Medical

Communication

Biosci. Biotech. Res. Comm. 9(4): 653-665 (2016)

Af ictions of enteric diseases in human population

with reference to diarrhoea – A Review

Pooja Rawat,

Riddhi Doshi,

Pawan Kumar Singh,

* and Vipin Kumar

Value Addition Research and Development-Human Health, National Innovation Foundation-India, Satellite

Complex, Jodhpur Tekra, Premchand Nagar Road, Satellite, Ahmedabad -380015, Gujarat, India

Society for Research and Initiatives for Sustainable Technologies and Institutions (SRISTI), Near Gujarat

University, Navrangpura, Ahmedabad – 38009, Gujarat, India

ABSTRACT

Diarrhoea is a worldwide profound problem for the people of all age groups including new born, young children, adults

as well as old age people. About 88% of diarrhoea associated mortality is mainly attributed to poor sanitization and lack

of awareness. Despite the global decline in diarrhoea associated mortality by 50% between 2000 and 2013, the disease

still carries a high burden of morbidity. Commonly used treatment regimen includes the measures for preventing dehy-

dration and use of antibiotics.Exclusive breastfeeding, vitamin A and Zn supplementation have been recommended as

preventive strategies. Recently, two live oral rotavirus vaccines have been licensed in more than 100 countries, including

India, which are very effective in lowering the incidence of diarrhoea and frequency of death. Treatment options for

diarrhoea are ORT such as glucose-based ORS, intravenous infusions, normal saline, Zn supplementation, antibiotics,

and anti-motility drugs such as loperamide hydrochloride.Ef cacy of the traditional phyto-medicines is evident from

long history of use of several plants to treat diarrhoea.Approximately 80% of world population relies on traditional

medicines using plant extracts or their active constituents.Pre-clinical evaluations of anti-diarrhoeal activity of several

medicinal plants have been extensively carried out which supports their traditional uses. However, lack of clinical data

is a major limiting factor towards development of phyto-drugs against diarrhoea. Phytochemicals identi cation from

these plants and their clinical studies are an excellent area to explore towards development of safe phyto-pharmaceuti-

cals for management of diarrhoea and associated enteric disorders. Probiotics are also one of the safe alternative options

which need to be given attention in future researches.Thorough review of different research databases was carried out

and compiled to depict overview of the disease, its pathophysiology, intervention strategies, drawbacks of current treat-

ment methods and safe alternate treatment options available against diarrhoea.

KEY WORDS: ENTERIC DISORDERS, DIARRHOEA, TRADITIONAL MEDICINE, PATHOGENS

653

ARTICLE INFORMATION:

*Corresponding Author: pawan@ni ndia.org

Received 20

Sep, 2016

Accepted after revision 12

Dec, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2015: 3.48 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

654 AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Pooja Rawat et al.

FIGURE 1. Percentage of deaths among children under age 5 attributable to

diarrhoea, 2013 (Source: UNICEF analysis based on WHO-CHERG estimates for

child causes of death 2000–2013).

INTRODUCTION

Despite substantial progress in the understanding of

pathogenesis and management, diarrhoeal diseases are

the second leading cause of death (after pneumonia) in

infants and young children, and are responsible for around

18% of all deaths, more than 5000 every day. The World

Health Organization (WHO) and UNICEF have estimated

that worldwide about two billion cases of diarrhoea occur

annually, mostly in developing countries (Fig 1). Diar-

rhoea has created a massive economic burden on health

services, and accounts for more than 578,000 deaths per

year in paediatric patients younger than 5 years in low

and middle income countries (Leung et al., 2016).

During last 15 years, various preventive and cura-

tive solutions were developed and systematically imple-

mented worldwide to combat diarrhoeal diseases. From

2000 to 2013, signi cant reduction of more than 50%

(from 1.2 million to 0.6 million approximately) in total

annual number of deaths due to diarrhoea was observed.

Oral rehydration and zinc supplementation are the key

therapies which have been recommended by WHO and

UNICEF for treating diarrhoea. Despite the cost effec-

tiveness, affordability and easy implementation, oral

rehydration therapy (ORT) covers only about 40 per cent

of the children under 5 years of age. From 2009 - 2013,

in sub-Saharan Africa and South Asian countries with

most death of children attributed to diarrhoea, the per-

centage of children receiving ORT encompasses 36% and

38% respectively. Surveys and studies conducted during

2009-2013 shows that the countries with highest num-

ber of child deaths due to diarrhoea are having lowest

number of coverage by ORT (Fig 2).

