Plants with Anti-Ulcer Activity and Mechanism: A Review of Preclinical and Clinical Studies

Introduction

The need to replace certain drugs due to their adverse effects exemplifies the universal role of plants in the treatment of disease and the maintenance of health. The utilization of medicinal plants for the treatment of various ailments has been practiced since ancient times and is commonly referred to as phytotherapy.¹ The healing effects of medicinal plants come from the fact that they accommodate a wide range of secondary metabolites, called phytochemicals, which can be synthesized again and again in nature. The richest sources of active metabolites are contained in seeds, bark, roots, leaves, and fruits of plants. Therefore, a multitude of plants have employed these phytochemicals as a defense mechanism against pathogens.

Phytochemicals have been used since ancient times for the treatment of various disorders and are generally considered safer as compared to synthetic medicines.^2–4 They are widely available in nature, and apart from therapeutic purposes, they are also consumed in the form of nutritional supplements.⁵ Several plant-derived chemical constituents have been reported to possess anti-ulcerative properties in various preclinical studies. These constituents belong to the class of alkaloids, tannins, flavonoids, terpenoids, glycosides, carotenoids, and saponins.^6–8 Numerous botanical products have been confirmed to exhibit antiulcer activity although most studies focused on pharmacological action in animal models.

Ulceration is a crater-shaped lesion or wound that can form on the oral mucosa, large intestine (colon), and stomach mucosa. The formation of an ulcer may cause the region to bleed or discharge unpleasant materials, creating a painful sore that is susceptible to infection. Ulceration can be characterized by flaws in the epithelium, underlying connective tissue, or both. The diagnosis of ulcerative lesions may be difficult due to the wide range of potential causes and presenting characteristics of every organ.⁹ Despite the existence of various conventional and non-conventional treatment modalities for ulcer management, each approach is associated with certain limitations, including toxicity, low efficacy, and high cost.¹⁰ It is crucial to highlight the fact that botanical products may contain a multitude of active constituents that possess both hazardous and advantageous effects. Thus, it is important to use herbal therapy and put in place regulations to ensure the quality of herbal products, especially when it comes to doing more randomized studies to find out how effective and safe different products are at treating ulcer disorders.¹

Taking all into consideration, this review aims to provide an in-depth exploration of plants possessing anti-ulcer activity, elucidating their mechanisms of action through a combination of preclinical and clinical studies. By consolidating the current body of knowledge, this review aims to shed light on the potential of plant-based interventions as viable alternatives for the management of gastrointestinal ulcers. This review will encompass a thorough analysis of preclinical studies investigating various plant species and their active metabolites with demonstrated anti-ulcerative properties, as well as a critical evaluation of clinical trials investigating the efficacy and safety of plant-based interventions in ulcer management. Special emphasis will be placed on elucidating the underlying mechanisms, including their impact on gastric mucosal protection, modulation of acid secretion, anti-inflammatory effects, assessments of symptom relief, ulcer healing rates, and potential preventive effects on ulcer recurrence.

Methods

Initially, the search included references published from 2013 until 2023. Articles were searched in Scopus and PubMed, in addition to Google Scholar. Throughout the search process, synonyms and related terms were used interchangeably as keywords, and the Boolean operator “AND” was utilized to combine and exclude terms as follows: (1) in the Scopus database using the keywords Plants AND Anti-ulcerative Activity AND Clinical Studies, searched within Article title, Abstract, and Keywords, resulted in n = 6; using the keywords Plants AND Anti-ulcerative Activity searched within Article title, Abstract, and Keyword, resulted in n = 90; and using the keywords Plants AND Antiulcer AND Activity searched within Article title, Abstract, Keywords, resulted in n = 364, with a total of 460 articles from Scopus database; (2) in the PubMed database using the keywords Plants AND Anti-ulcerative Activity searched within Abstract, free full text, and in the last 10 years, resulted in n = 239.

All articles found through these searches were further screened and those that met the review’s inclusion criteria (open access, written in English, related to antiulcer activity studied in animal models and humans, not studied in cells or computational simulation), were retrieved and evaluated by the authors. Finally, 55 articles were selected, as depicted in Figure 1. However, during the process, an additional search was conducted to obtain more articles to support the discussion.

