INTRODUCTION:

Inflammatory bowel diseases (IBD) termed as chronic inflammatory disorders of the gastrointestinal tract distinct by episodes of reversion and decline. There are two identified subtypes of the disease, ulcerative colitis (UC) and Crohn's Disease (CD), which differ in forms of involvement though varying in clinical presentation, the two subtypes share a presumed aetiology of genetic predisposition, environmental risk factors or exposures, and alterations of the gut microbiome that subsidies to the manifestation of disease.⁽¹⁾Inflammatory bowel disease (IBD reflects as a disease of white people of European descent living in industrial regions of the Western world. In South Asia and South East Asia, occasional case series of ulcerative colitis (UC) would surface; Crohn disease (CD) is measured as a rare entity.⁽²⁾

Ongoing changes in environmental factors, including infections, diet, lifestyle factors, and medication use have contributed to alterations in the global prevalence of the disease. Although the appropriate pathogenesis of IBD remains unknown, part of the underlying mechanism. It is a decontrol host immune response to intestinal flora, in genetically vulnerable Beings.^(3,4)In this literature survey, the authors have accounted the most prevailing studies concerning the effective use of natural products and plant in the treatment of IBD poses multiple cellular and molecular mechanism which explains their anti-inflammatory and immunomodulating action, side-effect of novel drug and their quite extensive use with some of them being life-threatening.

Epidemiology of Inflammatory Bowel disease.:

Currently, the annual frequency of CD is highest in North America (20.2 per 100,000, per person-years); whereas the annual occurrence of UC is highest in Europe (24.3 per 100,000 per person-years). The dominance of both UC and CD are highest in Europe (505 and 322, per 100,000 per person years respectively).⁽⁵⁾However, IBD seems to be developing in such as Scotland, and France. For example, there are now higher incidence rates of IBD in countries such as Australia.⁽⁶⁾ and New Zealand.⁽⁷⁾The incidence of IBD is persistently rising in other earlier low incidence areas, such as Asia and the developing world. As IBD arises in developing countries, UC appears first, followed by a mounting trend in CD is observed.⁽⁸⁾This pattern is being seen currently in Asia.⁽⁹⁾These data support the argument that lifestyle and environmental factors are the main cofactors in the aetiology of IBD. Importantly, there are only restricted data on the epidemiology of IBD to date in underdeveloped countries. More precise means of determining incidence and occurrence in these areas are desirable.

Inflammatory bowel disease (IBD) has been cautious as a disease of white people of European descent living in industrial regions of the Western world. In South Asia and South East Asia, occasional case series of ulcerative colitis (UC) would surface; however, Crohn disease (CD) has noticeably been considered an infrequent entity.⁽¹⁰⁾ Over the last two decades, India appears to be on the epidemiological crossroads where infectious diseases, as well as disorders hitherto measured to be diseases of the Western world, were both observed. A comparison of incidence and prevalence rates with other nations suggests that among Asian countries the disease burden is highest in India. A recent epidemiological study, entitled "The Asia Pacific Crohn's and Colitis Epidemiologic Study (ACCESS)" by Ng et al.⁽¹¹⁾

Table 1. Comparison of incidence IBD among Asian countries and India⁽¹¹⁾

Location	IBD	UC	CD
Mainland China
Chengdu	0.56	0.15	0.42
Guangzhou	3.14	1.09	2.06
Xian	0.5	0.05	0.4
Hong Kong	2.62	1.25	1.30
Indonesia	0.83	0.27	0.56
Malaysia	1.01	0.18	0.71
Singapore	0.97	0.39	0.51
India	-	6.02

Values are given as n/100,000 people. IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease.

Environment risk for inflammatory bowel syndrome

Smoking:

Smoking cigarette is one of the primary environmental risk factors were consistently related to IBD. But, hypothetical mechanisms by which smoking modulates the immune system in UC may involve the decrease in tumor necrosis factor (TNF alpha) making via the action of nicotine on the nicotinic acetylcholine receptor a7 subunit, increased production IL-10 in response to carbon monoxide in cigarette smoke, increased mucin synthesis, decrease in IL-8 expression, hypoperfusion of the rectum and acutely injured colonic tissue.⁽¹²⁾

Air pollution:

Air pollution has intensely increased in recent years, particularly in developing countries in Asia that are undergoing agile development and the highest increase in IBD incidence.^(13,14) Disclosure of the gut to air pollutants can occur via inhalation of gaseous pollutants, the mucociliary acquiescence of particulate matter (PM) from the lungs and contamination of food and water sources.

