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E. R. Puppala et al.

with food intake patterns being the most pervasive of these. The infant’s immune system and intestinal homeostasis are progressively shaped by the microbiota, conrming the notion that diet in early life inuences the later risk of developing immune diseases. Studies suggest that a calorie-rich diet, composed of fat and carbohydrate-based foods, leads to favourable development of Bacteroidetes phylum in adults. The overconsumption of omega-6 fatty acids is proinammatory and leads to loss of homeostasis because of its metabolised product arachidonic acid, a precursor for proinammatory eicosanoids. In contrast to this, a high intake of omega-3-fatty acids includes a-linolenic acid from plants and eicosapentaenoic acid and docosahexaenoic acid from sh are anti-inammatory. Additionally, there is a link between low dietary bre consumption and elevated risk for Crohn’s disease [55].

Western diets, which typically consist of a high calorie intake with large consumption of carbohydrates, are linked to less abundance of microbial diversity, contrary to the Mediterranean diet, which focuses on fruits, vegetables, and red wine. Western diet is rich in simple carbohydrates (such as fructose and sucrose) and fat (such as long-chain fatty acids like arachidonic acid) and has little to no bre. Moreover, it is supplemented with emulsiers and food colourings. SCFAs the products of bacterial digestion of bres, which are having homeostatic functions in the mucosa and anti-inammatory properties, were shown to plummet with Western diet. Several studies reported that consuming more simple carbohydrates induced dysbiosis and intestinal inammation. On the other hand, complex carbohydrates which are often obtained from vegetables and the bacterial metabolites they produce, have a protective effect. Many studies revealed that a high-fat diet boosts the anaerobic prevalence of Bacteroides. A high-fat diet is a key root problem of gut dysbiosis which may enhance gut inammation. Whey consumption and pea protein extracts promote the growth of Bidobacterium and Lactobacillus, while inhibiting the prevalence of Bacteroides fragilis and Clostridium perfringens. An essential amino acid tryptophan, which is present in dietary protein and is metabolised by the gut microbiota in the colon, regulates microbial diversity and gut immunity. Contrary to plant-based protein, animal-based protein consumption led to a rise in the number of bile- tolerant anaerobes like Bacteroides, Bilophila, and Alistipes [56].

Excessive consumption of food additives disrupts microbial composition and fosters gut inammation. Saccharin and other articial sweeteners induce dysbiosis in humans. Emulsiers disturb gut microbial community structure and elevate the risk of gut inammation. Likewise, titanium dioxide, typically used as a white powder in candies and sugar-coated chewing gums, reduces gut permeability and stimulates gut inammation. Nutrition also promotes epigenetic alterations either directly or indirectly through the

action of the gut microbiome, since some metabolites have the potential to impact gene expression, chromatin remodelling, and DNA methylation. Healthy diets with sufcient concentrations of vitamin D have been shown to be benecial in IBS by boosting dendritic cell proliferation and reducing the production of pro-inammatory cytokines. Zinc is also involved in DNA replication and transcription and has immune regulatory effects. Iron, folate, and vitamin B12 are critical for haemoglobin/blood cell formation. Additionally, specic carbohydrate diet (SCD, which excludes all carbohydrates except monosaccharides) and a diet low in fermentable oligo-, di-, and monosaccharides and polyols have shown favourable results in IBS. Micronutrients also have the potential to inuence the microbiota. One cohort study reported that the development of IBS has a positive correlation with the iron level of drinking water. These ndings provide credence to the notion that dietary manipulations might modify the gut microbiota [57].

3 Current Approaches forManaging IBS

andRelated Disorders

3.1 Marketed Drugs, Drawbacks ofConventional Treatment

Treatment for IBS is aimed at bringing about and keeping the disease in remission. The aims have altered in recent years from clinical remission to achieving “sustained profound remission” via mucosal healing. Nonbiological treatments that include anti-inammatory or immunosuppressive medicines comprise aminosalicylates, steroids, and 6- mercaptopurine. These drugs alleviate UC and CD symptoms but do not alter the progression of the disease.

For instance, despite their effectiveness in reducing mild inammation in UC patients, aminosalicylates are not very effective in treating symptoms of CD.Also, attempting to take these traditional drugs for a long time often weakens the immune system and has other serious side effects [4, 58–62]. So, there is a strong need for other treatments that can start and keep remission going. One of the ancient medical interventions is the use of therapeutic herbs. Hence, patients with inammatory bowel disease are more likely to use complementary and alternative medicine (21–60%), especially herbal treatments, because of the positive benets they have been documented to have on patients’ health. This alternative herbal therapy may still be the sole curative option available to communities as well as ethnic groups without a formal system of health care even today, especially in developing nations. By inhibiting the synthesis of intercellular adhesion molecules including NO, iNOS, COX-2, and NF-κB, as well as lowering ROS and enhancing antioxidant effects, these natural treatments decrease the course of IBS [59,

63–69]. Tables 2, 3, and 4 illustrate the application of medicinal

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

https://t.me/medicina_free

Table 2 Modern evidence with invivo studies with the efcacy of single plant-based bioactive on IBS

