Journal of Functional Foods 17 (2015) 189201

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Prebiotics, gut microbiota and metabolic risks:

Unveiling the relationship
Adeela Yasmin a,*, Masood Sadiq Butt b, Muhammad Afzaal a,
Marleen van Baak c, Muhammad Tahir Nadeem a,
Muhammad Zia Shahid a
a

Department of Food Science, Government College University, Faisalabad, Pakistan

National Institute of Food Science and Technology, University of Agriculture, Faisalabad, Pakistan
c
Department of Human Biology, Faculty of Health, Medicines and Life Sciences, Maastricht University, The
Netherlands
b

A R T I C L E

I N F O

A B S T R A C T

Article history:

The human gastrointestinal tract is colonized by trillions of microbes comprising thou-

Received 20 July 2014

sands of bacterial phylotypes. Recent metagenomic studies of the human gut microbiota

Received in revised form 1 May 2015

have revealed the presence of millions of genes, as compared to genes present in the entire

Accepted 8 May 2015

human body. Perturbation in the level of gut microorganisms may lead to the onset of meta-

Available online 6 June 2015

bolic disorders. However, compelling evidence has also suggested that a particular gut microbial
community may halt the occurrence of metabolic risk factors. Restoration of the beneficial

Keywords:

gut microbial balance is difficult to achieve but the exploitation of prebiotics has led to prom-

Metabolic disorders

ising outcomes in various studies.

Prebiotics

2015 Elsevier Ltd. All rights reserved.

Gut microbes
Bifidobacteria
Hypercholesterolaemia
Hyperglycaemia

Contents
1.
2.
3.
4.
5.
6.

Introduction ......................................................................................................................................................................................
Prebiotics and metabolic syndromes ............................................................................................................................................
Bifidogenic effects of prebiotics .....................................................................................................................................................
Hypocholesterolaemic perspectives ..............................................................................................................................................
Hypoglycaemic facets ......................................................................................................................................................................
Conclusion ........................................................................................................................................................................................
References .........................................................................................................................................................................................

190
190
191
193
195
197
198

* Corresponding author. Department of Food Science, Government College University, Faisalabad, Pakistan. Tel.: +92 3076744835; fax: 0419200671.
E-mail address: adeelayasmin2k@yahoo.com (A. Yasmin).
http://dx.doi.org/10.1016/j.jff.2015.05.004
1756-4646/ 2015 Elsevier Ltd. All rights reserved.

190

1.

Journal of Functional Foods 17 (2015) 189201

Introduction

Prebiotics are non-digestible food components that

selectively stimulate the growth or activity of specific indigenous bacteria in the digestive tract in a manner claimed to
be beneficial for the host. They were identified in the early
1950s by Gyorgy (1953) as bifidus factor, a bifidogenic substance that selectively improved the growth of bifidobacteria.
The term prebiotic was first devised in 1995 by Gibson and
co-workers (Gibson & Roberfroid, 1995; Sharma, Agarwal, &
Verma, 2012). Earlier work on prebiotics only elaborated on
the microbial changes in the human digestive ecosystem. Later
work provided evidence that prebiotics allow desirable changes
in the composition as well as the activity of the gastrointestinal microflora and confer health benefits to the host
(Kanakupt, Boler, Dunsford, & Fahey, 2011; Nagpal, Yadav, &
Marotta, 2014).
Prebiotics are primarily carbohydrates (oligosaccharides and
polysaccharides), but may include some non-carbohydrate moieties. Soluble fibres are the most prevailing type of prebiotics.
Nevertheless, various other forms of dietary fibre may serve
the purpose. In this context, criteria have been established to
categorize any food ingredient as a candidate prebiotics: they
have the ability to resist gastric hydrolysis by digestive enzymes
and remain unabsorbed in the upper gastrointestinal tract; they
undergo fermentation by resident microbiota in the large intestine; and they stimulate the activity/growth of potentially
beneficial intestinal bacteria (Xiao, Fei, & Pang, 2014; Yeo, Ooi,
Lim, & Liong, 2009).
Mechanistically, prebiotics are non-viable food constituents having pronounced effect on human health by modulating
colonic microflora (FAO, 2007). They induce specific changes in
the composition of gut microbiota, increase the number of
bifidobacteria and lactobacilli. Alongside, prebiotics decrease the
toxin-producing bacteria like bacteroides, proteolytic clostridia and Escherichia coli (Ogueke, Owuamanam, Ihediohanma,
& Iwouno, 2010). According to the criteria, many non-digestible
food oligosaccharides exhibit prebiotic activities. Likewise,
fructooligosaccharides, xylooligosaccharides, isomaltooligosaccharides and glucooligosaccharides as well as some sugar
alcohols and polysaccharides (modified and resistant starch)
are also included in this category. They can either be produced enzymatically or found naturally in some plants
(Cummings, Macfarlane, & Englyst, 2001).
The promising health benefits associated with prebiotics are
improvement in the gastrointestinal microflora, enhanced
mineral absorption, stimulation of the immune system, reduced
risk of irritable bowel syndrome and of constipation (Gibson,
Probert, van Loo, Rastall, & Roberfroid, 2004). They also prevent
colorectal cancer and exhibit cholesterol lowering potential
(Kelly, 2003). Nevertheless, the health enhancing effects of
prebiotics are not direct as they selectively nourish the microbial community i.e. lactobacilli and bifidobacteria that in turn
improve gut health. Approximately 300 to 500 species of bacteria occur in the human gastrointestinal tract that becomes
denser in the large intestine, approaching a concentration of
microbial cells 1011/g of luminal content (Guarner & Malagelada,
2003). It has been established that almost 55% of faecal bulk
consists of microorganisms. The microbial colonization in the

