuracy, and any discrepancies will be resolved through discussion.

5. Quality assessment

The risk of bias will be assessed using the Cochrane RoB 2 framework [28]. Assessments will be conducted across the following domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported result.

6. Statistical analysis

As appropriate, a quantitative synthesis will be conducted using established meta-analytic methods. Effect sizes will be estimated for both continuous and categorical outcomes, and between-study heterogeneity will be assessed. Statistical analyses will be performed using appropriate statistical software.

7. Additional analyses

If sufficient data are available, subgroup analyses will be conducted according to clinical purpose (prevention vs. treatment), type of NSAID used, intervention category, and outcome domain. Prevention and treatment studies will not be pooled together unless the clinical context, intervention, and outcome measures are sufficiently comparable. Sensitivity analyses will be performed to assess the robustness of the findings by excluding studies at high risk of bias. The overall certainty of the evidence will be evaluated using the GRADE framework [29], considering the methodological limitations, consistency, and precision of the findings.

DISCUSSION

NSAID-induced enteropathy has emerged as an increasingly important clinical issue, particularly in the context of widespread and long-term use of NSAIDs and aspirin [1, 2, 5]. Although substantial progress has been made in preventing upper GI complications, small intestinal injuries remain insufficiently addressed in current clinical practice [3, 4]. The lack of effective preventive or therapeutic strategies highlights a significant unmet clinical need [18, 19].

This protocol outlines a systematic review and meta-analysis designed to evaluate the efficacy of herbal medicines and natural products for preventing and treating NSAID-induced small intestinal injury. A key strength of this study is its emphasis on objective outcome measures. Unlike many previous reviews that relied primarily on subjective symptom-based assessments, this study will prioritize direct and quantifiable indicators of mucosal injury, such as VCE findings [11-13], and validated functional biomarkers, including measures of intestinal permeability [14, 15]. This approach is expected to enhance the reliability and clinical relevance of the synthesized evidence.

Another distinguishing feature of this review is its focus on the small intestine. Previous systematic reviews have often combined upper and lower GI outcomes or emphasized gastric mucosal protection [6, 25, 26], potentially obscuring the distinct pathophysiological characteristics of small intestinal injury [7, 13]. Although PPIs are considered the standard of care for upper GI protection, they do not protect against small intestinal injury and may potentially exacerbate this damage by suppressing intestinal motility [18] and inducing gut dysbiosis [22]. Despite advances in mechanistic understanding over the past decade, recent evidence indicates that small intestinal injury remains underrecognized and inadequately managed, resulting in substantial unmet therapeutic needs [19]. By limiting the scope to enteropathy, this study aims to provide a more precise evaluation of therapeutic interventions.

This review will additionally highlight the potential roles of herbal medicines and natural products as alternative or complementary therapeutic options. Individual clinical trials have reported promising effects across a range of interventions, spanning from traditional herbal formulations, such as the Weikang capsule [30], to natural minerals, such as muscovite [31], and dietary fibers [32]. Given the limitations of conventional pharmacological therapies, including the lack of efficacy of PPIs in the small intestine and their potential to exacerbate injury through dysbiosis [16-18], there is a growing interest in multitarget interventions, such as probiotics and synbiotics [33, 34], which can modulate oxidative stress, inflammation, and mucosal barrier dysfunction. The findings of this review may help clarify the clinical value of such interventions and inform future research into their mechanisms of action.

Despite the clinical importance of NSAID-induced enteropathy, global guidelines have been slow to provide specific preventive strategies. Although the Mexican Consensus on NSAID-Induced Gastropathy and Enteropathy [1] represents a significant step forward by explicitly addressing small intestinal injury, it also highlights the lack of robust evidence supporting effective therapeutic interventions compared with the available strategies for upper GI protection. This discrepancy highlights the persistent gap between clinical recognition and established treatment strategies and further justifies the need for a systematic evaluation of natural and herbal therapies.

Several potential limitations should be acknowledged. First, heterogeneity in study design, intervention types, and dosing regimens may limit the comparability of the included studies [12, 26]. Second, the number of eligible RCTs using objective outcome measures may be limited, which could affect the robustness of the quantitative analysis. Finally, publication bias cannot be excluded.