It is evident from the literature that about 78% of

child deaths due to diarrhoea occur in the African and

South-East Asian countries. Among 15 highest burden

countries, India is grouped in top three countries with

the maximum child deaths due to pneumonia and diar-

rhoea. Compared to developing countries, lesser number

of deaths are recorded in the less developed countries.

In African, South-East Asian and least developed coun-

tries, generally children from high income family groups

are more likely to receive ORT than the children from

low income families. Children in low and middle-income

countries have high risk of getting frequent diarrhoea

epidemics (Julian, 2016).

In 2013, the Global Action Plan for the Prevention

and Control of Pneumonia and Diarrhoea (GAPPD) was

developed and released by the WHO and UNICEF, with

an objective to eradicate the preventable pneumonia and

diarrhoeal mortality in the children by 2025. WHO and

UNICEF have adopted this cohesive approach because

of interdependency of many of the solutions desired

to combat diarrhoea and pneumonia. As per Pneumo-

nia and Diarrhoea progress report (2014), published by

International Vaccine Research Center (IVAC), India and

Nigeria are the two countries with highest burden of

child deaths. The slow implementation and poor acces-

sibility of children under  ve to vaccination programs

are key reasons for continued child deaths. About 20%

of the Asian countries have introduced rotavirus vac-

cination programs, compared to 47% of the countries in

the Africa. Various factors suggested for delayed intro-

duction of rotavirus vaccine in these regions are poor

acceptance by end users, logistic challenges and sup-

ply issues. Diarrhoeal treatment rates are far below the

GAPPD target (90%) in all the 15 highest-burden coun-

tries in which coverage of Zn supplements are extremely

lower than the ORS. Inclusive GAPPD intervention

scores in the 15 countries having highest burden of child

mortality due to diarrhoea and pneumonia, ranges from

23 to 63 per cent which is far below the set target (Fig 3).

Zinc supplementation coverage in India has increased

substantially from 2005-06 to 2012-13. Goa was among

the top performing states in terms of zinc and ORS cov-

erage with GAPPD score of about 66%. According to

IVAC report, 2014, overall GAPPD score in India across

all the states ranged from 38 to 66% (Fig 4).

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION 655

Pooja Rawat et al.

FIGURE 2. Diagram showing correlation between percentage of children with diarrhoea receiving

Oral rehydration therapy and percentage mortality caused by diarrhoea for children under age

 ve [Source: UNICEF global databases, 2014, based on DHS, MICS, and other national household

surveys, 2009-2013].

CLINICAL MANIFESTATIONS

Gastroenteritis is a generic medical term for various

pathological conditions of the gastrointestinal tract. The

primary indication of gastroenteritis is diarrhoea; which

may be generally accompanied by mild abdominal pain,

nausea and vomiting. Diarrhoea gets more complicated

due to occurrence of other gastrointestinal tract syn-

dromes such as emesis, abdominal pain and distension

(China, 2005). Diarrhoea, as de ned by WHO, is having

three or more stools per day, or having more stools than

is normal (Ahs et al., 2010). There are several causes for

diarrhoea which includes overeating or eating unhealthy

food, inadequate personal hygiene, food putrefaction in

intestine, nervous irritability, microbial fermentation

due to inadequate digestion of carbohydrate, intestinal

infection, overuse of antibiotics, drug reaction, food

intolerance and excess ingestion of purgatives. (Tarri-

cone et al., 2016, McQuade et al., 2016).

Rotavirus is the leading cause of severe diarrhoea in

children across the globe (Bahl et al., 2005, Kumar et al.,

2016). A wide variety of protozoans inhabits human intes-

tinal tract, but majority of them are non-pathogenic or

cause very mild diseased condition. Virulent strains includ-

ing Entamoeba histolytica, Giardia, Cryptosporidium par-

vum, Cyclospora species and microsporidia (Hashmey et al.,

1997) contributes to very less percentage (0-12%) of acute

traveler’s diarrhea. However, prevalence of such infection

is as high upto 30% in people with HIV or immune-com-

promised individuals (Ericsson et al., 2001). The microbial

species causing intestinal diseases include Shigella, Bacil-

lus, Vibrio, Salmonella, Listeria, Escherichia, Clostridium

(Hosokawa et al., 2016, DeMeo, 2016).