Type of model Plant source Bioactive molecules Role in IBS References DSS induced

murine colitis TNBS induced

acute colitis TNBS and DSS

induced colitis DSS induced

colitis

DSS and TNBS induced colitis

DSS-induced chronic colitis

DSS-induced colitis

TNBS-induced colitis

DSS-induced colitis

DSS and acetic acid induced colitis

DSS-induced colitis

DSS-induced enteritis

TNBS-induced colitis

TNBS and DSS induced colitis

DSS induced colitis

TNBS and DSS induced colitis

DSS induced colitis

TNBS induced colitis

Sophora alopecuroides Sophocarpine and

Sophora moorcroftiana and Sophora alopecuroides

Sophora alopecuroides Aloperine Inhibits PI3K/PKB/mTOR [75–77]

Coptis chinensis and Phellodendron chinense

Lindera aggregata Boldine,

Isatis tinctoria Isatin

Polygonum tinctorium Tryptanthrin

Citrus, grapefruits, and tomatoes Naringenin

Nicotiana tabacum Nicotine Suppress leukocyte recruitment,

Epimedium sagittatum, Epimedium pubescens, Epimedium wushanense, and Epimedium koreanum

Citrus fruits Hesperetin

Rhododendron Farrerol

Citrus fruits Quercetin

Myrica rubra, Myrica cerifera Myricetin and

Panax quinquefolius L. and other species

Rutaceae and Meliaceae families, Chinese medicine like Evodia rutaecarpa and Coptidisrhizoma

Cruciferous vegetables Indole-3-carbinol

sophoridine Matrine

(stereoisomer of sophoridine)

Oxymatrine

Berberine

Norisoboldine

Icariin Hinder p-STAT1, p-STAT3, and p-p65

kaempferol

Ginsenoside Anti-inammatory, Ginsenosides

Limonin

↓IL-1β, IL-6, MPO levels and ↓ICAM-1

↓TNF-α, IL-1β, and IL-6, IL-12/23p40, IFN-γ, IL-17

↓PI3K/AKT signalling, suppress Th1 and

Th17 cell in colon

↓ZO-1, IFN-c, IL-17, IL-6, IL-1β, and TNF-a cadherin expression while ↑IL-22 levels

Initiates the AKT1/SOCS1 signalling pathway and blocks p65 NF-κB subunit phosphorylation, ↓colonic pSTAT3, ↓MPO, IL-17 while ↑IL-10 expression levels

↓TNF-α, IL-6, and IL-17 secretion, ↓NF-κB and STAT3

↓TNF-α, COX-2, PGE2 and MPO, ↑colonic IL10, SOD, GSH-Px, and GSH-Rd levels

↓TNF-α, NO activation by regulating NF-κB/STAT3 signalling

↓ICAM-1, iNOS expression, MCP-1, TNF-α. Also ↓Cox2, MIP-2, NO, IL-1β, IL-6, ↑the colonic mucosal content

downregulates colonic TNFα, ↓IL-6in CD4T cells, ↓MAdCAM-1 expression, inhibits STAT3 signalling

expression; ↓T lymphocytic growth

↓p-JAK2 and p-STAT3, ↑SOCS3 expression

↓TNF-α, IL-6, and IL-1β, NF-κB

phosphorylation

↓Colon damage, iNOS, regulate MPO activity, MDA levels and ↑GSH expression

Kaempferol-↓IL-6, IL-1 β, COX-2, TNF-α, iNOS, MPO, PGE2, NO levels in colonic mucosa

Myricetin-↑TGF-β and IL-10, T regulatory cells, ↑claudin, occludins expression

Rd-downregulates inltration of neutrophil, inhibited inammatory cell recruitment into colonic tissue, ↓NLRP3 inammasome

Ginsenosides Rh2-↑TGF-β, Smad phosphorylation. But ↓NF-κB, MAPK

Ginsenoside RK3-↓TNF-α, IL-6 and IL-1β

Ginsenoside Rb1-↓IL-6, and TNF-α, IL1β,

↑IL-10 expression

↓STAT3/miR-214 signalling, IL6, TNF-α,

IL-1β

, IL-6, COX-2, iNOS, block PERK-

ATF4- CHOP pathway, NF-κB, ↑IL-10 level

↓IL-17in MLNs, ↑IL-22, CD4+ Foxp3+ cells

[70, 71]

[71–74]

[78]

[79, 80]

[81, 82]

[83, 84]

[85–87

[88–90]

[91–93]

[94–98]

[92,

99–101]

[102]

[103]

[104,

105]

[106–

109

]

[110–

120]

[121,

122]

[123]

(continued)

]

321

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(continued)