Water pollution:

Risk of disease: Ingestion of pollutants and PM via water sources may persuade systemic effects that may affect the incidence, frequency of flares, and success of therapy in IBD.^(15,16)

Antagonists of steroid receptors that hinders the treatment established in bottled water.⁽¹⁷⁾ Endocrine-disrupting chemicals(EDCs) such as phthalic acid(were used as plasticizers for polyvinyl chloride, polystyrene, and many other polymers) and nonylphenols (were employed in built -up of antioxidants, lubricating oil additives, laundry and dish detergents, emulsifiers, and solubilizers) may used for altering glucocorticoid action by unreliable steroid hormone metabolism through the pregnane X receptor(PXR).⁽¹⁸⁾EDC can impact several steroid receptor proteins such as the glucocorticoid receptor, androgen receptor, AHR, peroxisome proliferator-activated receptor gamma (PPAR-γ) as well as cytochrome P450 enzymes.⁽¹⁸⁾ In-vitro studies recommend that the glucocorticoid receptor and PPAR-γ may play a significant role in the pathogenesis of IBD.^(15-19)

Vitamin D:

Vitamin D has immunoregulatory properties in several autoimmune diseases via its genomic actions on the vitamin D receptor (VDR).^(20-21) There is gathering evidence that vitamin D may show a fundamental role in the incidence and disease activity in IBD.^(22-23)

Diet:

The human diet is subjective by environmental and cultural practices. Diet can affect intestinal inflammation via several pathways, such as altering the gut microbiome, distressing gastrointestinal permeability, and through dietary constituents acting as food antigens.⁽²⁴⁾

Fats:

Risk of disease: A systematic analysis of 19 studies (18 case-control and one cohort; n = 2609; 1340 UC and 1269 CD patients) described increased risk of developing UC with high consumption of total fat, polyunsaturated fatty acid (PUFAs), omega-6 fatty acids, and increased risk of CD with high intake of PUFAs, omega-6 fatty acids, saturated fats.⁽²⁵⁾ Consumption of high-fat diet lower dextran sodium sulfate-induced colitis in mice, possibly by increasing colonic epithelial non-classical natural killer T cells, and reducing circulating Treg-cells.⁽²⁶⁾ Bile acid composition altered by high saturated fat diet and increased expansion of sulfate-reducing bacteria (Biophiliawadsworthia), which lead to the production of more significant amounts of mucosally toxic hydrogen sulfide and inducing colitis in IL-10 deficient mice.⁽²⁷⁾

Fibre:

The contingency of disease:

A study using IL-10 deficient mice showed that consumption of soluble fibres reduced intestinal inflammation.⁽²⁸⁾ A high intake of dietary fibre, mainly fruits and cruciferous vegetables associated with decreased risk of CD in human, but not UC (HR = 0.59; 95%CI: 0.39-0.90).⁽²⁹⁾ To be statistically observed the protective effect of fibre was significant in those consuming more than 22.1 g/d in another study.⁽²⁵⁾ Additionally, a high intake of fruits was associated with a 73%-80% decreased the risk of CD in the same study.⁽²⁵⁾

The intake of Animal protein (red meat, processed meat, poultry, dairy products): Risk of disease: The link between high meat consumption and IBD is uncertain, a majority of studies show a progressive accumulation of total protein intake and IBD (87% to 148% amplified risk).⁽²⁵⁾