Figure 1 The study design of the review.

Results

Of the 55 articles, 50 discussed in vivo (preclinical) methods (Table 1) and 5 discussed clinical (human) studies (Table 2). For example, 16 articles described the mechanisms for peptic ulcer disease, 33 articles described the mechanisms for ulcerative colitis, and 3 articles described the mechanisms for aphthous ulcer. Moreover, 33 articles discussed the active metabolites that demonstrated mechanisms for healing ulcers. Of these studies, 5 confirmed the importance or empirical history of the plants that had mechanisms for healing ulcers.

Table 1 The Anti-Ulcerative Properties of Various Plants in Preclinical Studies

Table 2 The Anti-Ulcerative Properties of Various Plants in Clinical Studies

Most of the studies described Brazil (South America) and China as the origin locations of the plant collection, although other countries such as Iran, Egypt, Pakistan, Cameroon (Central Africa), Bangladesh, Poland, Malaysia, Korea, Nigeria (West Africa), and Indonesia were also mentioned.

In the preclinical studies, various types of ulcer inducers were used, eg, ethanol (9 articles), dextran sulfate sodium (8 articles), bethanechol (6 articles), acetic acid (6 articles), indomethacin (3 articles), histamine (2 articles), trinitrobenzene sulfonic acid (2 articles), and other inducers (pentagastrin, piroxicam, Helicobacter pylori, and a burnisher). Of those, rats (Rattus norvegicus) were more selected (54.54%) as the animal model than mice (Mus musculus) (45.45%). The description of the diseases is presented below.

Nine plants were confirmed for their strong anti-peptic ulcer disease activity in animal models, twenty plants have shown strong anti-ulcerative colitis activity, and no plant exhibited strong anti-aphthous ulcer activity. Studies in humans indicated that Nicotiana tabacum (Solanaceae), Glycyrrhiza glabra (Fabaceae), and Zingiber officinale (Zingiberaceae) possessed strong antiulcer activity.

Peptic Ulcer Disease (PUD)

Peptic ulcer disease (PUD) is characterized by the presence of damage or ulcers in the mucosal lining of the gastrointestinal tract (GI), which leads to the excessive secretion of gastric acid or pepsin. Typically, these symptoms appear within the gastric region and the proximal segment of the duodenum.⁵⁰ Peptic ulcer disease (PUD) is a global problem with a lifetime risk of development ranging from 5–10%.⁵¹ In general, there has been a global decline in the prevalence of peptic ulcer disease (PUD) as a result of enhanced hygienic and sanitary practices, as well as the implementation of effective treatment strategies and the cautious utilization of non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, epidemiological studies have demonstrated a reduction in peptic ulcer incidence, hospital admissions, and death but the case fatality rate has stabilized at 5–10%.⁵²

PUD has various multiple factors. Traditionally, mucosal disruption in patients with peptic disease is considered to be a result of a hypersecretory of acid together with dietary factors or stress. The primary risk factors associated with gastric or peptic ulcers are infection with H. pylori and the utilization of nonsteroidal anti-inflammatory drugs (NSAIDs).^53,54 Nevertheless, the incidence of PUD is relatively low among individuals affected by H. pylori or those who use NSAIDs. This suggests that individual susceptibility affects the initial onset of mucosal damage.

The primary goal of presently antiulcer medications is not only limited to controlling the progression of the disease. It also aims to induce remission as quickly as possible and to maintain it for a long time The management of PUD currently uses a variety of conventional treatment modalities, but it’s crucial to remember that each of these treatments has one or more negative side effects. The primary goal of currently used anti-ulcerative medications is not simply to manage the advancement of the ailment. It also aims to promptly initiate and sustain a state of remission over an extended period.^55,56 The primary negative consequences encompass gastrointestinal disruptions such as feelings of nausea, vomiting, constipation, and diarrhea, as well as impacts on the cardiovascular system.¹⁰