Table 2

Type of model Plant source Bioactive molecules Role in IBS References Oxazolone-

induced colitis in mice

DSS induced colitis

TNBS-induced colitis

TNBS, acetic acid induced and DSS induced colitis

TNBS-induced colitis

DSS and TNBS induced colitis

Cruciferous vegetables DIM

Radix Linderae, the dry root of Lindera aggregate

Indigo naturalis Indirubin

Pilocarpusmicrophyllus Epiisopiloturine

Piper nigrum L., Piper longum L. Piperine

Poncirus trifoliata Poncirin

Salvia miltiorrhiza Miltirone

Curcuma longa Curcumin

Norisoboldine

↓Colonic RORγt mRNA expression, MPO, IL-17A, ↑Foxp3 mRNA expression in colon

↑p-smad 2 and 3, IL-10 but ↓MPO, TNF-α, IL-17, IL-1β, SIRT1

Ameliorates MAPK NF-κB stimulation, ↓TNF-α, IL-6, Th17 cell differentiation, p-STAT3, ↑p-GSK-3β

↓IL-1β,MDA, iNOS, NO,COX-2

↓TNF-α, IL-1β, IL-6, NO, iNOS, ICAM-1, TLR4, IL-1β levels, CCR2, MCP-1, FFAs

↓COX-2, NF-κB, TNFα, iNOS, TLR4,

RORγt expression; Th17 cell differentiation. Unlike ↑differentiation of Treg cell, Foxp3, ZO-1 expression

↓TLR4-mRNA levels, NF-kB, IL-1β, IL-6, TNF-α IL-8, MyD88

↓TNF-α, IL-6, IL-17, ATG5, MPO NO, LC-3II, Beclin-1, ↑

IL-10, bcl-2

E. R. Puppala et al.

[124]

[125,

126]

[127–

131]

[132,

133]

[134–

138]

[138,

139]

[140]

[141–

144]

Table 3 Preclinical polyherbal drugs formulation in mitigating IBS treatment

Model Plant source Role in IBS References Acetic acid induced

model

DSS induced colitis CM102 þ and CM132

DSS induced colitis Red ginseng extract, Epimedium KoreanumNakai

Acetic acidinduced colitis

DSS induced colitis ZenWu Decoction (MZWD)—Poriacocos (Schw.) Wolf,

DSS induced colitis KM1608-A. lappa, T. chebula and Z. ofcinale

TNBS induced colitis

DSS induced colitis Bibhitaki Terminalia bellirica Roxb., Phyllanthus emblica

DSS induced colitis SHD-Scutellariabaicalensis Georgi, Coptis chinensis

TNBS induced colitis

DSS induced colitis ZWBQD-Poriacocos (Schw.) Wolf; Atractylodes

PHF-Eryngium foetidum, Manilkara zapota,

Murrayakoenigii

- Astragalus root; Barley and Lycium

fruit respectively

Terminalia chebula and Zingiber ofcinale

Paeonia lactiora, Atractylodes macrocephala Koidz., Zingiber ofcinale Rosc., Codonopsispilosula; Coptis chinensis

Triphala-Terminalia bellirica (Gaertn.) Roxb., Terminalia chebula Retz., Roxb., Emblica ofcinalis Gaertn.

Itis., Haritaki Terminalia chebula Retz.

Franch, Phellodendron chinense Schneid, Artemisia argyi

LévL et Vant

Mume Fructus, Ginseng Radix et Rhizoma, Zanthoxyli Pericarpium, Asari Radix et Rhizoma, Typhonii Rhizoma, Zingiberis Rhizoma, Angelicae Sinensis Radix, Coptidis Rhizoma, Cinnamomi Ramulus, Phellodendri Chinensis Cortex

macrocephala Koidz; Zingiber ofcinale Codonopsispilosula (Franch.) Nannf; Coptis chinensis

Franch

Rosc;

↓MPO levels, free radical scavenger, restore crypt architecture

↓IL-1β, IL-6, TNF-α

↓TNF-α, NO, iNOS, COX-2, IL-5, IL-6, IL-1β, IL-13, ↑CD19+ cells, Tregs cells

↓PGE2, MPO, TNF-α

↓NF-κB, TNF-α, IL-1β, PAR2

expression

↓IL-6, MCP-1 NO, iNOS, TNF-α

↓MDA, ↑SOD, GSH, CAT expression

↓MDA, CRP but ↑SOD, GPx level

Inhibits NF-κB, ↓TNF-α, IL-6, MPO, IL1β, MDA

↓NF-κBp65, STAT3, IL-6, IFN-γ while mitigates TGF-β/ Smad, Wnt/β-catenin signalling

↓, p-p38 MAPK, p-ERK1/2, p-AKT, p-JNK, NF-κB expression

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154]

[155]

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

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Table 3

(continued)

Model Plant source Role in IBS References DSS induced colitis STW 5-Iberis Amara, Glycyrrhiza glabra,

TNBS induced colitis

Table 4 Plant derived molecules under clinical trials for the management of IBS

Constituents Sponsor Study aim or objective/outcome measure Current status Curcumin Seattle Children’s Hospital To assess the curcumin tolerance in paediatric with

Diosmin Tanta University Diosmin effectiveness and tolerability in the

Berberine NCI Assess the safety of berberine in UC participants Completed

Triptolide Zhu Weiming Tripterygium glycosides safety and effectiveness in

Pentoxifylline Tanta University Pentoxifylline’s potential efcacy in patients with

Cannabidiol Meir Medical Center Cannabidiol used in IBS treatment Completed

Berberine Xijing Hospital of Digestive

Anthocyanin University of Zurich To investigate ACRE efcacy, safety, and

Black raspberry UConn Health A study of black raspberry freeze-dried for UC

Aloe vera National Institute of Medical

Herbal treatment (SA100)

Matricariarecutita, Silybum marianum, Angelica archangelica, Melissa ofcinalis, Mentha piperita, Carum carvi, Chelidonium majus

AA-Saccharum ofcinarum L., Terminalia arjuna (Roxb.) Wight and Arn. (TA), Woodfordiafruticosa (L.) Kurz., Vitis vinifera L., Madhuca indica J.F.Gmel.