PATHOPHYSIOLOGY OF DIARRHOEA

Absorption and secretion of ions and solutes is the fun-

damental process taking place throughout the length

of intestine, starting from duodenum to distal part of

colon. Secretion process takes place through a cyclic

AMP-dependent chloride channel, also known as cystic

 brosis trans-membrane conductance regulator (CFTR),

656 AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Pooja Rawat et al.

FIGURE 3. Overall GAPPD scores for the 15 countries with highest mortality, 2014

[Source: International Vaccine Research Center (IVAC) 2014- Pneumonia Diarrhoea

Progress Report].

FIGURE 4. GAPDD score relative to child Mortality in India, 2014 [Source: Interna-

tional Vaccine Research Center (IVAC) 2014- Pneumonia Diarrhoea Progress Report)].

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION 657

Pooja Rawat et al.

present in the apical or luminal membrane of crypt epi-

thelial cells. The channel regulates secretion of Cl

into

the lumen which leads to movement of Na

through

creation of electric potential. The osmotic gradient cre-

ated by net movement of NaCl results in the secretion

of water by crypt epithelial cells (Frizzell and Hanrahan,

2012, Camilleri et al., 2016).

Pathophysiology of enteric diseases involves several

mechanisms by which infectious agents interact with

intestinal mucosal cells. Infection with enterotoxin pro-

ducing bacteria can lead to diarrhoea through toxigenic

effects or in ammation. Cholera, an infection of small

intestine is caused by some strains of bacterium, Vibrio

cholera. The disease is characterized by severe diarrhoea

leading to dehydration and electrolyte imbalance. The

diarrhoea symptoms are due to the secretion of toxin,

known as cholera toxin (CT) by V. cholera. CT is an

84-kDa protein consisting of a dimeric A subunit and

 ve identical B subunits. CT irreversibly activates adenyl

cyclase resulting in increased mucosal concentration of

cAMP. Increased cAMP results in the increased secretion

of Cl

into the lumen, leading to loss of water through

creation of osmotic pressure (Fig 5). The toxin also medi-

ates its effect through inhibition of NaCl absorption by

decreasing the activity of NHE and Cl

bicarbonate anti-

porter which leads to electrolyte imbalance. However, CT

mediated toxigenic mechanism does not have any effect

on glucose-stimulated Na

absorption, which is inhibited

in case of infection with Shigella spp. or Salmonella spp.

(Anand et al., 2016, Barrett, 2016).

Diarrhoeal diseases in case of enterotoxigenic strains of

E. coli is caused by two enterotoxins, a heat-labile toxin

(LT) and a heat-stable toxin (ST). Action of LT is simi-

lar to CT, which mediates its action through activation

of adenylate cyclase. However, ST activates guanylate

cyclase, resulting in increased mucosal cyclic GMP. cGMP

has similar effects on ion transport as cAMP leading to

water secretion and impaired absorption. Enterotoxin

released by rotavirus has been identi ed to be nonstruc-

tural protein (NSP4), which mediates its effect through

impairment of lactase enzymatic activity in brush border

of human enterocyte-like Caco-2 cells (Beau et al., 2007).

An intact intestinal mucosa was detected in the histologi-

cal analysis of proximal intestinal biopsy samples from

infected individuals. Mild in ammatory in ltration into

the lamina propria was also observed in infected indi-

viduals (Troeger et al., 2009).

TYPES OF DIARRHOEA

Osmotic diarrhoea

Osmotic diarrhoea occurs when too much water is drawn

into the lumen and happens after ingestion of large

amount of poorly absorbable osmotically active solutes

such as lactulose, sorbitol etc. The condition may also

result when a person with a particular absorption defect

ingests such nutrients. Examples include lactose intoler-

ance in lactase de cient individuals, mal-digestion in

case of pancreatic insuf ciency and hydrolysis of unab-

sorbed carbohydrates into short chain fatty acids, which

exceed beyond the absorptive capacity of the colon.