Based on the findings, it has been reported by the World Health Organization (WHO) that approximately 80–85% of the global population relies on natural products for disease management and nutritional supplementation. Botanical products are being utilized as alternative medicines for the treatment of various diseases due to their perceived safety in comparison to synthetic medicines.⁵⁷ An in vivo or preclinical study of the active metabolites in a plant showed that the metabolites treat peptic ulcer disease by protecting the gastrointestinal mucosa wall, reducing the effects of ulcers, decreasing or reducing the lesion area caused by ulcers, inhibiting cytokine pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, an ulcerative agent, and reducing the bacterial load on the gastric mucosa caused by Helicobacter pylori in the test animal, and clinical studies of the active metabolites showed that the combination of metabolites as a supplement makes a better treatment for PUD.

Ulcerative Colitis (UC)

Ulcerative colitis is a long-lasting inflammatory condition of the colon that causes the wall of the colon to become easily detached and wear away at the surface, often with bleeding. Typically, this condition is characterized by inflammation that is localized to the mucosal and submucosal layers of the colon. In general, the onset of the disease occurs within the rectum and progresses in a contiguous manner towards more proximal regions. Ulcerative has no cure and is a lifelong disorder with a significant impact on both physical and mental health.⁵⁸ The etiology of inflammatory bowel disease remains uncertain. The prominent independent risk factor of familial disease history, which is present in about 8% to 14% of affected people, suggests that a primary genetic component plays a significant role. Individuals who have a family diagnosed with ulcerative colitis are at a significantly elevated risk, approximately four times higher, of developing the same disease.⁵⁹

There is a growing emphasis in treatment strategies on achieving intestinal healing rather than solely focusing on symptomatic relief, to mitigate the likelihood of long-term complications and the need for surgical interventions.^60,61 Treatments can be broadly categorized as those employed to initiate remission, either at the time of diagnosis or during a subsequent flare-up.⁶² Currently, the dietary management is to improve symptoms while offering support. In recent years, there has been a notable shift in dogma toward the utilization of dietary therapies that target specific mechanisms to induce disease remission.^63–65 Most research has focused on how the immune system changes in the early stages, but over the past 20 years, a lot of evidence has shown that ulcerative colitis (UC) is mostly a disease of the epithelial tissue.⁶⁶ The pathogenesis of the colonic epithelium is mostly caused by metabolic defects, which play a key role and may contribute to the breakdown of the mucosal barrier. Consequently, the epithelium may experience additional harmful effects due to the presence of microbial metabolites, such as hydrogen sulfide (H₂S) and nitric oxide (NO), which can be toxic when present in excessive amounts.⁶⁷

People with UC can get relief from their symptoms through a variety of pharmacological interventions. However, a large number of these therapeutic medications are linked to serious side effects.⁶⁸ Therefore, researchers are currently placing increased emphasis on natural compounds,⁶⁹ as they have the potential to mitigate adverse effects. A clinical study of gingerol and shogaol, which are the active metabolites in the Zingiber officinal plants, found that they were more likely to cause a clinical response and significantly improve a patient’s quality of life.⁷⁰ Recent research has shown that using natural lipid nanoparticles (nLNP) loaded with 6-shogaol (6S/nLNP) can effectively change the types of bacteria in the gut, cause metabolic changes in feces, and reduce inflammation in a model of acute colitis caused by DSS.⁷¹ An in vivo or preclinical study of the active metabolites in a plant showed that the active metabolites inhibited cytokine pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, an ulcerative agent, in the test animal, also the metabolites protected colon mucosa from ulceration through their strength aspect, such as antioxidant, or anti-inflammatory. According to preclinical and clinical studies.