digestive tract is markedly influenced by transit time and

luminal pH (Paineau et al., 2008).
The majority of colon bacteria are anaerobes that avail
energy through fermentation. In this context, main fermentative substrates from dietary source are non-digestible
carbohydrates i.e. oligosaccharides, fibres, resistant starches and
non-starch polysaccharides that escape digestion in the small
intestine. Nonetheless, carbohydrate fermentation products are
effective substrates leading to gradient utilization by the colon
(Macfarlane, Steed, & Macfarlane, 2008). The ascending colon
can break down the sugars and the mass of incoming carbohydrates is being fermented to short chain fatty acids (SCFAs),
mainly acetate, propionate and butyrate. Besides, other metabolites like pyruvate, lactate, succinate and ethanol as well
as gases H2, CO2, H2S and CH4 are produced (Whelan, Judd, &
Preedy, 2005).
SCFAs are captured by the colonic mucosa and contribute
towards energy needs of the host. Acetate is primarily metabolized in the kidney, heart, brain and human muscles, whilst
propionate, a glucogenic precursor, suppresses cholesterol production. Butyrate is utilized by the colonic epithelium where
it helps in cell growth regulation and differentiation (Sangwan,
Tomar, Singh, Singh, & Ali, 2011).
Prebiotics exhibit imperative technological properties as well
as attractive nutritional value. In food formulations, they appreciably upgrade sensory features and improve taste and
mouth feel. In order to become part of functional food, prebiotics
must be stable to processing conditions like heat, pH and
Maillard reaction because degraded mono- and disaccharides are not available for bacterial fermentation. Previous
investigations on prebiotics have shown that heating at low
pH causes reduction in prebiotic activity whilst other conditions did not alter stability (Al-Sheraji et al., 2013; Bohm, Kaiser,
Trebstein, & Henle, 2006).
Inclusion of prebiotics in food is a natural way to provide
healthy ingredients to the consumers. Most of the prebiotics
are easily consumable and give desired functionality to the food
items (Courtin, Swennen, Verjans, & Delcour, 2009). For instance, short chain prebiotics act like sugars and contribute
to crispiness and browning of the end product. Long chain
prebiotics work as fat replacer, escalate the texture and
mouthfeel. The majority of the prebiotics are not considerably distorted or damaged by processing treatments, thus
retaining their functionality throughout the alimentary tract.
Contrarily, most of the probiotics in the finished products have
been killed due to harsh processing conditions that are required to eradicate microbes for food safety reasons (Bohm
et al., 2006).

2.

Prebiotics and metabolic syndromes

Recent advances to curtail disease progression have opened

new avenues for the development of prebiotic-based dietary
interventions to halt the incidence of metabolic dysfunction
(Riccioni et al., 2012). In the present scenario, production of designer foods with natural ingredients like prebiotics is a
pragmatic approach. A number of epidemiological studies have
illuminated the cardioprotective effect of diets high in

Journal of Functional Foods 17 (2015) 189201

phytochemicals (vitamins, minerals, antioxidants) and fibres

(Ignarro, Balestrieri, & Napoli, 2007). In this context, a meta
analysis conducted by Anderson, Aziz, and Samra (2002) showed
a decrease in LDL by 6.2 and triacylglycerols by 22% with increased intake of soluble dietary fibres, oligosaccharides and
isoflavones.
The human gastrointestinal tract contains trillions of microorganisms (approximately 1013) including thousands of
bacterial phylotypes with a combined genome (micro-biome)
encoding a number of genes that even exceeds the human
genome (Neish, 2009; Suchodolski, Markel, & Garcia-Mazcorro,
2012). Innovations in metagenomic technologies have started
to unravel the relationship between composition of gut
microbiota and metabolic disorders like obesity and diabetes. Researchers have observed that obesity may cause a shift
in microbial composition both in animals and humans. Likewise, lean experimental animals have an abundance of
bacteroides compared to obese in which firmicutes are dominant (Turnbaugh, Backhed, Fulton, & Gordon, 2008; Xiao & Zhao,
2014). Moreover, the metagenome of obese animals is rich in
genes that encode complex polysaccharides catabolism, subsequently increasing the amount of energy absorbed from the
gut (Hooda et al., 2012). In this regard, an assenting impact of
prebiotics supplementation has been documented on food
intake, weight management, plasma lipid profiles, glucose homeostasis and related risk factors (Piche et al., 2003). The
underlying protective mechanisms of prebiotics includes modulation of gut microbiota, induction of enteroendocrine L cell
proliferation, alteration in secretion of gut peptides and changes
in inflammatory response (Furet et al., 2010).

3.

Bifidogenic effects of prebiotics

Dietary patterns based on therapeutic ingredients influence consumers health in multifarious ways. Likewise, the intestinal
probiotics affects numerous physiological aspects and are
helpful to generate desirable constituents. The association
between colonic microorganisms and vulnerability to diseases has set forth the demand of new functional products for
healthy intestinal activity (Peng, Geetika, & Debabrata, 2015;
Sonnenburg et al., 2010). Diet can alter the functional metabolism of the intestinal microbiome. Many molecules in foods are
substrates for the intestinal microbiota, which then produce
small molecules that after metabolism in the liver, affect host
physiology. For example, indigestible carbohydrates in the diet
are fermented by the intestinal microbiota to produce shortchain fatty acids, with a number of beneficial functions for the
host. The intestinal microbiota may also contribute to the development of atherosclerosis by producing metabolites of the
dietary lipid phosphatidylcholine that are associated with the
risk of coronary vascular disease (Albenberg & Wu, 2014; Le
Chatelier, Nielsen, & Qin, 2013).
Foods rich in phosphatidylcholine are a major source of
choline. Catabolism of choline by the intestinal microbiota
results in the formation of the trimethylamine (TMA), which
is metabolized by the liver into trimethylamine oxide (TMAO).
This small molecule is strongly associated with an increased
risk of coronary vascular disease in humans. A similar pathway