QRZSLXF-Glycyrrhiza uralensis Fish., Sophora

avescensAiton, Baphicacanthuscusia (Nees) Bremek., Coptis chinensis France., Bletilla striata Rchb. f.

IBS

Sheba Medical Center To compare Curcumin with 5ASA combinational

Diseases

Sciences and Nutrition, Salvador Zubiran

Stanford University Assessing the oral dose of SA100in patients with

therapy to 5ASA alone in terms of efcacy in patients with mild to moderate UC

management of mild to moderately active ulcerative colitis

the therapy of CD

UC treated with mesalamine

Medication with Berberine to sustain symptomatic relief in UC

tolerability in UC patients

management Aloe Vera’s impact on mild ulcerative colitis

inammatory response

mild, moderate, or severe ulcerative colitis for safety and effectiveness

↓MPO, TNFα, CINC-3, ↑GSH, SOD

↓NO, MDA, MCP-1, IL-6, TNF-α, IL-1β, while ↑SOD, GSH, CAT

↑FOXP3, Treg cells but ↓STAT3, Th17 cells, IL-6,

RORγt expression

Completed Phase I

Completed Phase III

Phase I Concluded

Phase III Ongoing

Phase II

Phase II Completed

Phase IV Completed

Phase II Completed

Phase I Concluded

Early Phase I

Completed Phase I

[156]

[157]

[158]

Clinical trials. Gov. identier

NCT00889161

NCT01320436

NCT05626166

NCT02365480

NCT02044952

NCT05558761

NCT01037322

NCT02962245

NCT04000139

NCT02267694

NCT01783119

NCT02442960

323

herbs acting independently or in combinational treatment for alleviating IBS.

3.2 Complementary andAlternative Medicine (CAM) Include Prebiotics andProbiotics

CAM encompasses a broad range of curative and preventative therapies, including herbal medicines, fundamental biological therapy, physical adjustment counselling, and spirit

concept therapy. Over the last several decades, CAM has grown in popularity in Western nations’ IBS patients. This offers an alternative to conventional medical knowledge for individuals who have not been healed or who are reluctant to use Western medications. Complementary and alternative medicine include non-mainstream drugs that are used alongside standard medicine, while non-mainstream procedures are utilised in place of conventional therapies. Since it has a mild nature, positive therapeutic efcacy, and signicantly fewer associated complications than Western medications, CAM is progressively embraced and appreciated by patients

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in opposition to traditional medical practices. Their failure to respond to traditional treatment with conventional medication, recognised favourable safety characteristics, and their perceptions of their capacity to exert further impact contribute to the high proportion of CAM usage among IBS patients [159–169]. Patients of all ages often use sh oil, probiotics, nutrients, and herbal products as CAMs. Acupuncture is another technique that works with the mind and body [160,

165, 170–173]. Individuals with IBS have varying microbi-

ota in their guts than individuals in good health. With a drop in the Firmicutes phylum, the number of bacteria in different Clostridium classes, like Faecalibacterium prausnitzii, has declined signicantly. Escherichia coli, an Enterobacteriaceae species, and Proteobacteria, a phylum, have both been found to show a dramatic increase. This means that CD patients have more faeces and mucosa-associated microbiota [174–

182]. Moreover, by in situ uorescence hybridisation, stool

specimens from UC patients lacked anti-inammatory Pediococcus acidilactici and Lactobacillus. However, these strains begin to multiply again after the restoration of UC [183, 184].

The human gut is home to 10–100 trillion benecial bacteria that aid in the digestion and synthesis of essential vitamins. However, stress, cleanliness, and antibiotic usage cause dysbiosis, making it challenging to maintain a better and healthier microora. Prebiotics are dened as “a substrate that is particularly utilised by host organisms conferring a health advantage” in the ISAPP consensus statement on the scope and denition of prebiotics. The term “probiotics” is derived from a Greek phrase that signies “for life” and is employed to characterise active, non-pathogenic microorganisms with their clinical efcacy on hosts through modulating immune system responses, boosting mucosal IgA secretion, and fending off infectious agents. In comparison to synthetic medicines like Mesalazine, which are typical treatments for UC, probiotics are also involved in the maintenance of remission. Probiotic bacillus forms such as

Lactobacillus caseistrains, Lactobacillus rhamnosus, L. reuteri, bidobacteria, Lactobacillus acidophilus-group, Bacillus coagulans, Enterococcus faecium SF68, the yeast Saccharomyces boulardii, and Escherichia coli strain Nissle 1917 are among them [182, 183, 185–190]. To maintain the

protective effect, these probiotics reduced TNF-α activation, cytokine secretion, and stimulated IL10, a cytokine known to have therapeutic properties, is encouraged [191–195] (Fig.3).