Secretory diarrhoea

Secretory diarrhoea results due to overstimulation of

intestinal tract’s secretory capacity or due to inhibition

of absorption. Bacterial toxins, luminal secretagogues

(such as bile acids or laxatives), reduced absorptive

surface area caused by disease or resection, circulat-

ing secretagogues (such as various hormones, drugs,

and poisons), and medical problems that compromise

regulation of intestinal function (Schiller, 1999) are the

key factors for secretory diarrhoea. The most common

example is cholera toxin that stimulates the secretion

of anions, especially Cl ions and subsequently results in

movement of Na along with water to maintain a charge

balance (Thiagarajah et al., 2015).

FIGURE 5. Secretion of Chloride ion in small intestine. Toxicity or in ammation caused by infection

results in activation of adenyl cyclase and increased cAMP production. Increased cAMP activates CFTR

to cause increased secretion of Cl- ion. Increased Cl- concentration in the lumen results in increased

passive transport of Na+. Loss of water follows as a result of osmotic effect of Na+ and Cl- ions.

Pooja Rawat et al.

658 AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

In ammatory and infectious diarrhoea

Gatroenteritis or infectious diarrhoea, is an in ammation

of the gastrointestinal tract that comprises the stomach

and small intestine. Epithelium destruction causes exu-

dation of serum and blood into the lumen and also asso-

ciated with the destruction of absorption function. In

such cases, absorption of water occurs very inef ciently

resulting in diarrhoea. Pathogens frequently associated

with infectious diarrhea include bacteria (Salmonella,

E. coli, Campylobacter), viruses (rotaviruses, coronavi-

ruses, parvoviruses, norovirus) and protozoa (Coccidia

sp., Cryptosporium, Giardia).

Diarrhoea associated with deranged motility

Disorders in motility may lead to poor absorption result-

ing in diarrhoea. Both increase and decrease in gut motil-

ity can lead to diarrhoea. Examples of the former are

dysthyroidism (Daher et al., 2009). Decreases in effective

motility in the small intestine due to large diverticula,

smooth muscle damage (scleroderma, dematomyositis,

amyloidosis, muscular dystrophy, or radiation injury), or

autonomic neuropathy (diabetic, idiopathic) can result

in bacterial overgrowth which may lead to diarrhoea.

Genetic factors implicated in susceptibility to enteric

disease

A number of studies have implicated association of

genes with the susceptibility of an individual to infec-

tions with enteric disease causing pathogens. Genes

associated with the susceptibility to enteric diseases

have been summarized in Table 1.

Preventive interventions

Several preventive measures have been recommended

by WHO on the basis of a systematic review. Exclusive

breastfeeding to infants has been recommended as one

of the preventive strategy for diarrhoeal disease (Shah

et al., 2012). Breast milk contains several antimicrobial

factors and exclusive breastfeeding excludes the con-

sumption of contaminated food and water. It has been

reported that breastfed children below age 6 months are

6 times less likely to die due to diarrhoea than other

infants (Victoria, 2000). Fewer than 4 in 10 children

worldwide are exclusively breastfed during their  rst six

months of life (Unicef, 2015).

Data from 2005- 2013 for 15 highest burden coun-

tries shows that the exclusive breastfeeding percent-

age of infants ranges from <3% to 64%. In India, this

percentage is 46% and less than GAPPD target of 50%.

WHO has also recommended vitamin A supplementation

for all HIV-infected and exposed infants and children

aged 6 months to 5 years, in doses given every 6 months

(100 000 IU for those aged 6–12 months and 200 000

IU for those aged > 12 months). Though no effect of

vitamin A supplementation was observed on occurrence

of diarrhoea in infants and children less than 6 months

(Shah et al., 2012, Organization, 2010). Zinc supple-

mentation (10 mg elemental Zn for 14 days for children

aged 2-6 months and 20 mg/day for older children) is

an important preventive measure to lower the incidence

rate, mortality and morbidity associated with diarrhoea

(Shah et al., 2012).

