nutrients

Review
Morinda citrifolia Linn. (Noni) and Its Potential in
Obesity-Related Metabolic Dysfunction
Aline Carla Inada 1 , Priscila Silva Figueiredo 1 , Rosângela Aparecida dos Santos-Eichler 2 ,
Karine de Cássia Freitas 1 , Priscila Aiko Hiane 1 , Alinne Pereira de Castro 3 and
Rita de Cássia Avellaneda Guimarães 1, *
1 Post Graduate Program in Health and Development in the Central-West Region of Brazil, Federal University
of Mato Grosso do Sul-UFMS, Campo Grande 79079-900, MS, Brazil; [email protected] (A.C.I.);
[email protected] (P.S.F.); [email protected] (K.d.C.F.); [email protected] (P.A.H.)
2 Department of Pharmacology, Biomedical Science Institute, University of São Paulo, São Paulo 05508900, SP,
Brazil; [email protected]
3 Post-Graduate Program in Biotechnology, Catholic University Dom Bosco, Campo Grande 79117-900, MS,
Brazil; [email protected]
* Correspondence: [email protected]; Tel.: +55-67-3345-7445

Received: 27 December 2016; Accepted: 26 April 2017; Published: 25 May 2017

Abstract: Cultural and economic shifts in the early 19th century led to the rapid development
of companies that made good profits from technologically-produced commodities. In this way,
some habits changed in society, such as the overconsumption of processed and micronutrient-poor
foods and devices that gave rise to a sedentary lifestyle. These factors influenced host-microbiome
interactions which, in turn, mediated the etiopathogenesis of “new-era” disorders and diseases,
which are closely related, such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease,
hypertension, and inflammatory bowel disease, which are characterized by chronic dysregulation
of metabolic and immune processes. These pathological conditions require novel and effective
therapeutic approaches. Morinda citrifolia (noni) is well known as a traditional healing plant due
to its medicinal properties. Thus, many studies have been conducted to understand its bioactive
compounds and their mechanisms of action. However, in obesity and obesity-related metabolic
(dysfunction) syndrome, other studies are necessary to better elucidate noni’s mechanisms of action,
mainly due to the complexity of the pathophysiology of obesity and its metabolic dysfunction. In this
review, we summarize not only the clinical effects, but also important cell signaling pathways in
in vivo and in vitro assays of potent bioactive compounds present in the noni plant which have been
reported in studies of obesity and obesity-associated metabolic dysfunction.

Keywords: Morinda citrifolia L.; obesity; obesity-related metabolic dysfunction; health

1. Introduction
The prevalence of obese individuals has doubled worldwide since the 1980s. In 2014, it was
estimated that more than 1.9 billion adults were overweight, corresponding to 39% of all adults in the
world. Of this latter group, 13% were already considered obese, i.e., 600 million [1]. In the United
States (USA), obesity is a problem that increased by approximately 50% among adults throughout the
1980s and 1990s [2] and may result in a reduction in longevity of the North American population [3].
Obesity is prevalent in low-income groups who often live in urban areas in the USA and Europe.
According to the World Health Organization (WHO), in 2015, more than 50% of adults were overweight
or obese in 46 countries across Europe, especially in the eastern part of the region. Nowadays,
overweight and obesity are estimated to result in the deaths of about 320,000 men and women in
20 countries in Western Europe every year [4]. In 2012, China’s Minister of Health indicated that in the