Aphthous Ulcer (Mouth Ulcer)

Aphthous ulcers, also known as mouth ulcers, show inflamed spots with a white-reddish appearance that develop on the mucous membrane that lines the oral cavity. Despite being painful, these injuries generally undergo spontaneous healing and do not result in any complications. There is variation in the recurrence of canker sores, with certain individuals experiencing a reoccurrence within a few weeks, while others may encounter them after months or even years.⁷²

Aphthous stomatitis is estimated to impact around 20% of the overall population. The prevalence of this phenomenon is slightly higher among females and individuals from affluent socioeconomic backgrounds and countries. Most people get them for the first time when they are a teenager or young adult. The age of onset may be during childhood, but more commonly in the second and third decades of life, becoming less common with advancing age. This disease is more common in women than in men. The cause of aphthous stomatitis is idiopathic and multifactorial but likely involves activation of the cell-mediated immune system. Since acute infections are not the cause of aphthous ulcers, they are not contagious. Local trauma, emotional or physiological stress, allergy or sensitivity, menstruation, or changes in the oral microbiome can all cause aphthous stomatitis. Aphthous ulcers are more prevalent in nonsmokers and smokers who quit and less common in individuals with good oral hygiene practices.^73–75

The present treatment plan for this disease primarily focuses on managing symptoms, aiming to alleviate pain, facilitate lesion resolution, and extend the duration between episodes.⁷⁶ The primary strategy for the treatment is to control the inflammation, suppress the inflammation-associated cells’ activity, reduce the pain of the lesion, and accelerate the healing process.⁷⁷ The most commonly used anti-inflammatory agents to treat oral cavity inflammations are topical corticosteroids.⁷⁸

Biological and laser therapies have emerged as novel therapeutic modalities for the treatment of mucosal diseases, garnering considerable anticipation in the medical community. Changes in oral microbiota have been linked to the development,⁷⁹ which paves the way for probiotic treatments that can be put directly in the mouth. However, long-term exposure to these medications may cause drug resistance, oral flora imbalance, and secondary fungal infections.⁸⁰

Natural extracts have already been proven effective for managing other oral health problems, apart from ulcers. Several clinical studies have shown the positive effects of natural extracts in reducing the pain and duration of mouth ulcers.^45,79,80 A clinical study revealed that patients with aphthous ulcers treated with Nicotiana tabacum E. metabolites were likely to show reduced ulcer lesions compared to placebo, which was the control of the randomized control trial. The metabolites contributed to the suppression of pro-inflammatory cytokines and decreased the size of lesions on oral mucosa.⁴⁶

Discussion

The investigation of anti-ulcerative activity has also encompassed the study of isolated metabolites derived from plants. The phytochemical constituents in plants have a variety of functions in anti-ulcerative activity, for example, alkaloids were reported for their anti-ulcerative effects by modulating the gastric acid secretion and cytoprotective properties.⁸¹ Flavonoids exhibit potent anti-inflammatory and antioxidant activity, contributing to ulcer healing and mucosal protection.⁸² Saponin has been found to inhibit gastric mucosal injuries induced by factors such as ethanol or indomethacin.⁸³ Tannins, a type of phytochemical can form protective barriers on the mucosal surface,⁸⁴ and polyphenols, which are also found in plants have multifaceted actions, such as anti-secretory and anti-inflammatory effects.⁸² Hence, plants are paving the way for the development of targeted and efficacious treatments for ulcerative disorders. The assessment of potential anti-ulcerative activities in plants that are often used to treat ulcers is a very important step in proving that these plants work as medicines. Various plant materials may exhibit multiple types of anti-ulcer effects, including safeguarding the mucosa against ulcers and impeding pro-inflammatory cytokine activity. This is attributed to the fact that individuals with chronic wounds, such as ulcers, tend to have elevated systemic and local levels of TNF-α.

The mitogen-activated protein kinase (MAPK) pathway plays a crucial role in the regulation of pro-inflammatory cytokine production, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). This substance is classified as a proinflammatory cytokine that is rapidly secreted in response to an inflammatory stimulus. It plays a critical role in initiating various intracellular processes and is involved in the development of both acute and chronic inflammatory responses. This leads to the activation of nuclear factor kappa B (NF-kappaB), as well as the promotion of the release of additional pro-inflammatory cytokines, chemokines, and proteases.⁸⁵ The overproduction of TNF-α has a direct correlation with various inflammatory disorders, including arthritis and inflammatory bowel disease. Consequently, regulating TNF-α levels can serve as an effective therapeutic approach for managing these diseases.⁸⁶