191

has been identified for conversion of dietary carnitine, which

is high in red meat, into TMAO. Researchers have identified the
bacterial gene family responsible for the conversion of choline
into TMA. These genes are choline TMA lyases. Using this information, it might be possible to develop technologies to
quantify patients risk of heart disease related to consumption of choline, based on proportions of bacteria in the gut that
carry choline TMA lyase genes. Eventually, it might also be possible to reduce or remove bacteria that express TMA lyases from
the intestine (Claesson, Jeffery, & Conde, 2012; David, Maurice,
& Carmody, 2014).
The gastrointestinal tract occupied by microbial cells is a
key component affecting the body defence system. In addition to providing physical barrier against toxins and pathogens,
the intestinal locale also provides protection in the form of gut
associated lymphoid tissues (GALT). The microbial composition of human gastrointestinal (GI) tract is diverse with more
than 90% of the cells belonging to Firmicutes or Bacteroidetes
(Hooper, 2009; Turnbaugh et al., 2009). Numerous factors influence the number and diversity of microbiota in different
zones of human GI tract like peristalsis, nutrient availability,
oxidation reduction potential, pH, host health and age, host
bacterial adhesion, mucin secretions containing immunoglobulins (Igs), bacterial antagonism and transit time. In this
regard a study conducted by Hedvig et al. (2015) highlights that,
genetically comparable animals housed in the similar facility
can have distinct microbiota and intestinal barrier structures. It was also noticed that microorganism and their resident
structure affect mucus barrier function in a manner that has
implication for health and disease interaction. Moreover,
changes in the diet, antibiotic treatment, inflammation, obesity
and weight loss may alter the communication and function
of microbial population residing in the gut (Frank et al., 2007).
Alteration in the typical microbial composition has been associated with several metabolic disorders (Frank et al., 2007).
Globally, gut infections are still one of the major causes of
ailments. Owing to large scale antibiotics consumption and development of resistant bacterial strains, various research
outcomes indicated that dietary non-digestible oligosaccharides have potential to modulate intestinal infections by altering
the composition of gut microbiota (Ogueke et al., 2010). Moreover, some studies have also revealed that oligosaccharides
facilitate the growth of bifidobacteria and lactobacilli. These bacteria enhance the production of SCFAs and compete for
nutrients and adhesion sites that create undesirable circumstances for pathogen invasion (Hosono et al., 2003). SCFAs such
as acetate, propionate and butyrate may reduce the survival
of acid-sensitive bacteria like salmonella. Additionally oligosaccharides augment the integrity of the intestinal mucosa by
increasing villous height, mucin release and mucosal biofilm
composition. Prebiotic oligosaccharides may help the function of probiotics and synbiotics, thus representing a novel
therapeutic strategy (Koropatkin, Martens, Gordon, & Smith,
2009). Several clinical studies have elucidated that oligofructose
and inulin administration significantly increases intestinal
bifidobacteria population. The optimum dose of inulin type
fructans ranged from 4 to 15 g/day, however some individuals respond to a low dose level of 1 g/day. Later, Bouhnik et al.
(2006) determined the bifidogenicity of FOS at a dose rate of
2.5 to 10 g/day. Forty volunteers consuming usual diet were

192

Journal of Functional Foods 17 (2015) 189201

Table 1 Summary of bifidogenic effects of prebiotics.

Substrate

Subjects/Animals

Dose/Duration

Result

Reference

Short chain
fructooligosaccharides
(FOS)
FOS

Human volunteers

2.5, 5.0, 7.5, 10 g/day

or placebo for one week

FOS has bifidogenic properties and

were well-tolerated

(Bouhnik et al., 2006)

Healthy men

20 g for three weeks

(Sandra et al., 2006)

Inulin
FOS

Healthy volunteers
Human subjects

(5 and 8 g/day) for two weeks

0 to 20 g/day for one week

Konjac Glucomannan
Hydrolysate (GMH)

In vitro
Human faeces

Polydextrose and soluble

corn fibre

Healthy adult men

14 g/day for 21 days

Significantly increased faecal wet

weight, lactobacilli, bifidobacteria and
lactic acid
Significant increase in bifidobacteria
Distinct increase in faecal
bifidobacteria
Significant increase in the number
of bifidobacterium genus,
lactobacillusenterococcus and the
atopobium
Greater increase in faecal
Clostridiaceae and Veillonellaceae
and lower level of Eubacteriaceae

randomly divided into 5 groups and given ScFOS at 2.5, 5.0, 7.5,
10 g/day or placebo for one week. The stool samples were collected at the initiation and termination of the study period and
analyzed for microbial counts. The increase in bifidobacterial
count was 9.15 to 9.39, 10.21 to 10.6, 9.28 to 9.8 and 9.00 to 10.18
log cfu/g for respective dose levels. They concluded that FOS
has bifidogenic properties and were well-tolerated at doses
ranging from 2.5 to 10 g/day. Likewise, a trial was conducted
in human subjects to explore the role of fructooligosaccharides
on intestinal health. Thirty four healthy men were provided
lemonade with 20 g FOS and the intestinal permeability marker
(chromium EDTA) for three weeks. It was observed that fermentation of FOS significantly increased faecal wet weight,
lactobacilli, bifidobacteria and lactic acid (Sandra et al., 2006). Later,
a double-blind cross over human study by Kolida et al. (2007)
explored the bifidogenic efficacy of inulin (Table 1).
The healthy volunteers were provided chocolate drinks containing maltodextrin (8 g/day) or inulin (5 and 8 g/day) for two
weeks. A significant increase in bifidobacteria was noted at the
termination of study as compared to the control, thus suggesting inulin as a bifidogenic agent. Bouhnik et al. (1999) fed
humans with different doses of fructooligosaccharides from
0 to 20 g/day for one week. They observed a significant modulation of gut microflora with distinct increase in faecal
bifidobacteria and concluded that a 10 g/day dose of FOS is welltolerated in humans. Increased microbial population further
contributes to faecal bulk and stool consistency and thereby
stimulates passage through the colon resulting in reduced
transit time. Prebiotics also reduce the colonic resorption of
water, hence the stool becomes softer with increased frequency, thereby alleviating constipation, root cause of many
disorders (Flint et al., 2007; Sharma et al., 2012; Tateyama et al.,
2005). In this connection, a study was conducted on constipated adults that showed significant laxative effect of inulin
type fructans (20 g/day) as compared to the control (Brandt,
2001). Later, contribution of polydextrose (PDX) and soluble corn
fibre (SCF) to human gut microbiome and host physiology was
studied by Hooda et al. (2012). Purposely, they enrolled twenty
healthy adult men who consumed 14 g/day dietary fibre (DF).
They used three treatments i.e., snack bars/day that contained no supplemental fibre (NFC), polydextrose, or SCF during

(Kolida et al., 2007)

(Bouhnik et al., 1999)
(Connolly et al., 2010)

