Harnessing nature’s pharmacy: investigating natural compounds as novel therapeutics for ulcerative colitis

Backgrounds Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease, and UC diagnosis rates continue to rise throughout the globe. The research and development of new drugs for the treatment of UC are urgent, and natural compounds are an important source. However, there is a lack of systematic summarization of natural compounds and their mechanisms for the treatment of UC. Methods We reviewed the literature in the databases below from their inception until July 2023: Web of Science, PubMed, China National Knowledge Infrastructure, and Wanfang Data, to obtain information on the relationship between natural compounds and UC. Results The results showed that 279 natural compounds treat UC through four main mechanisms, including regulating gut microbiota and metabolites (Mechanism I), protecting the intestinal mucosal barrier (Mechanism II), regulating intestinal mucosal immune response (Mechanism III), as well as regulating other mechanisms (Mechanism Ⅳ) such as cellular autophagy modulation and ferroptosis inhibition. Of these, Mechanism III is regulated by all natural compounds. The 279 natural compounds, including 62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others, can effectively ameliorate UC. Of these, terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC. It is noteworthy to highlight that a total of 54 natural compounds exhibit their therapeutic effects by modulating Mechanisms I, II, and III. Conclusion This review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC. Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future.


Introduction
Ulcerative colitis (UC) is an idiopathic, chronic, inflammatory bowel disease (IBD) characterized by continuous inflammation starting from the rectum (Hoivik et al., 2013;Conrad et al., 2014;Nanki et al., 2019).World Health Organization has classified UC as a clinically intractable disease.Its global prevalence and incidence have been increasing with time; currently, its incidence and prevalence are 8-10 cases/ 100,000 subjects and 150-200 cases/100,000 subjects, respectively (da Silva et al., 2014;Ungaro et al., 2017).The annual UC treatment costs (direct and indirect) are estimated to be approximately US$8.1-14.9 billion and €12.5-29.1 billion in the United States and Europe, respectively (Cohen et al., 2010).
UC is primarily treated with medicines, including aminosalicylates, immunomodulators, steroids, and biologics.However, due to potential adverse reactions and reduced efficiency of standard therapies, a comprehensive search for the identification of novel and natural medicines has been initiated to replace or complement present treatment options (Pastorelli et al., 2009;Wan et al., 2014).Many researchers are now turning to natural resources to seek effective compounds that can be used against UC (Cao et al., 2019).
Currently, there are some reviews on natural compounds and UC, such as summarizing some natural compounds or a class of compounds.These studies are significant for finding drugs for UC, but there is still a lack of systematic summaries.Therefore, this study reviews the current progress made in the intervention of natural compounds in UC, and provides a complete overview of natural compounds and their mechanisms of action.More importantly, we hope that such a systematic summary will lead to important natural compounds and mechanisms of action for the treatment of UC.This review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC.Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future.increasing meat, egg, and milk product intake, is the main reason for the increase in the prevalence of UC.Furthermore, although smoking cigarettes is a critical Crohn's disease (CD) risk factor, quitting it has been linked to UC.According to a meta-analysis, smoking is more protective against UC than not smoking (Mahid et al., 2006).UC individuals who smoked had a milder disease course than non-smokers.UC is harsher for those who stop smoking.It may be mediated by carbon monoxide that can suppress interleukin-10 (IL-10) through a heme oxygenase (HO)-1-dependent pathway in UC mice (Sheikh et al., 2011).

Immune-mediated factors
The immune response is intricately associated with the pathophysiology of UC.The buildup of innate lymphoid cells (ILC), natural killer (NK) cells, macrophages, dendritic cells, neutrophils, and abnormal T and B cells inside the intestinal mucosa, along with the production of chemokines and cytokines that may trigger an inflammatory response.This inflammatory process can lead to the disruption of the intestinal mucosa and ultimately result in the development of UC (Liu Y. et al., 2022).