Changes in public health policy also results in signi -

cant reduction in overall prevalence of diarrhoea (Emina

Table 1: Genes implicated in susceptibility to enteric diseases

Pathogens Genes implicated in susceptibility

Bacteria

EAEC IL-8 (Jiang et al., 2003)

Clostridium dif cile IL-8 (Jiang et al., 2006)

Salmonella spp. HLA-DRB1 (Dunstan et al., 2014), TNFA, IL-12B, IL-12RB1,

IFNGR1, HLA-DQB18*0201-3 allele (Dunstan et al., 2001)

V. cholera O blood group (Glass et al., 1985)

Virus

Norwalk Virus FUT2 (Lindesmith et al., 2003)

Protozoans

Cryptosporidium parvum/ hominis DQB1*301 allele, DQB1*301/DRB1*1101, HLA class 1B*15

(Kirkpatrick et al., 2008)

Entamoeba histolytica DQB1*0601/DRB1*1501(Duggal et al., 2004)

Pooja Rawat et al.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION 659

and Kandala, 2012). A median reduction of 55% (range

20–82%) in child mortality was observed with improved

access to sanitation facilities. Effective immunization

with the vaccines can have major impact on diarrhoea

mortality in developing countries. Since 2009, the WHO

has recommended inclusion of rotavirus vaccine in all

the national immunization programmes. The diarrhoeal

disease caused by the rotavirus kills about 500,000 chil-

dren annually; of which more than 85 per cent deaths

are from developing nations. (Verma et al., 2012).

Recently, two live oral rotavirus vaccines (one derived

from attenuated human strain of rotavirus and second

contains  ve bovine-human re-assortant strains) have

been licensed in more than 100 countries, including

India, which are very effective in lowering the incidence

of diarrhoea and frequency of death (Morris et al., 2012,

Glass et al., 2006). Eighty one countries have introduced

Rotarix or RotaTeq rotavirus vaccines into their national

immunization program (Burnett et al., 2016, Kuate Defo

and Lee, 2016).

There is, however, a signi cant debate on the intro-

duction of such vaccines in India, mainly because of

their high costs. Killed whole cell vaccines are being

used for vaccinization for cholera. Both oral and injected

vaccines are safe to use and effective for up to two years

after single dose and three to four years after annual

booster dose (Sinclair et al., 2011, Graves et al., 2010).

Killed whole cell oral cholera vaccine (Dukoral®) is rec-

ommended to combat the infections due to Entero toxi-

genic Escherichia coli (ETEC) bacteria, common cause of

travelers’ diarrhoea in the adults and children in devel-

oping countries. It contains a recombinant B subunit of

cholera toxin and is similar to heat labile toxin of ETEC.

However, an assessment of twenty four randomized con-

trolled trials (RCTs) was carried out which indicated lack

of suf cient evidences for use of Dukoral® for protecting

travelers’ against ETEC diarrhoea (Ahmed et al., 2013).

Several whole cell oral cholera vaccines have been tested

and found to be effective against diarrhoea (Desai et al.,

2015, Baik et al., 2015, Desai et al., 2016a, Desai et al.,

2016b).

Treatment methods

WHO has recommended following strategies for the

treatment of diarrhoea:

Oral and Intravenous Rehydration therapy

The introduction of ORT has played a crucial part in

reducing the mortality rate due to diarrhoea. For more

than 35 years, WHO and UNICEF have recommended a

single formulation of glucose-based ORS to prevent or

treat dehydration, irrespective of the cause or age group.

Administration of appropriate solutions by mouth, is

now routine therapy for managing diarrhoea. Modi ed

ORS such as polymer-based ORS is found to be better

than the standard one, due to its cost effectiveness in

managing acute gastroenteritis and also reduces hospi-

talization requirements in both developed and develop-

ing countries (Suh et al., 2010). Apart from oral rehy-

dration therapy, a number of solutions for intravenous

infusions are also available including Ringer’s Lactate

Solution (also called Hartmann’s Solution for Injection)

and Ringer’s lactate solution with 5% dextrose. Normal

saline (isotonic or physiological saline) is also an accept-

able solution, however it does not contain a base to cor-

rect acidosis and does not replace potassium losses.

Zinc Supplementation

Use of Zinc has been recommended by WHO for the

treatment of children with diarrhoea. Zinc supplementa-

tion is recommended for a period of 10–14 days, with

increased  uids and continued feeding, for all HIV-

infected and -exposed children with diarrhoea (10 mg

per day for infants under 6 months of age, 20 mg per

day for infants and children over 6 months) .