(Hooda et al., 2012)

each 21-day period. Faecal samples were collected at 1621 of

each period, afterwards DNA was extracted and amplification of the V4V6 regions of the 16S rRNA gene was done
using barcoded primers. They recorded greater increase in faecal
Clostridiaceae and Veillonellaceae and lower level of
Eubacteriaceae in PDX and SCF as compared to NFC consumption. Moreover a significant incline in faecal bacterium was
noticed as compared to NFC. This bacterium is known for its
anti-inflammatory properties.
Human milk contains high concentration of oligosaccharides and antibodies that maintain required bifidobacterial
population in infants and contribute to natural defence system
(Knol et al., 2005). However, formula-fed babies have altered
microbiota in their digestive tract with higher risk of pathogens (staphylococci, enterobacteria and clostridia) invasion. For this
reason, researchers are investigating the role of prebiotics in
infant formulation to enhance the bifidogenic effect and immunity (Arslanoglu et al., 2007). Bifidogenic features of
oligofructose and inulin were observed in children (aged 6
months) at a dose level 1.7 g/day. Correspondingly, another study
revealed momentous bifidogenic effect in formula-fed babies
(12 weeks of age) consuming 1.5 g/day of native inulin (Kim,
Lee, & Meyer, 2007). Furthermore, infant formulation comprising a blend of fructooligosaccharides and galactooligosaccharides (1:9) was found effective to promote microbiota
as in breast fed babies. In the tested groups, a higher level of
faecal short chain fatty acids, higher pH and a larger faecal
bifidobacterial population were recorded. There was also an improvement in stool characteristics, frequency and consistency
as compared to control formula (Knol et al., 2005). Recent studies
have also showed that prebiotics supplementation to infant
formula reduces the occurrence of systemic and intestinal infections and has a remarkable influence on immunity
development, microbial ecology and body defence (Sharma
et al., 2012).
Beneficial effects of oligosaccharides on gut health have also
been documented in various studies including animal species
besides human. Accordingly, Rodriguez-Cabezas et al. (2010) examined the synergistic effect of two types of dietary
fibres, fructooligosaccharides and resistant starch in healthy
or trinitrobenzenesulphonic acid (TNBS) colitic rats.

Journal of Functional Foods 17 (2015) 189201

Administration of prebiotics modulated the intestinal microbiota

by increasing bifidobacteria and lactobacilli in caecum and colonic
contents. Furthermore, they also improved the barrier characteristics of intestine in comparison to untreated rats. Earlier,
Hsu, Liao, Chung, Hsieh, and Chan (2004) investigated the
impact of fructooligosaccharides (FOS) and xylooligosaccharides
(XOS) on the alteration of caecal weight, pH, caecal microbiota,
serum lipids and pre-cancerous colon lesions in rats. For this
purpose, male Sprague Dawley rats were randomly assigned
to four groups and fed on test diets for 35 days. At the termination of study noticeable decline was observed in the caecal
pH and serum triacylglycerols level whilst a significant increase in caecal total weight and bifidobacteria population was
obtained. They concluded that dietary supplementation of
prebiotics is beneficial for gastrointestinal health. Additionally, intestinal indigestible oligosaccharides fermentation
resulted in enhanced production of faecal short chain fatty
acids, total anaerobes and bifidobacteria with concomitant reduction in faecal pH in rats (Campbell, Fahey, & Wolf, 1997).
Later studies in mice also proved the health enhancing effect
of oligosaccharides on bowel wet weight, caecal short chain
fatty acids (SCFAs) and caecal microbiota level (Pan, Chen, Wu,
Tang, & Zhao, 2009).
Earlier Xu et al. (2002) determined the effect of
fructooligosaccharides supplementation on intestinal microflora, digestive enzymes and morphology of growing pigs. One
hundred twenty eight growing pigs were allocated to four treatments during a forty-two day trial. They were given FOS at 0,
2, 4, 6 g/kg of diet. Comparison of the fructooligosaccharide
groups with control showed a significant increase in the growth
of bifidobacterium and lactobacillus in the small intestine and
proximal colon, accompanied by a decrease in the production of clostridium and E. coli. Moreover, supplementation of FOS
improved the activities of digestive enzymes and intestinal morphology. The bifidogenic potential of a konjac glucomannan
hydrolysate (GMH) was explored in vitro using batch culture inoculated with human faeces by Connolly, Julie, and Kieran
(2010). They used culture independent technique and fluorescent in situ hybridization for bacterial enumeration and gas
chromatography for SCFA quantification. They observed a significant increase in the number of bifidobacterium genus,
lactobacillusenterococcus and the atopobium group as a result
of GMH and inulin fermentation. Similar findings have also been
documented for other animals like dogs, cats, horses and
poultry birds (Berg, Fu, Porter, & Kerley, 2004; Faber, Hopkins,
Middelbos, Price, & Fahey, 2011; Kim, Seo, Kim, & Paik, 2011;
Rehman, Hellweg, Taras, & Zentek, 2008).

4.

Hypocholesterolaemic perspectives

Increased serum cholesterol and triacylglycerols (TAG) along

with (abdominal) obesity, insulin resistance and arterial hypertension are components of the metabolic syndrome.
Cholesterol is the main cause for the accumulation of fatty deposits in the inner lining of arteries leading to atherosclerosis
and onset of heart disease, stroke and other vascular diseases. It is estimated that about 18% of the stroke events and
56% of the heart diseases worldwide are ascribed to high cholesterol level (Alissa & Ferns, 2012).