Gut microbial factors
The gut microbiota directly impacts the maintenance of homeostasis in the intestinal pro-inflammatory and antiinflammatory responses.Germ-free conditions prevent the development of colitis in genetically susceptible mice (Veltkamp et al., 2001).Moreover, the introduction of proinflammatory bacteria or microbiota from patients with UC into healthy mice can induce inflammation (Ohkusa et al., 2003), while colonization of mice with intestinal microbiota from donors with IBD exacerbates colitis by modulating immune responses (Britton et al., 2019).

Genetic factors
Genetic factors have also been linked with UC. 12% of UC patients have a family history of IBD (Childers et al., 2014).Genome-wide association studies have identified 200 risk loci for IBD to date, with most genes contributing to both UC and CD phenotypes (Jostins et al., 2012;Liu et al., 2015).Examples of loci associated with increased UC susceptibility include human leukocyte antigen and genes associated with barrier function, such as HNF4A and CDH1 (Consortium et al., 2009).In addition, with increasing knowledge about UC pathogenesis, natural compounds have become a research hotspot because of their more efficient application prospects for preventing and mitigating UC occurrence and development.

The mechanism of natural compounds in intervention UC
We reviewed the scientific papers in the databases below from their inception to July 2023 to identify the studies relevant to the mechanism and activity of natural compounds against UC: PubMed, Web of Science, Wanfang Data, and the China National Knowledge Infrastructure.The present study provides a comprehensive summary of 279 natural compounds demonstrated to treat UC through various mechanisms primarily.These mechanisms include regulating gut microbiota and metabolites (Mechanism I), protecting the intestinal mucosal barrier (Mechanism II), regulating intestinal mucosal immune response (Mechanism III), as well as the other mechanisms (Mechanism Ⅳ) such as cellular autophagy modulation and ferroptosis inhibition (as depicted in Figure 2; Supplementary Table S1).It is noteworthy to highlight that Mechanism III is regulated by all natural compounds; Mechanisms II and III can be modulated by at least half of the compounds.Research on these mechanisms may give information on the etiology of UC.

Regulating gut microbiota and metabolites
The available evidence indicates that UC is an increased immune response in the mucosal lining, which is triggered by an imbalance in particular gut bacteria.This condition is defined by an abnormal composition of the microbiota and the presence of bacterial products.According to the data shown in Supplementary Table S1, there has been extensive research conducted on natural compounds to investigate their prebiotic qualities.These compounds have been found to have an impact on the makeup of the microbiota and its metabolites, as well as the prevention of colonization by intestinal pathogens and the reduction of the risk of recurrence of ulcerative colitis, as illustrated in Figure 3.
The present study has specifically examined the impact of pharmaceutical substances on the composition and diversity of the gastrointestinal microbiota.However, the gut microbiota exerts a significant influence on the chemical alteration, pharmacological action, and metabolic mechanisms of natural compounds (Zhao et al., 2022a).Certain gut microorganisms possess the ability to break down and convert organic substances, resulting in the production of metabolites and functional chemicals that exhibit physiological actions that are not naturally generated by the host organism (Koppel et al., 2017).There is currently a significant amount of research being dedicated to comprehending the distinct ways in which microorganisms alter natural products and the consequent effects of these metabolites on the health of the host organism (Luca et al., 2020).This is a matter that warrants further investigation in our research.

Protecting intestinal mucosal barrier
The intestinal mucosal barrier damage is a crucial UC characteristic (Ungaro et al., 2017).Complete healing of intestinal mucosa is the most desired goal in UC treatment (Du et al., 2020).As shown in Supplementary Table S1, natural compounds can improve the barrier function of the UC mucosa through multiple perspectives, these include upregulation of the expression of tight junction protein, reduction in the intestinal mucosal, permeability, regulation of the intestinal mucus function, reduction of oxidative stress, and protection of the intestinal epithelial cells (Figure 4).