Antibiotic treatment

Antibiotics aim at treating dehydration, shortening the

length of illness and reducing the infection period (Allen

et al., 2003). Formerly used antibiotics such as ampi-

cillin, doxycycline, and trimethoprim-sulfamethoxazole

for the treatment of traveler’s diarrhoea have become

less effective because of increasing microbial resist-

ance. Loperamide is the agent of choice for antimotility

in the adults but not in children below 2 years of age.

Cipro oxacin and azithromycin are indicated drugs for

moderate to severe disease to reduce the duration of ill-

ness. In recent times, rifaximin, a semi-synthetic, poorly

absorbed, broad-spectrum antibiotic with minimal

effects on gut  ora, has been added for the treatment

of noninvasive forms of traveler’s diarrhoea (Ouyang-

Latimer et al., 2011).

Although antibiotics are bene cial in certain types of

acute diarrhoea, these are customarily not used except

in speci c conditions. This is because drug resistance to

human pathogenic bacteria has been frequently reported

in recent years. In addition, antibiotics are sometimes

associated with adverse effects on host, including hyper-

sensitivity, depletion of bene cial gut and mucosal

micro-organism, immuno-suppression and allergic reac-

tions. Besides, antibiotics may disturb the natural bal-

ance of human intestinal tract as well as colonization

resistance of the gut  ora. This may lead to overgrowth

of certain enteropathogens such as C. dif cile, leading

to antibiotic-associated diarrhoea (Johnston et al., 2011,

Hempel et al., 2012).

Antimicrobials that are ineffective for treatment of

Shigellosis include metronidazole, streptomycin, tetra-

Pooja Rawat et al.

660 AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

cyclines, chloramphenicol, sulfonamides, amoxicillin,

nitrofurans (e.g. nitrofurantoin, furazolidone), amino-

glycosides (e.g. gentamicin, kanamycin),  rst and second

generation cephalosporins (e.g. cephalexin, cefaman-

dole). Antidiarrhoeal treatments also include adsorbents

such as; kaolin, attapulgite, smectite, activated charcoal,

cholestyramine, antimotility drugs such as; loperamide

hydrochloride, diphenoxylate with atropine, tincture

of opium, camphorated tincture of opium, paregoric,

codeine and Bismuth subsalicylate. These antidiarrhoeal

drugs are however not recommended for treatment due

to lack of practical bene t. Resistant strains of a number

of microbes including V. cholerae, Shigella dysenteriae

type I, Salmonella enterica subsp. Typhi, Enteropatho-

genic E. coli, have been reported over the past few dec-

ades (Cooke and Wain, 2004, Mwansa et al., 2007).

In developing countries, the major problem with anti-

microbials is the way these antibiotic therapies are used.

Most of such medicines are taken without prescription

and without monitoring the usage by the patients, not

completing the prescribed drug regimen resulting in

multidrug resistance. Another major factor contributing

to increased resistance is the substandard drugs availa-

ble in the market, containing doses lower than required,

further predisposing the population towards increased

drug resistant.

Traditional plant based medicines

Owing to the enormous clinical problems associated

with diarrhoea, there is a need to develop alternative

anti-microbial drugs for its treatment. Since ancient

times, traditional medicines have been in use to cure

several diseases (Rawat et al., 2016, Farag et al., 2016,

Patel et al., 2014). In developing countries, healthcare

management by the people living in rural areas depends

upon use of traditional plant based medicines (Gaikwad

et al., 2015, Pandit et al., 2015, Kumar, 2016).

As per WHO, approximately eighty percent of world

population relies on traditional medicines using plant

extracts or their active constituents (Umamaheswari et

al., 2008). The biological activity of extracts, combina-

tion of extracts, fractions and compounds of several

plants has been investigated against diarrhoea. These

plants are reported to have anti-spasmodic effects, gut

motility suppression activity, intestinal transit delay,

water adsorption stimulation or reduction in electrolyte

secretion. Numerous phyto-chemicals such as tannins,

alkaloids,  avonoids and terpenes identi ed in these

medicinal plants have been stated to be responsible for

anti-diarrhoeal activity. Anti-microbial properties of

medicinal plants are also being reported from different

parts of the world (Namita and Mukesh, 2012).