193

At present, management of serum cholesterol and TAG

through dietary intervention is attaining core attention of nutritionists. This is mainly driven to curtail the high expenses
of drug therapy and their side effects prevailing in developing regions. Current dietary interventions include use of plantbased bioactive ingredients like soluble fibres and soy proteins.
Similarly inulin-type fructans alter the digestion, metabolism and absorption of lipids resulting in the reduction of serum
lipids as well as redistribution of lipids among various lipoproteins (Guida & Koen, 2015).
Convincing lipid lowering potential of prebiotics has been
observed in an array of animal studies. These investigations
have demonstrated that inulin-type fructans decrease both
fasting and postprandial plasma triglyceride levels mainly due
to a decrease in VLDL and triacylglycerol concentrations in the
post-absorptive state (Busserolles, Gueux, & Rock, 2003). The
principal hypotriglyceridaemic mechanism is reduction in liver
lipogenesis through increased short chain fatty acids production in the bowel. Acetate and propionate arrive in the liver
after absorption by the colonic mucosa. Subsequently, acetate
is used as a substrate for de novo cholesterol and TAG synthesis whilst propionate exerts an antagonistic effect and inhibits
expression of lipogenic enzymes involved in cholesterol synthesis (Hosono et al., 2003). Therefore, the propionate/acetate
ratio formed during prebiotics fermentation is important in determining the cholesterol lowering capacity (Pereira & Gibson,
2002). Parnell and Reimer (2010) conducted a trial in lean and
obese 8 week old JCR:La-cp rats to identify the possible lipid
lowering mechanism of prebiotics. The rats were given 0, 10
and 20% prebiotic fibre for 10 weeks. At termination of the study
fasting blood samples were taken for lipid analysis. Liver and
caecal digesta cholesterol and TAG content were also quantified. They noted a decrease of 24% in serum cholesterol and
42% in TAG by providing 10% prebiotic enriched diet to obese
hyperlipidaemic rats. This decline was attributed to an increase in caecal digesta along with up regulation of genes
involved in cholesterol synthesis and bile production. The role
of chicory extract and inulin as a cholesterol reducing agent
was proposed by Kim and Shin (1998). They observed that rats
fed chicory extract (15%) and inulin (5%) have significantly
greater faecal lipids, cholesterol and bile acid excretions than
those fed on fibre free diet. The tested groups have significantly higher serum high density lipoprotein (HDL) and
decreased low density lipoprotein (LDL) concentrations, resulting in significantly greater HDL/LDL ratio as compared to
the control. The serum apolipoprotein B/apolipoprotein (A-1)
ratio was significantly lowered in rats fed on diet containing
chicory extract or inulin than fibre free diet due to significant
reduction in apolipoprotein B concentration. Considering the
results, they documented improvement in lipid metabolism due
to alteration in the synthesis or absorption of cholesterol, resulting from changed caecal fermentation or increased excretion
of cholesterol and bile acids. Some researchers have also delineated that consumption of fructooligosaccharides (10
15%) supplemented feed induced significant reduction in total
body fat deposition and triacylglycerol by 25% in rats (Ogueke
et al., 2010). The decrease is due to reduction in circulating VLDL
particles. Ingredients exhibiting prebiotic activity are able to
alter the accumulation of either TAG in the liver (steatosis) or
serum lipids in rats and hamsters (Delzenne & Cani, 2008).

194

Journal of Functional Foods 17 (2015) 189201

Table 2 Summary of hypocholesterolaemic effects of prebiotics.

Substrate

Subjects/Animals

Dose/Duration

Result

Reference

Prebiotic fibre

Lean and obese rats

0, 10 and 20% prebiotic fibre

(Parnell & Reimer, 2010)

Chicory extract
inulin

Rats

Chicory extract (15%) and

inulin (5%)

FOS

Rats

(1015%)

FOS

Healthy dogs

1% of diet for 6 weeks

Long chain fructan

Raftiline

Mice

Fructans

Rats

Inulin

Broilers

0 and 10% Raftiline was

given to the mice along
with isocaloric purified diet
for a period of 16 weeks
Semi-purified diets
supplemented with
oligofructose (5 or 10% of
diet) and chromium as
Cr(III) propionate complex
(0.5 or 5 mg/kg of diet)
90 g/kg of diet for 34 days

Decrease of 24% in serum cholesterol and

42% in TAG by providing 10% prebiotic
enriched diet to obese hyperlipidaemic
rats
Significantly higher (HDL) and decreased
(LDL) concentrations, resulting in
significantly greater HDL/LDL ratio as
compared to the control
Significant reduction in total body fat
deposition and triacylglycerol by 25% in
rats
Increase uncoupling protein 2 and
carnitine palmitoyltransferase 1
expression in adipose enhance substrate
oxidation in the adipocyte
A significant reduction in plasma
cholesterol, LDL, IDL and VLDL from 9.12
to 6.41, 2.36 to 1.70, 1.27 to 0.77 and 1.53
to 0.96 mmol/L, respectively
Significant reduction in TAG level in rats
fed oligofructose plus chromium.
Non-significant differences for other
parameters including fat digestibility

Likewise, in non-obese rats and hamsters fed on high carbohydrate diet, a reduction in hepatic and serum TAG was
observed after supplementation of inulin type fructans at 2.5
to 10% for 212 weeks.
In animal trials, reduced triglyceridaemia or steatosis is attributed to decrease in de novo lipogenesis in the liver (Delzenne
& Williams, 2002). Nonetheless, in obese Zucker rats, dietary
supplementation of inulin type fructans decreased the hepatic
steatosis without affecting postprandial triglyceridaemia
(Daubioul, Taper, & De Wispelaere, 2000). Additionally, in obese
dogs, supplementation of short chain fructooligosaccharides
increase uncoupling protein 2 and carnitine palmitoyltransferase
1 expression in adipose tissues thereby enhancing substrate
oxidation in the adipocyte without imparting significant
changes in TAG (Respondek, Swanson, & Belsito, 2008) (Table 2).
Such decline in TAG synthesis and accumulation might be
associated with a decrease in glycaemia, since glucose (along
with insulin) triggers lipogenesis. Earlier, Mortensen, Poulsen,
and Frandsen (2002) reported the modulatory role of long chain
fructan Raftiline against hypercholesterolaemia and atherosclerosis. During the entire trial 0 and 10% Raftiline was given
to the mice along with isocaloric purified diet for a period of
sixteen weeks. There was a significant reduction in plasma cholesterol, LDL, IDL and VLDL from 9.12 to 6.41, 2.36 to 1.70, 1.27
to 0.77 and 1.53 to 0.96 mmol/L, respectively. Likewise, Krejpcio,
Wjciak, Staniek, and Wis niewska (2009) probed the
hypocholesterolaemic effect of fructans through rats modelling study. The rationale was to evaluate the effect of inulin
type fructans and chromium supplementation on blood lipid

Decrease in liver total lipids,

triacylglycerol concentrations and serum
very low density lipoprotein as compared
to the control

(Kim & Shin, 1998)

(Ogueke et al., 2010)

(Respondek et al., 2008)

(Mortensen et al., 2002)

(Krejpcio et al., 2009)