Non-steroidal anti-inflammatory drugs (NSAID): Cyclooxygenase (COX) is an essential enzyme was found in two isoforms in the body COX-1 and COX-2 .⁽³⁰⁾Presence of COX-1 is at constant levels in some tissues. However, an inducible enzyme that can be up-regulated by inflammation is COX-2. In the intestine to maintain the gut epithelial barrier, COX-1 produces prostaglandins (PG) and COX-2 mediates inflammation.⁽³⁰⁾ Prostaglandins (PGs) promote inflammation, mucus production, and vascular flow in the gut. nonsteroidal anti-inflammatory drugs (NSAIDS)'s inhibit both COX-1 and COX-2, whereas COX-2 inhibitors selectively inhibit COX-2.⁽³⁰⁾

Stress:

Stress is a state of disagreement or defenceless homeostasis.⁽³¹⁾ When the body confronted with a traumatic response, the hypothalamic-pituitary-adrenal (HPA) axis and the immune system work tightly together. When stimulated by a stress episode, the immune system triggers the HPA axis by generating cytokines that ultimately result in the production of potent anti-inflammatory agents such as glucocorticoids.⁽³¹⁾ Disruptions of the HPA axis and immune system loop could potentially lead to diseases with an inflammatory and behavioural component due to abnormal responses to stressful stimuli.⁽³⁰⁾The connected loop to the immune system to the HPA is involved, and disruptions at different levels could lead to varying retrospectives of the disease.⁽³²⁾

Pathogenesis:

Genetics:

There have been multiple advances in our understanding of genetic contributions to IBD.⁽³³⁾ Due to the technological advances in DNA analysis and sequencing and the procedure of vast multinational databases.⁽³⁴⁾The number of IBD-associated gene loci to 163, of which 110 were related was studied Recently with both the diseases, 30 CD precise and 23 UC specific.⁽³⁵⁾Studies of gene loci shared by UC and CD may provide a new way to find their common pathogenesis. The era of recent IBD genetic research began in 2001 with the discovery of NOD2 (nucleotide-binding oligomerisation domain containing 2), the first vulnerability gene for CD.⁽³⁶⁾The NOD2 gene codes for a protein that was first described as an intracellular receptor identifying the muramyl dipeptide (MDP), a conserved motif present in peptidoglycan from both Gram-positive and -negative bacteria.⁽³⁷⁾ MDP stimulation induces autophagy which controls bacterial replication and antigen presentation^(38-39) and modulates both innate and adaptive immune responses.⁽⁴⁰⁾. NOD2 participates in distinct MDP-independent pathways such as the regulation of the T-cell response.⁽⁴¹⁾ At the genome-wide significance level, the association between CD and NOD2 was replicated.⁽⁴²⁾ Genetic analyses have shown an indispensable role for autophagy in immune responses in IBD and reported two autophagy-related genes called ATG16L1 and IRGM.^(43-44) Autophagy is involved in intracellular homeostasis, contributing to the deprivation and reuse of cytosolic contents and organelles, as well as to the resistance against infection and exclusion of intracellular microbes.⁽⁴⁵⁾ ATG16L1 is essential for all forms of autophagy, and the coding mutation T300A was associated with an increased risk of the CD. IRGM belongs to⁽⁴⁷⁾ dendritic cells containing ATG16L1, and NOD2 variants show defects in antibacterial autophagy.^(39,46) With the general use of GWAS and SNPs, a substantial association between IBD and the IL23R gene has recently been defined.⁽⁴⁷⁾ For the pro-inflammatory cytokine interleukin (IL)-23, the IL23R gene translates a subunit of the receptor, A peptide elaborated in the generation of Th17 cells. The Th17 and IL-23 pathway are well proved in the pathogenesis of IBD, with susceptibility gene loci IL23R, IL12B, JAK2, and STAT3 having been approved in both UC and CD.^(48-49)

Environment:

Since the first described the inverse association between UC and smoking in 1982, subsequent studies have confirmed the protective effect of heavy smoking on the development of UC with a lower rate of relapse.^(50-52) Contrary to its outcome on UC, smoking increased the risk of CD and was associated with a higher percentage of postoperative disease.⁽⁵³⁾There has been a raised acknowledgement of the immunologic role of vitamin D.⁽⁵⁴⁾

Immunological factor:

CD has long been considered to be determined by a Th1 response, and UC was associated with a non-conventional Th2 response.^(55,56) The newly described Th17 cells are also involved in the gut inflammatory answer in IBD.⁽⁵⁷⁾Immunological studies have newly concentrated on the mucosal innate immune responses, such as epithelial barrier integrity, innate microbial sensing, autophagy and unfolded protein response.

