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Table 8 Potential phytoconstituents for inammatory bowel syndrome treatment and related diseases

Class/phytochemical constituents Pharmacological activity References Flavanoids—Naringenin Facilitate monocyte chemotaxis and colonic secretion of pro- inammatory factors

(ICAM-1, iNOS). Downregulate mRNA expression of TNF-α, Cox2, reduced the expression of NF-κB

Catechins

Rutin Decrease MPO activity, inhibit the IL-17, and NO syntheses, increase IL-4, reduce

Hesperetin Decrease the protein expression of p-JAK2 and P-STAT3, reduce the MPO, MDA,

Genistein

Anthocyanin Improve gut microbiota [292] Farrerol

Icariin

Quercetin

Myricetin and Kaempferol

Resveratrol

Apigenin

Luteolin Suppress the JAK/STAT pathway, the activation of the Nrf2 signalling pathway,

Terpenoid—Ginsenoside Inhibit macrophage activity, modulate Th1/Treg cell differentiation, reduce the

Limonin Reduce the disease activity index (DAI), downregulate the p-STAT3/miR-214 [121] Geraniol

Ursolic acid Suppress the JNK/JAK/STAT signalling pathway, upregulate T-SOD and CAT [298] Glycyrrhizic acid

Polysaccharides- Astragalus polysaccharide

Laminarin Suppress the proliferation of the pathogenic bacteria, decrease ICAM-1, IL-2 [301] Alkaloids—Oxymatrine Facilitate the Th1/Th2 cytokines balance, reduction of colonic IL-2 expression,

Piperine Reduce MPO and MDA activity, upregulate PXR, Cyp3aII, MDR1a, mRNA,

Boldine

Skimmianine

Aloperine Upregulate the Foxp3 levels, inhibit the colonic p-PI3K p85, p-mTOR, and p-Akt

N-methylcytisine

Improve Th1/Th2 balance and reduce TLR4/MyD88/NF-κB pathway expression. Suppress level the IL-6, MCP-1, TNF-α, reduce the MPO and LPO activity

the IL-1β, and suppress the proinammatory cytokines

and pro- inammatory levels Increase the protein expression of SOCS3

Facilitate the M1 macrophage to M2, reduced IL-6, TNFα, MCP-1, IL1β

Reduce the expression of TNF-α, IL-6, and IL-1β by suppressing the phosphorylation of NF-κB

Suppress p-STAT1, p-STAT3, and p-p65 expressions, inhibit the IL-6, TNF-α

Inhibit the cytokine production, induce NOS through suppression of NF-κB signalling pathway, regulate MPO activity, MDA level, increase GSH content, improve intestinal oxidative stress, decrease TNF-α, IFN-γ, IL-17A, IL-6, COX-2, iNOS, IL-1β levels Activate Nrf2, upregulate the expression of Interleukin-10 and reduce gut inammation

Decrease pro-inammatory factors such as IL-6, IL-1b, TNF- α, and iNOS Upregulate the expression of trefoil factor family3 (TFF3) gene, TGF-1β, and IL-10

Decrease IL-1β, TNF-α, IL-1β, IL-6, MPO activity, SphK1 activity. Downregulate NLRP-3, Wnt/β-catenin pathway, SUMO1

Induce protective cytokines and enzyme, reduce Cox-2, MMP-3, iNOS, TNF-α and IL-1b via inammasome pathway, decrease MPO activity

and increase the intestinal ora (Lactobacillus, Prevotella-9)

NLRP3 inammasome via the AMPK pathway and JNK activation, decrease IL-1β, IL-6, TNF-α, inhibit LPS and TLR4, and recover the balance of Th17, Tregs. Activate the TGF-β signalling pathway, suppress the MAPK and NF-κB signalling pathway

Decrease TNF- α, IL-1β, IL-6, MPO activity, iNOS and COX-2, inhibited NF-κB (p65)-DNA binding

Reduce IL-6 production, decrease the expression level IL-1β, IL-α, increase IL-10

Regulate TNF-α, IL-1β, and NFATc4 expressions, facilitate expression of GATA-3 and T-bet, balance, reduce the NF-ĸB phosphorylation and downregulate IL-6, IL-1β, and TNF-α

increase IL-10 levels, inhibition of p65 NF-kB and increase 2-β-adrenergic receptor (2BAR), decrease TNF-α and IL-6, ICAM-1

decrease ICAM, iNOS, IL-1β, MCP-1, IL-6, IL-1β, TNF-α, increase SOD activity

Reduce MPO and MDA activity, decrease TNF-α, IL-6, IL-17, N and F κB expression, and increase IκB-α expression