(Velasco et al., 2010)

indices and fat digestibility. For the purpose, rats were administered semi-purified diets supplemented with oligofructose (5
or 10% of diet) and chromium as Cr(III) propionate complex
(0.5 or 5 mg/kg of diet) in order to measure the total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein
(LDL) and triacylglycerols (TAG). At the termination of trial, there
was a significant reduction in TAG level in rats fed oligofructose
plus chromium. However, there were non-significant differences for other parameters including fat digestibility. Similarly,
Velasco et al. (2010) explored the effect of inulin on the performance of liver lipids, blood serum metabolites and fatty acids
of abdominal adipose tissue of broilers. At the termination of
34 days trial, a decrease in liver total lipids, triacylglycerol concentrations and serum very low density lipoprotein was noted
as compared to control. The results from the current study suggested that addition of inulin to broiler diet is favourable for
serum lipids by decreasing triacylglycerol concentration.
Previously, Chen, Nakthong, and Chen (2005) expounded that
supplementation of layers diet with oligofructose and inulin
(1%) significantly reduces yolk cholesterol level by 18.64 and
16.44% whilst serum cholesterol concentration by 17.75 and
16.23%, respectively. Furthermore, they increase the cholesterol concentration in the small intestine (jejunum) and
excretion from faeces. Earlier, Agheli et al. (1998) evaluated the
effect of short chain fructooligosaccharides on plasma lipids
and fatty acid synthase activity (FAS) in insulin resistant rats
for three weeks. They randomly divided male Sprague Dawley
rats in two groups fed either on sucrose rich diet (575 g sucrose/
kg diet) or sucrose rich diet supplemented with (10 g/100 g)

Journal of Functional Foods 17 (2015) 189201

fructooligosaccharides (S/FOS). At the termination of study, it

is deduced that addition of FOS to the diet resulted in 11% lower
liver and adipose tissue weight. Besides, plasma triacylglycerols,
free fatty acids and hepatic FAS activity were also reduced in
FOS supplemented group. They claimed that short chain
fructooligosaccharides in addition to being non digestible are
helpful for addressing dyslipidaemia and insulin resistance.
In order to determine the influence of diet on host metabolism and gut microbiota, Cox et al. (2013) carried out a research
trial on mice. They used hydroxypropyl methylcellulose (HPMC),
a nonfermentable fibre to investigate whether they alter the
gut microbiota and correlation of these changes to metabolic
improvement. For the purpose they fed C57B/L6 mice with
control (high-fat diet) (HFD), HFD supplemented with 10% HPMC
or a low-fat diet (LFD). They observed that when compared to
control both LFD and HPMC reduced the weight gain by 11.8
and 5.7 g, respectively, plasma cholesterol by 23.1 and 19.6%,
and liver triacylglycerols by 73.1 and 44.6%. Moreover, microbialdiversity was decreased and intestinal microbiota was altered
differentially as revealed by 454-pyrosequencing of the microbial 16S rRNA genes. They inferred that HPMC is a potential
prebiotic that influenced gut microbiota and improved the host
metabolism. Later, Martnez et al. (2013) unravel the association of faecal microbiota with cholesterol reduction in hamsters.
They proposed that diet based therapy comprising plant sterol
esters extensively modulated the cholesterol metabolism,
reducing the level of different bacterial taxa within
Coriobacteriaceae and Erysipelotrichaceae. They further narrated that association between bacterial taxa with faecal and
bile cholesterol excretion suggested that host cholesterol excretion can modulate microbiota structure due to antibacterial
action of cholesterol.
Human studies tend to confirm the data in experimental
animals. The effect of daily intake of inulin-enriched pasta on
glucose and lipid metabolism as well as gastrointestinal motility was investigated in young healthy subjects. Twenty-two
volunteers participated in a randomized double blind cross over
study consisting of a 2 week run in period followed by two study
periods (11% inulin enriched or control pasta) with 8 weeks
wash out period in between. Results showed significant differences among control and treated groups for HDL,
triacylglycerols, cholesterol/HDL ratio and glucose level. Additionally, gastric emptying was significantly delayed in the
treated group. The study provided evidence that prebiotics enriched pasta modulated lipid and glucose metabolism along
with insulin resistance (Russo et al., 2010). Earlier, Causey,
Feirtag, Gallaher, Tungland, and Slavin (2000) explored the
impact of inulin from chicory root on serum lipid parameters
and faecal composition in hypercholesterolaemic subjects. They
observed a significant reduction in serum triacylglycerols
(40 mg/dL) level by daily intake of 20 g inulin (added in vanilla
ice-cream) for three weeks. Likewise, a trend towards reduction in cholesterol and modification in SCFA was recorded.
Furthermore, research has established that addition of inulin
to a moderately high carbohydrate, low fat diet is beneficial
for plasma lipids by declining hepatic lipogenesis and
triacylglycerol concentrations. Purposely, eight healthy volunteers were given a moderately high carbohydrate, low fat diet
plus 10 g inulin/day for 3 weeks. The results indicated diminishing plasma triacylglycerol concentration and hepatic

195

lipogenesis after inulin ingestion at the termination of study

(Letexier et al., 2003). Furthermore, prebiotics effect was seen
in hyperlipidaemic subjects with pronounced reduction in cholesterol whilst in normocholesterolaemic subjects, plasma
triacylglycerols level was altered (Pereira & Gibson, 2002). According to Wong et al. (2010), intake of prebiotic fortified soy
caused significant reduction in low density lipoproteins thereby
improving the level of high density lipoproteins.
The protective effect of FOS against elevated lipid level was
investigated by Kelly (2009), who conducted a clinical trial on
subjects with type 2 diabetes. The subjects were given daily
dose of 8 g FOS for 14 days. Kelly (2009) found a 6 and 10% decrease in total cholesterol and LDL levels, respectively.
Balcazar-Munoz, Martinez-Abundis, and Gonzalez-Ortiz (2003)
probed the beneficial effects of inulin on serum lipid profile
of hypercholesterolaemic individuals. The subjects were provided inulin 7 g/day along with placebo for 4 weeks. They
concluded that inulin administration caused a significant decrease in total cholesterol from 248.7 to 194.3 mg/dL,
triacylglycerols 235.5 to 171.1 mg/dL, LDL 136.0 to 113.0 mg/
dL and VLDL concentrations from 45.9 to 31.6 mg/dL.
Accordingly, Brighenti (2007) performed a meta-analysis to
assess the protective role of oligofructose and inulin type
fructans against elevated serum cholesterol and triglyceride
levels. They examined human subjects to determine the
role of inulin type fructans on blood lipid profile. Fructooligosaccharides and inulin were shown to have potent serum
cholesterol and triacylglycerols lowering effects. The metaanalysis suggested that inulin type fructans are associated with
momentous decrease in serum triacylglycerols by 0.17 mmol/L
and have modulatory role against high cholesterol level. The
mechanism is related to colonic fermentation and release of
incretins from the distal gut.

5.