Individuals with mild or moderate UC were given salicylates, but E. coli Nissle 1917 had similar effectiveness and safety characteristics [196–199]. The anti-inammatory impacts of mesalazine therapy alone are not as strong as those of adjuvant with Lactobacillus rhamnosus GG and mesalazine, where it signicantly expanded complete improvement in patients with UC. Moreover, adjuvant thera-

E. R. Puppala et al.

Fig. 3 Mechanisms involved in probiotic-induced protection against intestinal dysbiosis. Probiotics suppress pathogens through various actions, including lowering luminal pH, production of antimicrobial proteins, inhibition of adhesion and translocation of ora, competitive exclusion of pathogens, improvement of the epithelial barrier, enhancement of adhesion of commensal bacteria to the intestinal mucosa, and modulation of the gastrointestinal mucosal immune system

pies with Bidobacteria and lactic acid bacteria have been shown to slow the progression of the illness and maintain clinical remission in UC patients [196, 200]. Also, Lactobacillus reuteri ATCC 55730 rectal enemas delivered as additional treatment to 5-ASA resulted in endoscopic and histological recovery as compared to the placebo group in neonates and adolescents with mild to severe UC [201]. Another commercially available and exceptionally concentrated (450 billion bacteria/sachet) probiotics supplement, VSL#3 cocktail, has allegedly shown benets in sustaining response to therapy in active UC patients by downregulating interferon-γ, TNF-α expression, and MMP-2 and 9 which have comparable exacerbations as 5-ASA.This is supported by meta-analysis research data that indicate markedly higher therapeutic efcacy compared to conventional therapy alone [202–207]. However the meta-analysis found that the effectiveness of VSL#3 and E. coli Nissle 1917 in keeping UC patients in remission was only moderate. This requires more validation in terms of research ndings before it can be utilised as a probiotic [196, 197]. Also, the same bacteria are present in the VSL#3 probiotic blend, but there is no scientic evidence to support its efcacy in treating IBS patients [196, 199] (see Table5).

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

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325

Indigestible food items called prebiotics are known to favourably encourage the growth and activity of specic bacterial species in the intestine. The host organism’s wellbeing would be improved by this. The most often used prebiotics are inulin, lactulose, oligosaccharides such as soya- oligosaccharides, xylo-oligosaccharides, GOS, FOS, derivatives of β-glucans, and galactose [209–212]. Prebiotics are digested as fermentation products by anaerobic gut microbes, SCFA, and gas inside the colon microenvironment. This lowers the colon pH, allowing Bidobacteria, Lactobacilli, and the proliferation of non-pathogenic E. coli

Table 5 Role of prebiotics in some colitis models with the possible outcomes

Animal model Prebiotic component Outcome References DSS-induced

colitis

HLA-B27 transgenic rat

DSS and Hapteninduced colitis

DSS induced colitis

Dietary inulin Reduces colitis

Oligofructoseenriched inulin

Oligosaccharides derived from goat milk

Oligofructose No effect on

in the distal part of the colon

Suppress the severity of colitis

Colitis reduction

colitis

[208]

while suppressing Bacteroidaceae and other possibly harmful bacteria [213–215]. Such microorganisms enhance gut barrier integrity and regulate mucosal and systemic immune function by modulating the pro-inammatory cytokines IL-17, IL-10, TNF-α, and IL-1β [216, 217]. Following the consumption of resistant starches (RS), particularly RS1 and RS2, both studies on animals and humans demonstrate higher SCFAs with selective enrichment of Bidobacterium. In individuals, RS seems to trigger primarily Ruminococcus

bromii colonisation and boost butyrogenic species Faecalibacterium prausnitzii and Eubacterium rectale [212,

218–221]. GBF, which is high in glutamine and hemicellu-

lose, improves DAI in patients with mild-to-moderate UC by enhancing the growth of protective microbes such as Bidobacterium and Eubacterium, in addition to the faecal butyrate level, whilst also signicantly reducing serum CRP, IL-6, and IL-8 levels, and lowering mast cells. Moreover, in TNBS-induced colitis and CD patients, FOS enhanced the benecial bacterial growth with a signicant increase in the butyrate level. In UC patients, oligo-fructose-enriched inulin reduced faecal calprotectin, implying a decline in inammation and endoscopic histology with an elevation in butyrate and microbiota changes [222–235]. Nevertheless, prebiotics generate GI adverse effects such as nausea and stomach discomfort, leading to patient intolerance [215]. Table6 shows several probiotic organism investigations in clinical trials for IBS treatment.

Table 6

Clinical trials using probiotics for IBS

Prebiotics strains

Lactobacillus species like L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp. Bulgaricus, Bidobacterium species like B. longum, B. breve and B. infantis, Streptococcus salivarius subsp. Thermophils (VSL#3)

Escherichia coli Nissle 1917 CD Malchow HA etal.