Decreased permeability of intestinal mucosal
The permeability of the intestinal mucosa controls the transport of molecular substances across the epithelium of the intestinal mucosa by the process of simple diffusion.Increased mucosal permeability (Nakarai et al., 2012) has been reported in UC patients (Wang et al., 2022), allowing the entrance of intestinal pathogens as well as their toxic metabolites in the liver, lymph, peripheral tissues, and blood, causing enhanced oxidative stress and inflammation.Intestinal permeability allows accurate, direct, and quantitative evaluation of the colonic epithelial barrier (Huang et al., 2016).Generally, FITC-dextran (fluorescein isothiocyanate dextran) permeability is utilized for the elucidation of epithelium integrity.It has recently been revealed that after taking FITC-dextran orally, the serum of DSS mice had markedly increased FITC-dextran levels (Zhang et al., 2022c).Interestingly, berberine (Zheng et al., 2021), cannabidivarin (Pagano et al., 2019), dioscin (Cai et al., 2021), ginsenoside compound K (Wang et al., 2022), luteolin (Xie et al., 2022), platycodin D (Guo et al., 2021), vitexin (Zhang et al., 2022c), and wogonoside (Huang et al., 2020), can decrease serum FITCdextran level in UC animals.

Regulating intestinal mucosal immune response
The intestinal mucosal immunological disorder is the essential factor for UC pathogenesis, characterized by innate immune system alterations, adaptive immune system activation, increased proinflammatory mediators, and anti-inflammatory signals inhibition, causing chronic intestinal inflammation.Currently, 283 natural compounds have been indicated to improve mucosal immune response in UC, primarily by regulating cytokine, inflammatory signaling pathways, and immune cells as shown in Figure 5.
Interestingly, these compounds are mainly phenols.The endoscopic findings consistently indicate that supplementation with phenols has demonstrated benefits in individuals with IBD.However, to acquire a more comprehensive understanding of the influence of phenols, it is necessary to conduct long-term trials that incorporate both clinical and mechanistic investigations (Hagan et al., 2021).

Regulating intestinal mucosal signaling pathways
The pathogenesis of UC is associated with multiple complex inflammatory signaling pathways.Natural compounds directly or indirectly interact with the immune system, stimulating different  S1.
molecular and cellular pathways and producing anti-inflammatory effects.Therefore, UC prevention and therapy by natural molecules regulate one or more complicated signaling pathways.

Inhibition of the ROCK-MLC signaling pathway
The Ras homologous protein A-Rho kinase (RhoA-ROCK) signaling pathway modulates TJ synthesis, polymerization, and epithelial cell gap permeability, typically linked with the ROCK-MLC pathway (Liu et al., 2020).ROCKs is a serine-threonine kinase family member, including Rho-associated kinase 1 (ROCK1) and ROCK2.ROCK1 directly modulates myosin light chain 2 (MLC2) activation and myosin contraction for TJ depolymerization, accompanied by increased intercellular permeability (Fu et al., 2019).According to a study, UC animals have increased ROCK1 and MLC2 phosphorylation in the colon; however, barbaloin (Gai et al., 2019), geniposide (Xu et al., 2017), and βpatchoulene (Liu et al., 2020) substantially downregulate them to improve the colonic barrier.

Regulation of the Wnt/β-catenin signaling pathway
It has been observed that the Wnt signaling pathway substantially affects epithelial cell proliferation to repair mechanical barriers (Kuhnert et al., 2004).Wnt modulates βcatenin expression and is involved in the pathological and physiological mechanisms of injury (Whyte et al., 2012).Multiple research indicates that berberine (Dong et al., 2022c) and 6-gingerol (Ajayi et al., 2018) alleviate UC by maintaining intestinal mucosal barrier function and structure and function, regulating the homeostasis of intestinal mucosal immunity via the Wnt/βcatenin pathway.