Hypoglycaemic facets

The high prevalence of diabetes in the developing world is shifting towards an epidemic. The striking increase in obesity and
weight gain are major risk factors contributing to various metabolic complications. The risk of insulin resistance increases with
advancing obesity (Deguchi & Miyazaki, 2010). Obesity may lead
to an insulin resistant state in the liver, muscle cells and adipose
tissue, resulting in distorted function of insulin targeted cells
and buildup of macrophages that secrete pro-inflammatory mediators. The excessive consumption of high glycaemic diets and
sucrose enriched soft drinks may further augment the incidence of dysglycaemic episodes (Manders, Pennings, Beckers,
Aipassa, & van Loon, 2009). Various studies have shown that
high fibre diets being statiogenic add viscosity and bulk to the
meals thereby slowing the gastric emptying. Additionally, foods
high in fibre slow down the process of glucose absorption which
decreases postprandial insulin. The fibre-enriched foods escape
digestion in the upper gastrointestinal tract and undergo fermentation in the colon, thus generating short chain fatty acids
(SCFAs), responsible for lowering gluconeogenesis and modulating insulin sensitivity.
Numerous epidemiological studies are indicating that the
incidence of diabetes has increased enormously in Western as

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Journal of Functional Foods 17 (2015) 189201

well as in Asian countries. Diabetes mellitus is a metabolic disorder characterized by impaired insulin action and secretion
leading to increased blood glucose level. The worldwide estimated cases of diabetes in the year 2000 were 171 million
comprising 2.8% of the total population. This endemic is thought
to put a huge burden due to several allied complications and
mortality risks (Nakamura & Omaye, 2012). It is imperative to
identify the modifiable risk factors involved in the development of this silent killer. The soluble fibres, i.e. inulin and
fructooligosaccharides, have been reported to stabilize blood
glucose level and exert their effect on lipid metabolism through
absorption of bile salts in the small intestine (Alegria & Vivanco,
2004). Everard et al. (2011) investigated a deep analysis of microbial communities of gut, after administration of prebiotics
in obese diabetic rats. They involved genetically or diet induced
diabetic mice and fed a prebiotic enriched or control diet. After
the end of study period they noticed decline in Firmicutes and
increase in Bacteroidetes phyla of microbiota. Additionally, they
recorded improvement in glucose tolerance, L-cell number and
associated parameters i.e., intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels, reduced
fat-mass development, oxidative stress, and low-grade inflammation. Moreover in high fat-fed mice, prebiotic administration
also improved the leptin sensitivity as well as metabolic associated parameters. They deduced that modulation of specific
gut microbiota improves glucose homeostasis, leptin sensitivity and target enteroendocrine cell activity in obese diabetic
mice. Moreover they can affect host metabolism in the state
of obesity and diabetes. In another experiment, Zaky (2009)
studied the impact of a diet supplemented with Jerusalem artichoke tubers powder in alloxan-induced diabetic rats. They
were daily supplied diets containing respective powder at 5,
10 and 15%. At the termination of study, a significant decrease in serum glucose level was noted in all groups (5, 10 and
15%) as compared to diabetic rats on control diet. Moreover,
improvements in liver and kidney functions were noticed. Conclusively, the jerusalem artichoke tubers powder was beneficial
against hyperglycaemia due to its soluble fibre content of mainly
fructooligosaccharides and inulin.
Substantial evidence has suggested that prebiotics may influence blood glucose and insulin levels positively by a variety
of mechanisms involved. They can trim down the amount of
glucose going to be absorbed in the blood stream and prevent
undue elevation of serum glucose by delaying gastric emptying or small intestine transit time after ingestion of food
(Respondek et al., 2008).
Modulation of glucose homeostasis by prebiotic oligosaccharides has been explored in animals under various genetic
or nutritional conditions leading to diabetes or glucose intolerance. Improvement in glycaemic response may be attributed
to increased insulin secretion or improved insulin sensitivity.
Prebiotics supplementation increased plasma insulin level and
ameliorated glucose intolerance associated with destruction
of -cells in streptozotocin treated rats. Treatment with inulin
type fructans restored -cells and pancreatic insulin secretion due to increased production of glucagon-like peptide 1
(Genta, Cabrera, & Habib, 2009; Reimer & Russell, 2008). Previously, Respondek et al. (2008) observed that 1%
fructooligosaccharides addition in the diet of obese dogs during
6 weeks considerably reduced insulin resistance. There were

also some modifications in expression of genes involved in

glucose homeostasis and lipid metabolism in adipose tissue.
It is hypothesized that insulin resistance (IR) results from
a combination of elevated blood glucose and fatty acids leading
to impaired hepatic -oxidation, increased fatty acid synthesis and hepatic steatosis. The fatty liver disease or steatosis
is a reversible condition where large fat vacuoles accumulate
in the liver cells (Lebovitz, 2002). Kaume, Willliam, Gadang, and
Devareddy (2011) explored the role of dietary fructooligosaccharides in reducing hepatic steatosis associated with
insulin resistance in obese zucker rats. Thirty-six 3 month old
female lean and obese rats were housed under controlled conditions and fed a diet containing 5% FOS for hundred days. At
the termination of the study period, serum concentrations of
glucose, glycosylated haemoglobin (HbA1c), lipid profile and
peroxisome proliferator activated receptor (PPAR) gene expression were determined. They noticed a significant decrease (12%)
in total liver lipids and liver weight as compared to control
group. Serum insulin concentration was also reduced by 3.6
times in the FOS treated group. It was concluded that supplementation of fructooligosaccharides was supportive against the
peril of non-alcoholic fatty liver disease associated with insulin
resistance. Additionally, it was observed that high fat diets
induce a state of low grade inflammation related to decreased number of bifidobacterium species in caecum and
increased plasma endotoxin (lipopolysaccharides), called metabolic endotoxaemia. Therefore, lipopolysaccharides are
considered as unique factor triggering high fat diet-induced
obesity and type 2 diabetes (Deopurkar et al., 2010; Ghoshal,
Witta, Zhong, de Williers, & Eckhardt, 2009). Conversely,
bifidobacteria may improve mucosal barrier function by reducing the level of endotoxins. Hence, research is being focused
to increase the gut bifidobacterial number through prebiotic
dietary supplementation. In this context, Cani, Joly, Horsmans,
and Delzenne (2006) conducted a 14 week study in mice to judge
the effect of fructooligosaccharides on high fat diet-induced
diabetes. They recorded that high fat diet considerably reduced
the intestinal gram-positive and gram-negative bacteria, including bifidobacteria that are physiologically beneficial for the
host. Fructooligosaccharides administration restored the number
of bifidobacteria and ultimately soothing the endotoxaemia. They
inferred that higher bifidobacterium population is positively correlated with the modulation of glucose tolerance and insulin
secretion due to decreased endotoxaemia and proinflammatory
cytokines. In another study conducted by Tachon, Zhou, Keenan,
Martin, and Marco (2013), it was revealed that age-related debilities in health can be prevented or reversed through dietary
interventions by modification in the composition as well as activity of intestinal microbiota. They applied 16S rRNA gene
amplicon sequencing to determine the bacterial structure. For
the purpose they used 20-month-old healthy mice fed controlled energy diets comprising 0, 18, or 36% type 2 resistant
starch (RS) from high-amylose maize (HAM-RS2). They observed that caecal microbiota of mice fed amylopectin (readily
digestible carbohydrate) were dominated by Firmicutes. Contrarily, mice fed HAM-RS2 rich diets were colonized by higher
levels of Bifidobacterium, Bacteroidetes, Akkermansia, and
Allobaculum species that were dependent on the concentration of the dietary fibre. They further narrated that the
proportions of Bifidobacterium and Akkermansia were