Saccharomyces boulardii CD Plein K. etal.

UC/ CD Study Studied group

CD Fedorak RN. etal.

Clinical Gastroenterology and Hepatology. 2014

Day AS. etal. Gastroenterology 2012

J.Clin. Gastroenterol 1997

UC Petersen AM etal. J

Crohns Colitis. 2014

Gastroenterol. 1993

UC Guslandi M. etal. Eur

J Gastroenterol Hepatol. 2003

Batch assessment Outcome References

Juvenile, adolescents

Adolescents 28 In comparison to

100 Adolescents No advantage of adding

20 Adolescents Strong advantages in research

24 Adolescents Higher efcacy of probiotic

120 and 17 No endoscopic recurrence

prevention benets over placebo and compared to placebo, diminishes disease activity and enhances bodyweight and albumin thresholds respectively

conventional therapy alone, probiotics minimise relapse and decrease corticosteroid usage

probiotics to standard treatment

for maintaining remission as an adjunctive treatment

as add-on therapy in inducing and maintaining remission compared to mesalazin monotherapy

[236]

[237]

[238]

[239]

[240]

(continued)

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Table 6

(continued)

Prebiotics strains

Lactobacillus GG CD Bousvaros A. etal.

B. breve, B. bidum, Lactobacillus acidophilus, YIT 0168 (Bidobacteria-Fermented Milk-BFM)

UC/ CD Study Studied group

Inamm Bowel Dis. 2005

CD Gupta P. etal. JPGN

2000

UC Zocco MA, Aliment

Pharmacol Ther. 2006

UC Ishikawa etal. J Am

Coll Nutr 2003

E. R. Puppala et al.

Batch assessment Outcome References

75 Juveniles Probiotics do not prolong

relapse-free time when added to traditional treatment

4 Juveniles Improved gut barrier function

and clinical state with probiotic as an add-on medication

36 Adolescents Probiotic add-on treatment

improves mesalazin monotherapy in extending relapse-free duration

21 Adolescents Greater effectiveness of

probiotic combination as add-on treatment in sustaining remission and avoiding recurrence than conventional therapy alone

[241]

[242]

[243]

[244]

4 Herbal Approaches forTreating

Inammatory Bowel Disease (IBS) andRelated Disorders

Before discovering the modern medical system, herbal medicine with active constituents (natural products) and their extracts were used and recorded for treating inammatory bowel disease (IBS). The imbalance between proinammatory and anti-inammatory responses may be a fundamental cause of chronic inammation later on accolated with inammatory bowel disease [245]. The burden of IBS is relatively high in Asian continents and the Western world, affecting the patient’s quality of life and health-care system [246]. However, conventional therapies for IBS patients are available in the market, like salicylates, steroids, immunosuppressants, and anti-TNF-α drugs [247, 248] newly approved biologicals treatments to trigger immune responses (e.g. anti-IL-6, anti-IL-12/23, anti-IL13, and integrins) [249, 250] But the long-term side effects such as quiescent illness, poor tolerability, high rate of noncompliance, perceived ineffectiveness, and variable response rates of these conventional therapies [251] were always a primary concern and have augmented the interest in complementary and herbal medicines for their safe and acceptable treatments.

Several recent reports suggested that herbal medicine is becoming more popular among IBS patients. To maintain healthy homeostasis and chronic inammation, there is crosstalk between diet, gut microbiota, colonocytes, and immune cells [245]. Over 50% of IBS patients have used natural products, including herbs and their formulations, vitamins, probiotics, prebiotics, nano-based formulations, emulsion-based formulations, and dietary bres [252]. These herbal formulations tend to downregulate various aberrant

signalling pathways and modulate various inammatory mediators, such as IL-1β, IL-6, IL-10, TNF-α, PGE-2, iNOS, COX-2, and IL-8. A bre-rich diet is crucial for both preventing and treating constipation. If these preventative measures are ineffective and nutritional supplements are insufcient, patients must consider the usage of laxatives. Anthraquinone laxatives (senna, cascara, etc.) are preferred because they are easily tolerated and have a mild action in cases of constipation brought on by atonia of the colon, acute constipation, and in chronic constipation. Anthraquinone laxatives are incredibly helpful medicines when administered properly. Thus, the use of herbal medicine is an immensely vast eld in IBS and constipation [253, 254].

So, in this book chapter, we have mainly focused on herbal medicine and its formulation, showing some evidence of efcacy and safety in preclinical and clinical settings with the proposed mechanisms of action. We performed a literature search in PubMed, including the terms “IBS”, “colitis”, “natural products”, “phytochemical”, “herbal”, “nanocarriers”, “probiotics”, “gut microbiota”, “dietary”, “immune”, “macromolecule”, “colon”, “constipation”, and “inammation” which resulted in around 900 references.