Inhibiting ferroptosis
In 2012, ferroptosis was formally stated as an iron-dependent, non-apoptotic cell death manifested by the accumulation of lipid peroxidation products and the depletion of membrane polyunsaturated fatty acid (Dixon et al., 2012).It is characterized by lipid peroxidation, iron accumulation, and increased ROS generation.Iron sagging includes iron deposition, increased lipid peroxidation, reduced GSH, inactivation of glutathione peroxidase 4 (GPX4), and enhanced lipoxygenase (LOX), all of which are linked with UC pathogenesis (Huang et al., 2022).These findings validate that ferroptosis inhibition might be a novel target for treating UC (Wang et al., 2020;Chen et al., 2021;Dong et al., 2021;Tang et al., 2021).β-Caryophyllene is widely found in various plant essential oils, and its flavor and fragrance resembles bicyclic sesquiterpene (Jha et al., 2021).A study revealed that β-caryophyllene acts as an inhibitor of ferroptosis that represses lipid peroxidation and inflammation, thereby alleviating UC (Wu et al., 2022).

Regulating metabolism pathway
The literature suggests that metabolic reprogramming can regulate the activation of macrophages.The metabolic signals furnish energy and polarize macrophages.M1 macrophages substantially depend on glycolytic metabolism, whereas M2 primarily depends on oxidative phosphorylation (Saha et al., 2017).Glucose is converted to pyruvate and lactic acid glycolysis via a series of cytoplasmic enzymes.Pyruvate dehydrogenase kinase 1 (PDK1) knockdown is a key modulator enzyme of glucose metabolism, reducing M1 but enhancing M2 macrophage activation (Tan et al., 2015).Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) reduces M1 macrophage activation and proinflammatory cytokines secretion (Wang et al., 2018).It has been revealed that tiliroside alleviates UC by restoring the M1/ M2 macrophage balance via the HIF-1α/glycolysis pathway (Zhuang et al., 2021).

Inhibiting endoplasmic reticulum stress responses
The endoplasmic reticulum (ER) is an essential cellular organelle with multiple functions to store free calcium and synthesize, mature, and transport various lipids, proteins, sterols, etc.Because of multiple cellular factors, proteins are unable to fold correctly, resulting in the accumulation of newly synthesized unfolded proteins in cells, thereby promoting ER stress (Song et al., 2021).Much research indicates that ER stress is associated with UC progression.Highly secretory cells, such as intestinal paneth and goblet cells, are specifically impressionable to ER stress (Kaser et al., 2010).Inhibition of ER stress responses is thus an important therapeutic rationale for UC.Limonin might be utilized for this purpose as it blocks the PERK-ATF4-CHOP pathway of ER stress (Song et al., 2021).Furthermore, berberine (Shen et al., 2020) and artesunate (Yin et al., 2021) reduce ER stressrelated marker proteins (glucose-regulated protein, GRP78, C/EBP-homologous protein, CHOP) to treat UC.