Several RCTs have been conducted to evaluate the

anti-diarrhoeal potential of herbal medicines. In one

of the study, compared with the patients in placebo

group, patients in the group treated with Chinese herbal

formulations showed signi cant improvement in the

symptoms (Bensoussan et al., 1998). Pre-clinical safety

and ef cacy studies of SP-300, a standardized botani-

cal extract formulated from the latex of Croton lechleri

was conducted. Ef cacy studies in cholera mouse model

demonstrated signi cant inhibitory effect on  uid secre-

tion into the intestinal lumen. The effect was found to

be mediated through inhibition of cAMP mediated Cl

ion secretion. Clinical studies of SP-303 was also con-

ducted in travelers’ diarrhoea. Signi cant reduction in

diarrhoea and improvement in the subjective symptoms

such as; relief from cramping and urgency was observed

compared to placebo controlled group. Crofelemer, a

puri ed proanthocyanidin oligomer from bark latex of

the plant has been investigated against secretory diar-

rhoea. It was found that the oligomer inhibits the Cl

channel with maximum inhibition of 60% and an IC

7μM (Tradtrantip et al., 2010). Indigenous anti-diar-

rhoeal plants such as; Acacia burkei, Brachylaena trans-

vaalensis, Cissampelos hirta, Sarcostemma viminale,

Psidium guajava, Catharanthus roseus, Melia azedarac,

Sclerocarya birrea and Strychnos madagascariensis etc.

are reported from KwaZulu-Natal Province, South Africa

(de Wet et al., 2010, Of ah et al., 2011).

Holarrhena antidysenterica, Curcuma amada, Ficus

glomerata and Butea monosperma are reportedly used

for treating diarrhoeal condition by tribals from Mad-

hya Pradesh, India (Singh and Sharma, 2011). Pharma-

cological activity against diarrhoea was investigated for

Acacia nilotica, Acanthospermun hispidum, Gmelina

arborea, Parkia biglobosa and Vitex doniana, the plants

used for diarrhoea treatment in Kaduna State, Nigeria

(Agunu et al., 2005). Randomized controlled trials for

the herbs; Curcuma longa, Cynara scolymus, Hypericum

perforatum, Iberis amara, Maranta arundinacea, Men-

the piperita, Paeonia lacti ora and Plantago psyllium

revealed that herbs are effective in management of IBS

associated symptoms. However, no relief was observed

in case of herbal preparations made up of Aloe vera,

Curcuma xanthorriza and Fumaria of cinalis. Apart

from single herbs, several polyherbal preparations such

as; Carmint, Padma Lax, STW 5, Tong-xie-ning and

Tong-Xie-Yao-Fang (traditional Chinese herbal prepa-

ration) and DA-IBS have also been found effective in

management of symptoms. STW-5 is most ef cacious

among these preparation, with different mechanisms of

action such as anti-in ammatory activity, prosecretory

activity, and effect on gastrointestinal motility (Rahimi

and Abdollahi, 2012).

Antidiarrhoeal activity of Psidium guajava Linn.

(Myrtaceae) is well studied (Salgado et al., 2006,

Gakunga et al., 2013). The plant is reported to show anti-

Pooja Rawat et al.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS AFFLICTIONS OF ENTERIC DISEASES IN HUMAN POPULATION 661

diarrhoeal activity through several mechanisms such as;

anti-microbial activity (Lutterodt et al., 1999), reduction

in gastrointestinal motility (Ezekwesili et al., 2010), inhi-

bition of adherence and invasion by pathogen (Birdi et

al., 2010). Broad spectrum antibacterial properties was

observed in case of Terminalia chebula and Syzygium

cumini.. The study revealed inhibition of multidrug

resistant strain of V. cholerae non-O1, non-O139 (strains

PC4 and PC65), Klebsiella pneumoniae strain PC36, A.

hydrophila strain PC16, Escherichia coli strain PC80

(ETEC), E. coli strain VT3 (Enterohaemorrhagic E. coli,

EHEC), Pseudomonas aeruginosa ATCC 15442 and Bacil-

lus subtilis ATCC 6623, with MBC ranging from 0.25

to 4 mg/ml (Acharyya et al., 2009). Medicinal Plants,

Caesalpinia bonducella, Gardenia gummifera and Acacia

arabica from Melghat Forest in India, showed antibac-

terial potential against Escherichia coli, Staphylococcus

aureus, Klebsiella pneumoniae, Proteus vulgaris, Sal-

monella typhi, Shigella  exneri, Salmonella paratyphi,

Salmonella typhimurium, Pseudomonas aeruginosa, and

Enterobacter aerogenes (Tambekar et al., 2009).