Nutrients 2017, 9, 540; doi:10.3390/nu9060540 www.mdpi.com/journal/nutrients

Nutrients 2017, 9, 540 2 of 29

country with 1.2 billion individuals, 300 million Chinese were obese [5]. In Brazil, more than a half of
the Brazilian population was overweight (52.5%), of which 13.9% were considered obese in 2014 [6].
Although obesity is the result of an imbalance between energy intake and expenditure, it is likely
that a disturbed metabolism due to inadequate nutrition contributes to an abnormal or excessive
fat accumulation associated with impaired health. Central obesity is a sign of the most prevalent
chronic metabolic disorder of our era with important global public health challenges. Genetic factors,
together with inappropriate food supply, entertainment, and labor-saving devices, and the advertising
of highly-appealing foodstuffs by the food industry, results in energy-dense diets and decreased
physical activity. This constitutes a gene-environment interaction, where endocrine factors mediate
and stimulate some of the pathways that lead to obesity [1,7,8]. Recently, many groups have been
focusing their studies on the involvement of the gut microbiota in obesity and metabolic dysfunction.
In 2006, one of the first studies that found a relationship between gut microbiota and weight gain
reported that the latter was putatively caused by an increase in energy-harvesting capabilities of the
microbiota in obese persons [9].
Central, as opposed to peripheral, obesity predisposes individuals to metabolic abnormalities,
cardiometabolic complications, such as insulin resistance, type 2 diabetes mellitus (T2DM)
dyslipidemia, hypertension, and non-alcoholic fatty liver disease (NAFLD), which are components of
obesity-related metabolic syndrome (MetS) that put individuals at risk of developing cardiovascular
disease (CVD) [10,11]. Nowadays, the term ‘metabolic syndrome’ is used widely and is defined as
when an individual shows at least three of the following cardiovascular risk factors: central obesity
(excessive upper body and visceral fat), dyslipidemia (high triglycerides or low high density lipoprotein
cholesterol (HDL) levels), or hypertension or hyperglycemia (T2DM) [12].
There are various pharmacological and non-pharmacological options which are broadly accepted
as treatment and prevention of obesity and obesity-related diseases, including dietary control, physical
activity, lifestyle changes, weight-loss medications, weight-loss surgeries, or specific medications [13].
Various dietary patterns have been extensively studied for health promotion and to diminish the risks
of chronic diseases. A “healthy eating concept” has been put forward in which functional foods and
nutraceuticals are important parts [14].
In this context, according to Health Canada, the term nutraceutical is conceptualized as a product
isolated or purified from foods that is generally sold in medicine formulations not usually associated
with food. A nutraceutical has been shown to have a physiological benefit or provide protection
against chronic diseases. The term ‘functional food’ is distinguished as a food that is similar in
appearance to, or may be, a conventional food, that is consumed as part of a usual diet, and has
demonstrated physiological benefits and/or to reduce the risk of chronic disease beyond basic
nutritional functions [15].
Due to the complexity of obesity pathogenesis, the majority of the treatments are not related to
obesity alone, seeing that it is associated with other metabolic disorders, such as oxidative stress and/or
inflammatory alterations that can occur concomitantly in several tissues [11]. Recent studies have
focused on the development of innovative therapeutic agents from natural sources as an alternative
medicine. Nevertheless, the challenge of natural product studies is to evaluate, in a consistent way,
the mechanisms of action and bioactive compounds which could assure the beneficial effects of the
products [13,16].
Morinda citrifolia L. (noni) is an example of a plant used as a functional food and has been widely
studied due to its apparent beneficial effects on human health. It has been investigated as an alternative
in anticancer, antibacterial, and antimicrobial therapies, and in the treatment of esophageal reflux
and ulcers in animals [17–21]. In humans, there are few studies showing the beneficial effects of
noni. Sattar et al. [22] and Siddiqui et al. [23] demonstrated the effective benefits of a topical ointment
prepared from noni stem extract against cutaneous leishmaniasis. Palu et al. [24] showed a 25%
reduction in lipid peroxidation in the blood of athletes, after an endurance test, taking noni juice (NJ)
compared to controls, thereby demonstrating an antioxidant effect. The antioxidant properties of noni
Nutrients 2017, 9, 540 3 of 29

juice were also demonstrated by Wang et al. [25] in a study involving 132 heavy cigarette smokers.
They reported reduced plasma levels of superoxide anion radicals and lipid hydroperoxide, which
are considered biomarkers of degenerative diseases associated with cigarette smoking, in smokers
who drank NJ compared to smokers who did not. Moreover, Issell et al. [26] reported less fatigue and
maintenance of physical functions in patients with cancer.
Recently, more attention has been directed to the anti-obesity properties of the noni plant in
animal models. However, studies are still scarce in humans and more investigations are needed.
Therefore, the aim of this review was to assess specific in vitro and in vivo studies related to the
mechanisms of action and bioactive compounds that promote the benefits of Morinda citrifolia L. (noni)
in the treatment of obesity and obesity-related metabolic dysfunction, such as insulin resistance/T2DM,
dyslipidemia, hypertension, NAFLD [27,28], and its influence on the gut microbiota.