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Journal of Functional Foods 17 (2015) 189201

Table 3 Summary of hypoglycaemic effects of prebiotics.

Substrate

Subjects/Animals

Dose/Duration

Result

Reference

Prebiotic

Obese diabetic rats

0.3 g/mouse/day for 5

weeks

(Everard et al., 2011)

Artichoke tubers
powder

Male albino rats

5, 10 and 15% daily for 5

weeks

FOS

Healthy dogs

1% of diet for 6 weeks

FOS

Obese zucker rats

Diet containing 5% FOS

for 100 days

Resistant starch

Mice

0, 18, or 36%

Inulin-type
fructans (IFT)

Healthy adults

Xylooligosaccharide
(XOS)

Type 2 diabetic
patients

16 g prebiotics/day or
16 g dextrin maltose/
day for 2 weeks
4 g/day for 8 weeks

Improvement in glucose tolerance, reduced

fat-mass development, oxidative stress,
and low-grade inflammation
Significant decrease in serum glucose level
in all groups (5, 10 and 15%) as compared
to diabetic rats on control diet
Considerably reduced insulin resistance.
Modifications in expression of genes
involved in glucose homeostasis and lipid
metabolism
Significant decrease (12%) in total liver
lipids and liver weight Serum insulin
concentration also reduced by 3.6 times in
treated group
Microbiota that modulated by dietary
intervention resulting in overall
improvement of health
Decrease in postprandial glucose response
after breakfast owing to increased
production of GLP-1
Supplementation beneficially modulated
blood glucose and lipids in these type 2
diabetic patients

correlated positively with mouse feeding responses i.e., gut

weight, and expression levels of proglucagon, the precursor of
the gut GLP-1 (anti-obesity/diabetic hormone). They concluded that aged mice port a distinct microbiota that can be
modulated by dietary intervention resulting in overall improvement of health.
One of the researchers groups, Cani et al. (2009) conducted a fifteen day study in human subjects to judge the
response to inulin-type fructans (IFT). They deduced that supplementation of diet with IFT decreases postprandial glucose
response after breakfast owing to increased production of GLP-1
(Table 3).
Likewise, Sheu, Lee, Chen, and Chan (2008) elucidated the
therapeutic role of xylooligosaccharide (XOS) for reducing blood
glucose, lipids and oxidative stress in subjects with type 2 diabetes. They were provided xylooligosaccharides 4 g/day for 8
weeks. The XOS supplementation beneficially modulated blood
glucose and lipids in these type 2 diabetic patients. In another
study on non-insulin dependent diabetic subjects, administration of inulin-type fructans (8 g/day) significantly lowered
the blood glucose concentration after one month (Kelly, 2009).
A recent report has explained that obesity and long-term intake
of high fat or high glycaemic diets are connected to systemic
inflammation, oxidative stress, type 2 diabetes and other metabolic disorders (Styskal, Remmen, Richardson, & Salmon, 2012).
The high fat diets are linked with inflammation that triggers
the onset of insulin resistance and obesity (Ding & Lund, 2011).
Inflammation is categorized by macrophage accumulation in
adipose tissues, which ultimately up-regulates pro-inflammatory
cytokines and fuels the dysregulation of lipid metabolism, ultimately causing insulin resistance (Kellogg, Debora, Mary,
Slavko, & Mary, 2015).
Though, the research on human gut microbiota is succeeding logarithmically, the field still remains an emerging and

(Zaky, 2009)

(Respondek et al., 2008)

(Kaume et al., 2011)

(Tachon et al., 2013)

(Cani et al., 2009)

(Sheu et al., 2008)

in-progress area of research. Our gut microbiome includes more

than three million genes; however, we do not know much about
the functions or interactions of most of these genes. Investigators are making incredible advances in comprehending not
just what the gut microbiota does or can do, but also how these
microbes do whatever they do, how this mystifying group of
gut microbes could positively and negatively impact our nutrition, physiology, healthiness, and diseases, and how we can
manipulate or engineer it for better clinical health (Allen-Vercoe,
2013).
Certainly, it can easily be envisaged that this evolution of
research on gut microbiota shall revolutionize the notion of
we are what we eat to we are what our gut microbiome is.
Optimistically, we may soon witness an era where the gut
microbiome clinics shall be prevalent all around and the individuals gut microflora will be widely used as a diagnostic,
prophylactic as well as therapeutic target for a myriad of health
problems, and more fascinatingly, the gut microbiome at infant
stage shall be used to predict predisposition to numerous ailments in later years, and individuals diet regimens shall be
designed exclusively according to their gut microbiota profile
for a better and disease-free health and well-being (Nagpal et al.,
2014).

6.

Conclusion

Results from these studies support the potential of prebiotics

especially fructooligosaccharides against physiological threats
including hypercholesterolaemia, hyperglycaemia and intestinal disorders. Prebiotics appear to exert their beneficial effects
through various mechanisms.The studies discussed here provide
clinical and experimental evidence for supplementation of diet

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Journal of Functional Foods 17 (2015) 189201

with prebiotics. However, there are only few human studies

which support this hypothesis that warrant the need for further
research in this area, especially long-term, interventional studies
involving human subjects.

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