Reduce the expression levels of LBP, TNF-α, NFκB, TLR4, PGE2

expressions, upregulate the protein phosphatase 2A (PP2A) expression and suppress the PI3K/Akt/mTOR signal transduction pathway

Suppress pro-inammatory factors via activates NF-κB

E. R. Puppala et al.

[93]

[289]

[290]

[102]

[291]

[103]

[293]

[294]

[92]

[272]

[295]

[296]

[116]

[297]

[299]

[300]

[302]

[303]

[84]

[304]

[92]

[305]

Herbal Medicines fortheManagement ofIrritable Bowel Syndrome andConstipation Problem

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(continued)

Table 8

Class/phytochemical constituents Pharmacological activity References Berberine

Theophylline Decrease the cytokine levels (IL-6, IL-1b, and TNF-a) and MPO activity and

Cavidine

Pentoxifylline Decrease the MDA levels, TGF-b1 MPO, MMP-1, and MMP-3 levels [309] Fatty acid—oleic acid

Linoleic acid The histological score is improved by decreasing MPO and alkaline phosphatase

Vitamin E—α-tocopherol

Iridoid

—Secoiridoids-

Oleuropein Acids—Sinapic acid Decrease MPO activity, facilitate SOD, GSH-Px, and catalase, and downregulate

Suppress STAT3, NF-κB signalling, reduce IL-1, IL-1β, IL-6, IL-12, TNF-α, TGF-β, and interferon-γ, upregulate IL-4 and IL-10 expressions. Downregulate the MPO and MDA activity, decrease the IκB degradation

activating the Nrf2/HO-1 signalling increase the IL-4, decrease AMCase and CHI3L1 expression

Reduce NF-κB, TNF-α, IL-6, MPO, and MDA activity, increase SOD activity

Decrease expression of p65, upregulate PPARγ

activity, TNFα, IL-1β, and LC n-6PUFA Decrease MPO, MDA, and alkaline phosphatase activity; inhibit NO, PGE2,

TNF-α, iNOS, COX-2 Reduce MDA, MPO, and NO levels and elevate SOD, CAT, and GPX levels.

Reduce the expression of Bax and increase the Bcl2 expression

the NLRP3 inammasome Increase the expression of ZO-1, occluding and Claudin-1

[306]

[307]

[308]

[310]

[311]

[312]

[313]

[314]

331

had overcome the challenges faced by pharmacokinetics and pharmacodynamics. These nanomedicines are available with unique characteristics such as a size range of ~ 100nm, several coated delivery systems, which include transferases; liposomes; dendrimer; solid lipids; microspheres, and cellular carriers such as recombinant bacteria and macrophages [316].

4.2 Natural Products Encapsulated Drug Delivery System

Recently, alkaloid, phenolic acids, and avonoid encapsulated nanoparticles (NPs) exhibited various immunemodulatory and anti-inammatory effects by altering the IL-1β, TNF-α, and NF-κB signalling. Curcumin, thymoquinone quercetin, piceatannol, andrographolide, berberine, silymarin, embelin, and resveratrol are natural alkaloids; avonoid, polyphenolic, and their acids from plants have shown various clinical pharmacological effects via reducing the production of NOD, caspase-1, NLRP3, MPO activity, IL-8, IL-6, MDA activity, Nrf2, HIF-αIL-1b, and TNF-a matrix metalloproteinase—2/3/9/13 Nrf2-, NF-κB, haeme oxygenase- 1 (HO-1), and STAT3-dependent signalling pathways [259, 261, 317]. β-Lactoglobulin-nanosphere, silk and pectin NPs, gold and silver NPs, chitosan-based hydrogel nanosystem, albumin-coated polymeric, liposomes solid lipid exosome, polymeric (PVP and CMC) NPs, and polyactidecoglycolide [318] were designed for prolonged and controlled release. In addition, an amphiphilic curcuminbased polymer is reported for IBS treatment.