Oxidative stress and inflammatory bowel disease:

An imbalance between oxidants (ROS, RNS) and antioxidants is defined as oxidative stress in favour of the oxidants, leading to a disturbance of redox signalling and switch little damage.⁽⁶¹⁾ ROS is generally taken to encompass the initial species generated by oxygen reduction as well as their secondary reactive products, and include free radicals such as the radical anion superoxide O2, hydroxyl radical (HO), peroxyl (RO2), alcohol (RO) and hydroperoxyl (HO2), and non-radical species such as singlet oxygen (1O2), H2O2 and hydrochloric acid (HOCl). RNS include free radicals like nitric oxide (NO), nitrogen dioxide (NO2), anions like peroxynitrite (ONOO–), as well as nonradicals such as nitrous oxide (HNO2), nitryl chloride (NO2Cl) and alkyl peroxynitrites (ONOOR).⁽⁶²⁾

The critical source of ROS production is Gastrointestinal (GI) tract. Despite the shielding barrier provided by the epithelial layer, ingested materials and pathogens can cause inflammation by activating the epithelium, polymorphonuclear neutrophils (PMNs), and macrophages to produce inflammatory cytokines and other mediators that contribute further to OS.⁽⁶³⁾Dysfunction of the intestinal barrier accompanied by increased intestinal permeability is another characteristic symptom in the pathophysiology of IBD.⁽⁶⁴⁾

Ulcerative colitis⁽⁶⁷⁾

Crohn’s disease⁽⁶⁸⁾

Animal model to study inflammatory bowel disease⁽⁵⁸⁾

Animal model	Type	Immune mechanism	Incitant	Advantage	Disadvantage
C. elegans	Invertebrate	I	B	• Cost-effective • Minimal ethical considerations • Genetic manipulations • Microbial interactions • High throughput Simple husbandry	• No adaptive component • Limited applications • No complex microbiome research
Drosophila	Invertebrate	I	B	• Cost-effective • Minimal ethical considerations • Genetic manipulations • Microbial interactions • High throughput Simple husbandry	• No adaptive component • Limited applications • No complex microbiome research
Zebrafish	Invertebrate	I	B	• Cost-effective • Adaptive immunity a factor at three weeks of age • Minimal ethical considerations • Similar microbial community • Germ-free, transparent embryo/larvae Simple husbandry	• Small tissue size • Different nutritional requirements • Cost of germ-free facilities • Cannot do diet or nutritional comparisons
Rodent	vertebrate	A I	B C	• Easy genetic manipulation • Microbiome studies possible • Germ-free • Gut-brain axis studies Use of adequate numbers for statistical relevance	• Small tissue size in murine model • Coprophagy limitation • Difficult for invasive surgical techniques • Cost and establishment of Level 2/ germ-free handling facilities
Dog/Guinea Pig/Rabbit	Vertebrate	A I	B C	• Easy genetic manipulation • Microbiome studies possible Intestinal loop models applicable	• Cost and establishment of Level two handling facilities Longer gestation periods
Swine	vertebrate	A I	B C	Composed genetic manipulation Microbiome studies possible Anatomically similar to humans Germ-free Gut-brain-axis studies	Cost and establishment of Level 2/ germ-free handling facilities Overwhelming amount of tissue Husbandry and personnel training Slight variation in immune cells and colossal intestine orientation
Ruminant	Vertebrate	A I	B C	Intestinal loop models applicable Beneficial for enteric pathogen studies i.e. O157: H7	Level 2 handling facilities Overwhelming amount of tissue Husbandry and personnel training Intestine not well studied Microbial fermentation occurs in the rumen rather than the cecum/colon
Non-human primate	Vertebrate	A I	B C	Anatomically and genetically comparable to humans Gut-brain axis studies Microbiome studies possible Human disease present with similar sequelae to human	Ethical considerations Level 2 handling facilities Disease transmission Husbandry and personnel training Overwhelming amount of tissue