Apart from these, several plant preparations men-

tioned in Ayurveda such as; Pashanbhed churna,

Arjuna churna, Bilba churna, Amla churna, Gokharu

churna, Panchasakar churna, Trikatu churna, Avipatti-

kar churna, Chandanadi churna and Pushyanug churna

used for treatment of various infectious diseases have

been shown to possess antibacterial activity (Tambekar

et al., 2010). The natural compounds have proven to be

a rich source of biologically active materials. This has

resulted in the development of several new lead chemi-

cals for pharmaceuticals. The plant extracts and their

phyto-constituents can therefore be utilized as an alter-

native to antibiotics and other medicines for treatment

of enteric infections and diseases caused by microbes.

The plant based medicines though considered to be safe

for human consumption also presents with the problem

of drug resistance, known as herbal antimicrobial drug

resistance (HADR), with cases of resistance observed in

case of a number of clinical and non-clinical isolates

(Kavanaugh and Ribbeck, 2012, Pattiyathanee et al.,

2009, Vadhana, 2015).

Probiotics

Probiotics, are live organisms which when consumed in

adequate amount confer a health effect on host (Hotel,

2001). There is mounting evidence that several de ned

strains of non-pathogens such as; Lactobacilli and Bi -

dobacterium are safe for human consumption and ben-

e cial for prevention and treatment of acute infectious

diarrhoea (Allen et al., 2010, Johnston and Thorlund,

2009) as well as antibiotic associated and travelers’ diar-

rhea byrestoring the natural balance in the intestinal

tract. Culturelle, one of the probiotics, reduced the inci-

dence of diarrhoea by 41% in one of the study. The daily

dose for Culturelle is one pill containing 10 billion CFU.

There are no reports suggesting its signi cant side-

effects except for the rare cases of people having com-

promised immune systems. In one of the metaanalysis

study of sixty-three randomized and quasi-randomized

controlled trials, effect of probiotic agent was studied

and it was concluded that the probiotics provide bene -

cial effects in shortening of the duration and reduction

in the stool frequency in case of acute infectious diar-

rhoea (Allen et al., 2010). Similar results were observed

in another meta-analysis study evaluating the use of

probiotics for prevention and treatment of antibiotic

associated diarrhoea (AAD). A total of 82 RCTs of pro-

biotics (Lactobacillus, Bi dobacterium, Saccharomyces,

Streptococcus, Enterococcus, and/or Bacillus) were ana-

lyzed. Signi cant association of probiotic administra-

tion with reduction in AAD was observed(Hempel et al.,

2012).

SUMMARY

Child mortality due to diarrhoea in developing coun-

tries can primarily be attributed to infections caused

by pathogenic microorganisms. Signi cant reduction

in mortality has been achieved over the past 15 years

by adopting simple prevention initiatives such as; better

sanitization practices, encouraging longer breast feed-

ing of infants and vaccination. Complete eradication

of the diarrhoea related mortality is possible by timely

management and prevention of severe dehydration

associated with the disease. Oral rehydration therapy is

simple and cost effective to achieve the targets. Herbal

medicines and phyto-ingredients based therapeutics is

well proven through scienti c studies and long history

of their traditional use. These potential therapeutics are

economical to produce and easily accessible to the peo-

ple who generally don’t have easy access to antibiotics

and other treatment methods. Phytochemicals therefore

represent a potentially effective management strategy

for diarrhoea in high risk populations.

ACKNOWLEDGEMENTS

Authors are grateful to Prof Anil Gupta, Executive Vice

Chair, National Innovation Foundation India for his

honorary guidance and encouragement for carrying out

research activities.

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