Sometimes single natural products are not so practical for

treatment. Thus, a phyto-derived nanocarrier (size ~ 230nm)

[318] was used, including nano-size particles extracted from medicinal herbs or food. They have colossal biocompatibility and a stronghold in large industries. It is suggested that these phyto-derived nanocarriers, such as grape, ginger, blueberry, shitake mushroom exosomes, can transport across the cell membrane, can modulate intestinal tissue renewal processes, expression of inammatory genes, accumulate in the inamed colon, and exert potential therapeutic [319] Thus, these delivery systems can protect against liver toxicity and maintain the gut microbiota and pro-inammatory balance.

4.3 Fermented Formulation andDietary Supplements Used forInammatory Bowel Syndrome (IBS) andRelated Disorders

It is noteworthy to mention that the metabolism of gut microbiota or change in the intestinal metabolic state by some of the IBS conventional medicine has been reported. These conventional medications were reported to enhance carbohydrate metabolism and citrate cycle, which leads to bacterial sensitisation to oxidative stress, and decrease bacterial colonisation and polyphosphate level [320]. Thus, fermented formulations were used to overcome these side effects. FDA and WHO dened probiotics as live microorganisms which, in adequate amounts, can be benecial to humankind. In IBS, the primary cause of inammation is an unbalanced gut microbiota environment which facilitates the pathogenic pathways and restricts the movement of the bowels. Therefore, increasing the benecial bacteria subsequently decrease the inammation associated with IBS and other

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Table 9 Various fermented and dietary formulations for the management of IBS

Fermented products Probiotic strain Activity References Lactic acid bacterium Pediococcus acidilactici Induce IL-10 [322] Dietary Lactobacillus L. plantarum Increase the total Bidobacteria and

Lactobacilli, decreased Enterococci and C. perfringens

Dietary probioticbacteria Bidobacteria and Lactobacillus, L. plantarum

(Lp91)

Bidobacterium strains B. bidum Bif1, Bif2, Bif3; Bidobacterium

longum

Lon4, Lon5, Lon6; Bidobacterium catenulatum Cat7, Cat8, Cat9; B. breve Bre10, Bre11, and Bidobacterium adolescentis Ado12

Fed Saccharomyces

boulardii

Bidobacterium breve

strain Yakult and Bidobacterium bidum strain Yakult

Administration of VSL#3

Dietary probiotic yogurt L. rhamnosus and L. reuteri

Dietary probiotics powder

Administered Lactobacillus spp.

Administered probiotics Lactobacillus casei, Lactobacillus acidophilus

Administration of Lactobacillus plantarum 299v (L. plantarum)

Dietary bre Soluble corn bre, STA-LITE III polydextrose,

Dietary pectin Pectin

S. boulardii

B. breve, B. bidum

Marketed product

Bidobacterium bidum

Lactobacillus paracasei, Lactobacillus reuteri

and Bidobacterium lactis L. pantarum

Bio gum, Pullulan, RROMITOR-resistant starch-75, inulin, orange pulp, guar gum, a mixture of orange pulp and guar gum, germinated barley foodstuff, fermentable dextrin bre, germinated barley foodstuff

Down-regulate TNF-α and COX-2 Up-regulate IL-10

Inhibit TNF-α, IL-8 production

Inhibit NF-κB signalling, inhibition of CD4+ T-cell inltration, reduce production of IFN-γ

Induce secretion of IL-10, inhibit TNF-αinduced secretion of IL-8

Decrease mucosal secretion of TNF-α, IFN-γ, prevent the epithelium from bacterial invasion

Decrease IL-12, TNF-α, IL-12

Inhibit IFN-γ, MCP-1, increase IL-10

Decrease TNF-α, reduced mucosal IL-12 mRNA

Reduce diarrhoea in B lactis, decrease TNF-α Production, iNOS, COX-2 expression

Decrease mucosal IL-12, IFN-γ

RROMITOR-resistant starch-75 and inulin decrease IFN-γ production; STA-LITE III polydextrose, bio gum, pullulan, and RROMITOR resistant, starch-75 up-regulate colonic PPAR-γ expression; a mixture of orange pulp and guar gum increases PGE2 level

Increase IFN-γ and IL-2, reduce TNF-α, GATA-3, IgG, and IgM

E. R. Puppala et al.

[323]

[324]

[325]

[326]

[327]

[328]

[329]

[330]

[324]

[301]