Different herbal medicines or derivatives have been used for IBS and related disorders in the Ayurvedic medical system. Categorially, these medicinal plants contain diverse secondary metabolites with complex functionality, such as alkaloids [71], avonoids, phytosterols, steroids [255], terpenoids, tannin, glycosides, xanthone, polyphenolic acids, and coumarins [256] as core pharmacophores which are responsible for the treatment of IBS [257]. These herbs have various active mechanisms of action such as the downregulation of nuclear factor kappa B (NF-κB) [258], mitogenactivated protein kinase (p38-MAPK) [259], prostaglandin E2 (PGE2), laryngotracheobronchitis (LTB), nod-like recep-

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tor (NLR), jun-N-terminal kinase (JNK), extracellular signal- regulated kinase (ERK) [260], signal transducer and activator of transcription (STAT), vascular endothelial growth factor (VEGF), intercellular adhesion molecules (iCAM-1), activation of peroxisome proliferators activated receptor-gamma (PPAR-γ), and AMP-activated protein

Table 7 Herbal plants, their active constituents, possible mechanisms of action, and their targets that are used to treat inammatory bowel syndrome and related disorders

Medicinal plants Mechanism of action Target/activity References Aloe barbadensis miller, Aloe vera active

constituents: anthraquinones and their C-glycosides, anthrones, chromones, and lectins

Andrographis paniculate

Kalmegh Ethanol extract active constituents: andrographolide, neo-andrographolide

Artemisia absinthium

Wormwood, active constituents: α-thujone, (Z)-epoxyocimene, trans-sabinyl acetate and chrysanthenylacetate

Artemisia capillaris

Fragrant Wormwood, active constituents: dimeric guaianolides absinthin (up to

0.28%) and anabsinthin

Boswellia serrata

Indian olibanum active constituents: β-boswellic acid (β-BA), 11 keto-β boswellic acid (KBA), and acetyl-11-ketoβ-boswellic acid (AKBA)

Cannabis sativa

Marijuana active constituents: high cannabidiol-rich extract 9-tetrahydrocannabinol (THC), cannabinoids 1 and 2

Curcuma longa

Turmeric active constituents: Curcumin-I

Triticum aestivum

Wheatgrass Juice

Ginkgo biloba

Maidenhair trees active constituents: Ginkgolides, ginkgetin, bilobetin, diterpenes and its extract

Punica granatum

Pomegranate active constituents: Tannins, ellagicacid, punicalagin, ellagitannins, proanthocyanidin

Vitis vinifera

Grape active constituents: Resveratrol

Downregulation of PGE2 and LTB4 synthesis; increase in SOD and CAT levels

Inhibit the proliferation of Th1 and Th17 cell lines, NF-κB, and P38-MAPK pathways

Inhibition of NF-κB signalling; downregulation of iNOS activity

Downregulate the expression of ERK,JNK, and NF-κB

Inhibition of the increase in lipid peroxidation and iNOS expression

Downregulation of the p38-MAPK pathway; inhibition of the increase in iNOS expression; inhibition of ERK and NF-κB signalling, stimulation of PPARγ

Downregulation of NF-κB and JAK/STAT signalling Inhibition of p38-MAPK activity, and iNOS and COX-2 expression, ↑PPAR-γ activation

Downregulation of COX-2, iNOS, CCL2, and ICAM1 expression; inhibition of NLRP3 inammasome pathways, caspase-1 and caspase-11 enzymatic activity

Downregulation of platelet-activating factor (PAF), deceased MPO activity

Downregulation of NF-κB, PPAR-γ, COX-2 expression, reduction of iNOS, facilitating action towards bidobacterial, decreased MPO activity, lipid peroxidation

Activation of PPAR, AMPK, and FoxO signalling pathways, downregulate the NLRP3 inammasome, cytokine IL-1β

kinase pathways. Subsequently, a decrease in the expression of pro-inammatory cytokines (IL-1β, IFN-γ, IL-1β, IL-6, IL-22, IL-17A, TNF-α, COX-2, IL-4, and IL-23), peroxidase activity (MPO and MDA), and matrix metalloproteinase (MMP-9/12/7/) [261] via these medicinal herbs is listed in Table7.

↓IL-1β, IL-8 and TNFα

↓TNF-α, IFN-γ, IL-1β, IL-6, IL-22,

IL-17A, and IL-23; ↑IL-4

Decrease in TNF-α, IL-1β, and IL-6

↓TNF-α, IL-6, IL-1β, and PGE2 Protein expression

↓COX-2

↓TNF-α, IFN-γ, IL-1β, IL-6, and IL-12; ↑IL-4 and IL-10

↑IL-4 and IL-10 ↓TNF-α, IFN-γ, IL-1β, IL-6, and

IL-10

↓TNF-α, IFN-γ, TGF-β, IL-1β, IL-6, IL-12, IL-15, IL-17, and IL-23

↑IL-4 and IL-10 ↓adhesion scores, ↓colonic damage, ↓protease activity, ↓LPS activity, ↓TLR-4, ↓PG-2

↓IL-1β, IL-6, and TNF-α

↓TNF-α, ↓iNOS, and ↓Cox-2

↓PKB/AKT activity, ↓IL-8, IL-12,

IL-6, TNFinhibit the production of NO and

↑IL-1β stimulation

↓TNF-α, TGF-β1, IL-8, IL-6,

INF-γ, mRNA downregulated the procollagen I, procollagen III, IGF-mRNAs

α ↓growth of pathogenic,

[262]