Analysis of important natural compounds
Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy for the search of new drug candidates.Therefore, we analyzed the relationship between the 279 natural compounds and mechanisms covered in this review.The 279 natural compounds, including 62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others, can effectively ameliorate UC.Of these, terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC.It is noteworthy to highlight that a total of 54 compounds are linked to Mechanism Ⅰ, Ⅱ, and Ⅲ; 151 compounds are associated with Mechanism Ⅰ and Ⅱ; 18 compounds are associated with Mechanism Ⅱ and Ⅲ; 4 compounds are associated with Mechanism Ⅰ; 50 compounds are associated with Mechanism Ⅱ; 2 compounds are related to Mechanism Ⅲ (Figure 6).
Furthermore, we conducted a comprehensive search of the Pubchem and Drugbank databases to obtain pertinent data regarding the clinical studies associated with the aforementioned natural compounds.Consequently, a total of 6 compounds (andrographolide, berberine, berberine hydrochloride, butyrate, curcumin, and diosmin) for the therapeutic management of UC were identified to be either in the clinical stage of development or already available on the market (Table 1).Interestingly, the vast majority of these compounds can alleviate UC by Mechanism Ⅰ, Ⅱ, and Ⅲ.This indicates that we should pay more attention to the compounds with multiple mechanisms in the follow-up UC drug research (Figure 7).
Many synthetic drugs are currently in use to treat UC such as 5-aminosalicylic acid (5-ASA) (Hossen et al., 2020).Therapeutic mechanisms of 5-ASA for UC include inhibition of cyclooxygenases and lipoxygenase, activation of peroxisome proliferator activated receptor γ, inhibition of T-cell proliferation and activation, reduction of chemotaxis, adhesion and phagocytosis, inhibition of nuclear factor-κβ (Hauso et al., 2015).Overall, 5-ASA appears to exert its therapeutic effect by topical action on the affected areas of inflammation.This is the Displays the total amount of natural compounds associated with various mechanisms.The natural compounds involved in this paper are shown in Supplementary Table S1.54 natural compounds that can treat ulcerative colitis by regulating multiple mechanisms (Mechanism Ⅰ, Ⅱ, and Ⅲ).
Frontiers in Pharmacology frontiersin.org14 Huang et al. 10.3389/fphar.2024.1394124same as one of the mechanisms (Mechanism III) by which natural compounds treat UC.However, the mechanism of natural compounds against UC is more complex compared to synthetic drugs.Furthermore, 5-ASA have some drawbacks as long-term use results in side effects including nausea, vomiting, fatigue, diarrhea, abdominal pain, pulmonary fibrosis, etc (Rogler, 2010).For centuries, herbal treatments have shown their potential to ameliorate countless diseases and disorders with no or fewer side effects.In conclusion, natural compounds have a richer mechanism for treating UC than synthetic drugs, and natural compounds are more abundantly available and have fewer side effects.

Concluding remarks and future directions
This review provides a comprehensive overview of the protective effects exhibited by natural substances against UC, while also delving into their probable mechanisms of action in mitigating colitis.Results indicated that 279 natural compounds (62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others) can act on various mechanisms to improve UC, such as regulating gut microbiota and metabolites (Mechanisms I), protecting the intestinal mucosal barrier (Mechanisms II), regulating intestinal mucosal immune response (Mechanisms III), as well as the other mechanisms (cellular autophagy modulation and ferroptosis inhibition).More importantly, (1) 54 natural compounds exhibit their therapeutic effects by modulating Mechanisms I, II, and III, which can be used to develop multitargeted drugs for UC; Terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC. (2) Mechanism III is regulated by all natural compounds; Mechanisms II and III can be modulated by at least half of the compounds, which may give information on the etiology of UC.In conclusion, this review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC.Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future.

FIGURE 3
FIGURE 3Illustrates the utilization of natural compounds in the management of ulcerative colitis through the modulation of gut microbiota and metabolites.Red pentagrams indicate compounds involved in Mechanism Ⅰ, Ⅱ, and Ⅲ.The natural compounds involved in this paper are shown in Supplementary TableS1.

FIGURE 4
FIGURE 4 Natural compounds against ulcerative colitis via intestinal mucosal barrier protection.Red pentagrams indicate compounds involved in Mechanism Ⅰ, Ⅱ, and Ⅲ.The natural compounds involved in this paper are shown in Supplementary TableS1. S1 .

FIGURE 5
FIGURE 5 Natural compounds against ulcerative colitis via regulation of intestinal mucosal immune response.Red pentagrams indicate compounds involved in Mechanism Ⅰ, Ⅱ, and Ⅲ.The natural compounds involved in this paper are shown in Supplementary TableS1.

TABLE 1
Natural compounds in clinical trials for the treatment of ulcerative colitis.
Note: Drugbank and Pubchem databases were used to obtain natural compounds used in clinical studies.