[331]

related diseases. Furthermore, these probiotics decrease visceral hypersensitivity and low-grade inammation and increase pro-inammatory cytokines and toll-like receptors to support the immunoregulatory effect. Pre-biotics are a substance utilised by probiotics, and postbiotics are nonliving microorganisms with or without their cell components that directly give health benets. Concerning this, the eightstrain combinations of Lactobacillus plantarum and

Lactobacillus paracasei subsp. paracasei, Lactobacillus aci- dophilus, Lactobacillus delbrueckii subsp bulgaricus, Bidobacterium breve, Bidobacterium longum subsp. longum, Bifdobacteriuminfantis, Bidobacteriumlongum subsp., and Streptococcus salivarius subsp. Streptococcus thermophilus are recommended and listed in Table9.; Apart

from these, prebiotics such as inulin, starch gum, dietary bre, pectin, and poly oligosaccharides [318] are reported to

have a potential effect in the treatment of IBS. This carbohydrate- rich diet includes long and short-chain carbohydrates (FOS and GOS) such as cellulose, hemicellulose, β-glucan, and fructans showing anti-inammatory and immunoregulatory activities. Additionally, facilitate myenteric and colonic motility, improving the total gut movement by providing the gelling of the intestinal tract. Primary sources such as bananas, beans, onion, raw leeks, asparagus, gum acacia, barleys, husks, seaweed, oats, dandelion, wheat, garlic, and fruit vegetables rich in high bre and carbohydrates are considered good sources of prebiotic bres and healthy diet [321].

The incorporation of bioactive compounds via nanotechnology provides a way of developing clinical candidates for health wellness. There is an existing gap in the literature for the toxicity risk of these bioactive molecules in long term.

Herbal Medicines fortheManagement ofIrritable Bowel Syndrome andConstipation Problem

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333

5 Future Prospect

In response to the rising prevalence of IBS in Westernised countries, steadily increasing costs of IBS treatments, and the ineffectiveness of current IBS drug therapies, a substantial amount of research has been done to develop alternative therapies based on natural substances that are both highly effective and safe. A focus on recognising and addressing the dietary and environmental risk factors for IBS will be a priority in the future. In the search for natural alternative treatments for IBS, the introduction of unique cell models that can imitate the GI tract is thought to be a forthcoming model of research. It is also essential to have a thorough understanding of the pathogenic mechanisms underlying IBS which will enable the researchers to develop effective treatments for this ailment employing herbal medicines.

Clinical studies indicate that herbal medicines have a promising future in IBS therapy. A few issues must rst be rectied before administering the herbal medicine safely to the UC patients. There are still not enough large casecontrolled studies and reliable data on the specic mechanism of use of the herbs in invitro and invivo studies, and only a small number of UC patients have so far taken part in clinical trials using herbal medicine treatments. This could hasten the future research and development of herbal treatments for IBS.Additionally, since herbal formulations are a mixture of a wide variety of biological compounds, it is vital to know which component in the herbs provides the precise pharmacological effects, even in certain situations where the herb mixtures exhibit clinical effects. Thus, the determination of components of herb, dosage, and course of herb treatment plays a signicant role in their clinical employment. Furthermore, herbal therapy generally could carry risks and produce side effects such as liver and renal failure like other types of alternative therapy. Lead, arsenic, and mercury are just a few of the toxic ingredients found in many herb remedies. Therefore, there is a need for extensive research on the safety of herb medicines, particularly on long-term use.

6 Conclusion

From ancient times, these natural products, herbal extracts, and fermented formulations have been used to prevent and treat IBS and constipation. We now have a deeper insight into the genetics, mucosal changes, environmental triggers, and aberrant signalling that are the fundamental causes of IBS, constipation, and associated disorders. Novel therapies are being developed, yet approval of these new treatments must garner caution due to the unique and serious side effects that immunomodulator therapy entails. So, these diverse herbal formulations with complex functionality can be considered to overcome the drawbacks of conventional drugs. In addition, encapsulated bioactive molecules combination therapy is an

emerging strategy for IBS treatment to synergise the protective and therapeutic potential of IBS through various signalling pathways (cellular and molecular); improving the gut microbiota and can decrease the burden on the healthcare system and improving the quality of life. Their safe nutritional amount is required for clinical trials with larger sample sizes and periodic follow-ups for future medical benets.

Conicts of Interest

The authors declare that there are no conicts of interest to disclose.

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