A-Adaptive immune response with associated mechanism; I-Innate response with associated immune tool; B-Biological incitant; C- Chemical incitant

Table 2: Novel treatment agents for inflammatory bowel disease

CLINICAL STATUS
DRUG	TYPE	TARGET	CROHN’S DISEASE	ULCERATIVE COLITIS
Anti – adhesion molecules
Vedolizumab	Monoclinal Ab	α₄β₇	Approved	Approved
Etrolizumab	Monoclonal Ab	Β₇integrin	-	Phase III
Natalizumab	Monoclonal Ab	α₄ integrin	Approved	-
PF-00547659	Monoclonal Ab	MadCAM-1	Phase II	Phase II
Blockade of the downstream signaling pathways
Tofacitinib	Small molecule	JAK1/JAK3	Phase iii	Phase iii
Mongersen	Anti sense oligonucleotide	SMAD7	Phase ii	-
Blockade of proinflammatory cytokines
Other Ozanimod	Small molecule	S1P1	Phase ii	Phase iii

CONCLUSION:

Inflammatory bowel disease is a chronic inflammation bowel disease (IBD) of unknown origin. It is observed from various scientific studies that conventional treatment is mainly based on the use of corticosteroids, immunosuppressant, antibiotics and biological agents. The cost of these treatments is unexpected globally as time passes with the list of side-effects related to their use is quite broad and life-threatening. In past years, many natural products, e.g., products derived from plants are used by the patient suffering from IBD. The herbal therapy is cost-effective. Due to its multiple phytoconstituent, it strengthens the beneficial effect of the drug. According to The World Health Organisation (WHO) estimates that 80 per cent of the population of some Asian and African countries presently use herbal drug for some aspect of primary health care such as curcumin, aloe vera, Boswellia serrateand many other herbals are one of the effective medical systems of the worldused as therapeutic agents in treating IBD.

ACKNOWLEDGEMENT:

Our sincere thanks to Dean, SRM College of Pharmacy and the management for the continuous support and encouragement towards research and development.

AUTHOR’S CONTRIBUTON:

The information from various sources were collected and manuscript were drafted by the authors equally.

CONFLICT OF INTEREST:

We declare that we have no conflict of interest for the publication of the paper.

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Received on 12.11.2018 Modified on 15.12.2018

Research J. Pharm. and Tech. 2019; 12(3): 1432-1440.

DOI: 10.5958/0974-360X.2019.00238.5

Herbals	cellular, molecular, systemic effect
Anthocyanins	• Anti-inflammatory effects
Boswellia serrate (Boswellic acid)	Selective inhibition of 5-lipoxygenase • Anti-inflammatory effects • Direct inhibition of intestinal motility • Reduction of chemically induced oedema and inflammation in the intestine in rodents
Curcumin	Decreased activity • Interferon-γ • Mitogen-activated protein kinase • IL-1, IL-4, IL-5, IL-6, IL-12 • Tumour necrosis factor-α • Myeloperoxidase • Lipid peroxidase activity • Ιnducible nitric oxide synthase • Cyclooxygenase-2 • Toll-like receptor-4 • Nuclear factor-κB • Binds to thioredoxinreductase and irreversibly changes its activity Increased activity • IL-10, IL-4 • Prostaglandin E2
Germinated barley foodstuff	• Increases luminal butyrate production by modulating the microfloral distribution • Prebiotic action • High water holding capacity
Oenotherabiennis	The mature seeds contain 7–10% γ-linolenic acid
Plantagoovata	• Anti-inflammatory and anti-oxidative properties • Inhibits the protein kinase C • Down-regulates the expression of intercellular adhesion molecule-1 • Inhibits the inflammation produced from 5-hydroxy-6,8,11,14-eicosa-tetraenoic acid and leukotriene B4
Xilei San	• Anti-inflammatory effects
Aloe vera	• In vitro inhibition of prostaglandin E2 and IL-8 secretion
Mastic Gum	• Anti-inflammatory • Anti-oxidative