[263]

[264]

[265]

[266]

[267]

[268]

[269]

[270]

[271]

[272]

(continued)

328

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(continued)

Table 7

Medicinal plants Mechanism of action Target/activity References

Aconitum laciniatum

Compass plant extract

Plantago ovata

Psyllium Husk-gel forming property

Euphorbia tirucalli

Milk bush active constituents: Euphol

Ganoderma lucidum

Lingzhi mushroom active constituents: polysaccharides, triterpenoids, proteins, ganoderic acids C and D

Ipomoea asarifolia

Morning-glory Decoction

Styrax japonica

Japanese snowbel active constituents: jegosaponins and benzofurans Styraxoside B, egonol, masutakeside, and styraxlignolid

Silybum marianum

Milk thistle active constituents: silybinin, silychristin, silydianin, and isosilyibinin

Combretum fragrans

Four-leaved bushwillow extract

Camellia sinensis

Green tea active constituents: epigallocatechingallate (EGCG), catechin, gallocatechin, and epicatechin

Olea europaea

Olive active constituents: hydroxytyrosol, avonoids, secoiridoids, oleuropein

Gardenia Jasminoides

Cape jasmine ethanol extract

Garcinia Cambogia

Gambooge Aqueous extract

Inonotus obliquus

Chaga Aqueous extract

Patrinia scabiosaefolia

Golden lace Methanol extract

Prunus mume

Japanese apricot Aqueous extract

Commiphoramyrrha

Myrrh Resin extract

Protect colonic inammation and reduce colonic IFN-γ mRNA levels

Downregulate the expression of ERK

Downregulation the expression of NOS2, VEGF, and Ki67

Inhibition of NF-κB ↓level of IL-6, IL-8, MMP-2,

Downregulation of the gene expression of JNK1, NF-κB-p65, and STAT3

Downregulation the expression of nitric oxide synthase (NOS) and Cyclooxygenase-2 (COX-2)

Reduce expression of oxidative stress, NF-κB, and proinammatory cytokines

Reduce the expression JNK/JAK/STAT signalling pathways, upregulated the protein levels of p-AMPK, SIRT1, PCG-1α

Inhibit signalling pathways involved in inammation, including nuclear factor B

Reduce the expression of pro-inammatory mediators (IL-1β, TNF-α and iNOS)

Inhibit myeloperoxidase activity Downregulate (iNOS), COX-2, and

Inhibit expression of myeloperoxidase, COX-2, and iNOS

Downregulate of the expression of TNF-α, IL-4 and STAT1, STAT6

Downregulate the expression of nitric oxide synthase (NOS) and Cyclooxygenase-2 (COX-2)

Downregulate the expression of TNF-α, COX-2, IL-4, STAT6, INF-γ, STAT1

Mediate TNF-α expression ↓CXCL-3, TNF-α, IL-1β, IL-6,

↓TNF-α, ↓iNOS and ↓Cox-2

↓protein kinase C, downregulate the

expression of intercellular adhesion molecule1

↓IL-1β, CXCL1/KC, MCP1, ↑MIP-2, and IL-6 TGF-β

MMP-9

↓TNF-α, IL-1β, ↑IL-10, reduce MPO activity

↓mRNA expression levels of NOS and COX-2, TNF-α, IL-1β; ↓DNA binding activity of NF-kB pathway

↓TNF- α, IL-1β, ↑IL-6

↓IL-1β, CXCL1/KC, MCP 1, ↑MIP-2, and IL-6 TGF-β

↓MPO activity, ↓TNF-α, IFN-γ,

NF-kB, and p65

Improving the intestinal epithelial barrier integrity restoring the expression of ZO-1, MUC-2

NF-kB

↓PGE2 and IL-1β

↓TNF-α, STAT1, pSTAT1, COX-2,

IFN-γ, STAT6, and pSTAT6, suppress the expression of IgE and IgA

↓TNF-α, IL-1β, and IL-6, mRNA level

↓IL-1β, IL-6, IL-8, inhibit myeloperoxidase (MPO) activity elevation

TNF-α, PGE2, NO, ↑IL-10 and increase endogenous antioxidant activity

E. R. Puppala et al.

[273]

[274]

[275]

[276]

[277]

[278]

[279]

[280]

[281]

[282]

[283]

[284]

[285]

[286]

[287]

[288]

4.1 Nanotechnology inInammatory Bowel Diseases andRelated Disorders

In the past decades (Fig. 4, Table 8), conventional drugs, phytoconstituents, and herbal formulations have been critical mediators fortuitously and mediated a range of signalling

pathways and proteins for treating IBS and related disorders [315]. However, lack of oral bioavability, cell specicity, and rapid rst pass metabolism leads to nd efcient way to overcome reported drawbacks. So, with advances in science, the development of phyto-derived nanoisation and micronisation of these herbal medicine has covered a wide range and

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Fig. 4 Chemical structure of secondary metabolite for treatment of inammatory bowel disease and related diseases

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