Cytokine proinflammatory factors, such as IL-1, TNF-α, IL-6, and IFN-γ, were found to be upregulated.⁸⁷ These factors are known to be involved in gastric inflammation caused by H. pylori. The involvement of the acute phase response pathway and NF-kappaB signaling pathways was also suggested.⁸⁸ TNF-α plays a key role in mediating inflammatory events, involved in both acute and chronic responses.⁸⁹ IL-6 produces an acute phase response, promoting the induction of intracellular signaling cascades, which give rise to the production of other inflammatory cytokines.⁹⁰ At first, proinflammatory cytokines help acute wounds heal by boosting the growth of keratinocytes and making them make more antimicrobial peptides. Nevertheless, excessive production of proinflammatory cytokines can result in the persistence of inflammation and impaired wound healing.^91,92 Hence, the therapeutic efficacy of chronic wound healing can be attributed to the inhibition of excessive proinflammatory cytokines.⁹³ The extract contained phenolic compounds that demonstrated antioxidant properties by inhibiting oxidative stress, reducing the production of nitric oxide (NO), and preventing the activation of p38. Consequently, this inhibition led to the suppression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), thereby exhibiting anti-inflammatory and antiulcerogenic effects.¹⁶

The suggested mechanisms of action are explained through cytoprotective mechanism (causing an increase in gastric mucus), antioxidant activity (preventing depletion of sulfhydryl groups and reducing levels of lipid peroxidation and myeloperoxidase activity in the gastric mucosa), and finally healing ability.^94,95 The small size of metabolites facilitates their passage through the mucus layer, enabling them to interact with colonic cells and initiate immune responses.^91,93,96,97 Hence, metabolites derived from plants possess the potential to modulate the advancement of intestinal inflammation, thereby offering translational prospects.⁷¹ Ulcer, being a chronic inflammatory disease, exhibits distinct characteristics during the progression of chronic inflammation in the colon.⁹⁸ Notably, the integrity of the mucus layer remains largely unaffected, and the permeability of the epithelial lining undergoes minimal alterations. In contrast, the acute colitis model demonstrates significant compromise to both the mucus layer and the permeability of the epithelial lining.⁷¹

In the present study, we found two plants with double anti-ulcerative activities, ie, T. erecta (strong anti-peptic ulcer disease and anti-ulcerative colitis) and M. citrifolia (strong anti-ulcerative colitis and weak anti-aphthous ulcer), thus presuming their potential to be further developed as anti-ulcer botanical drugs.

Conclusion

This review elaborates on an overview of the preclinical and clinical studies that have been done on medicinal plants. It focuses on how well they work to treat conditions such as peptic ulcer disease (PUD), ulcerative colitis (UC), and aphthous ulcers. The phytochemicals and pharmacological properties have also been elucidated. These active metabolites, derived from various plant sources such as alkaloids, flavonoids, tannins, saponins, and polyphenols, have a variety of functions in the treatment of ulcers and contribute synergistic interactions to the anti-ulcerative efficacy of plant extracts. For most of the plants that have been looked at, however, there is a clear lack of anti-H. pylori activity and clinical studies on metabolites derived from plant studies. The opportunity to conduct such studies is available to determine whether these plants possess both clinical and non-clinical properties. Also, there is a limitation of the study, we found that not all articles explain the controls used in preclinical and clinical studies, not all articles explain where and when the plants were collected, and not all articles explain the extraction method and solvent used which makes this article a constraint. More pharmacological activity assays are needed to figure out the mechanism of how each metabolite works, for example, by studying what proteins, pathways, or genes are altered by the plant extract or metabolite. These studies will be essential to validate the potential use of these metabolites in the treatment of ulcers. From a future perspective in the realm of plants, we can anticipate the isolation and synthesis of the active metabolites from plants for their capability as targeted therapies with enhanced efficacy and reduced potential for adverse effects. This review provides a piece of scientific evidence supporting the utilization of plant metabolites as a potential therapeutic approach for the treatment of ulcers.