2. Morinda citrifolia Linn. (Noni)

The genus Morinda belongs to the Madder or Coffee family Rubiaceae and includes approximately
80 species, including Morinda citrifolia Linn (Morinda citrifolia L.), which is popularly called noni or
Indian Mulberry [29]. Noni was used as a medicinal plant by the Polynesians 200 years ago, but it
has never been a traditional food, although it has been called as a starvation fruit. Currently, noni
is a typical plant found in tropical climate regions of the USA, such as Hawaii, to Brazil, reaching
Tahitian, Malaysia, and Fiji Islands [30,31]. The first idea of potential benefits of noni fruit started
with Heinicke [32] who demonstrated that noni contained the alkaloid xeronine. Even though noni
fruits showed insignificant amounts of free xeronine, they contained considerable amounts of the
precursor of xeronine, which was named proxeronine. One of the explanations for the medicinal
action of noni fruits is that xeronine could modulate the conformation and stability of specific proteins.
Heinicke described beneficial effects of noni fruits, such as in menstrual cramps, hypertension, burns,
depression, atherosclerosis, digestion, relief for pain, and many others.
In 1996, because of the nutraceutical and therapeutic properties of noni, commercial NJ was
marketed as a dietary supplement. Afterwards, in 2003, the European Commission approved Tahitian
noni juice as a novel food by the Health and Consumer Protection Directorate General. Many
investigators have studied the bioactive compounds present in noni fruits, as well as in other parts of
the plant, such as leaves, roots, roots bark, seeds, stems, and flowers, because of their potential benefits
to health [33–35].
On the other hand, noni fruit and juice display some challenging peculiarities, such as a bitter
and astringent flavor, as well as a strong rancid odor, which prompts some companies to change these
organoleptic properties to create a more palatable product. These companies have been producing
flavored NJ with the addition of other fruit juices to create a better-tasting product [36]. Other issues
concerning the noni plant are the toxicity, adverse side-effects, the safety of long-term consumption,
bioactive compounds, and mechanisms of action, which are important factors to be elucidated in
in vitro and in vivo studies to be totally acceptable for human consumption [37].

2.1. Nutritional Values of the Noni Plant

Relevant nutritional and chemical analyses have demonstrated that noni fruit contains 90% water
and 10% dry matter. The dry matter is composed of soluble solids, dietary fibers, and proteins.
Chunhieng et al. [38] reported that 5% of soluble solids are reducing sugars (glucose and fructose)
and 1.3% is sucrose. Approximately 11.3% of the dry matter is protein and the main amino acids are
glutamic acid, aspartic acid, and isoleucine. Moreover, 10–12% are minerals, which include calcium,
sulfur, potassium, magnesium, sodium, phosphorus, and traces of selenium. The main vitamins
reported in noni fruit puree are ascorbic acid (vitamin C), which corresponds to 250 mg ascorbic acid
per 100 g fresh matter, niacin (vitamin B3), and vitamin A [33,39,40].
Nutrients 2017, 9, 540 4 of 29

2.2. Chemical Composition of the Noni Plant

Despite the issues surrounding Morinda citrifolia fruit, especially its taste and odor, people still
use the bottle-pasteurized juice, either in pure form or mixed with other juices, due to the various
phytochemicals in the noni plant totaling approximately 200 compounds. These bioactive compounds
are present in different parts of the plant. Noni fruit and other parts of the plant contain large amounts
of phytochemicals, including phenolic compounds, anthraquinones, carbohydrates, organic acids,
alcohols, vitamins, flavonoids, iridoids, ketones, lignans, triterpenoids, nucleosides, sterols, fatty acids,
carotenoids, and many others [29,35,37].
The content of phenols, antioxidants, and ascorbic acid present in the noni fruit increase from
the green to white hard stage, whereas they diminish from the white hard stage to the ripe/soft
stage [36,41]. In the white hard stage, noni fruits have approximately two times more antioxidant
activity, 1.5 times higher phenol content, and seven times higher ascorbic acid content, in comparison
to immature green fruits, which have 1.1–1.5 times the antioxidant activity, 1.3 times the total phenols,
and 1.3 times the content of ascorbic acid [36,42].

2.3. Important Phytochemicals of Morinda citrifolia on Obesity and Obesity-Related Metabolic Dysfunction
The high prevalence of obesity and obese-related metabolic dysfunction has led to extensive
investigations to seek out alternative therapies because of several reports of side-effects that are
promoted by synthetic drugs. Noni can provide important natural products that have been widely
studied and may be considered an alternative therapy for many diseases [14]. Many scientific
publications have shown that the noni plant contains a variety of nutritional and functional compounds.
However, our current knowledge of these compounds is still not satisfactory. Some studies have
demonstrated that the principal bioactive compounds from Morinda citrifolia have potentially beneficial
effects in obesity and obesity-related metabolic dysfunction, and they are listed in Table 1.

Table 1. Principal phytochemicals from Morinda citrifolia as bioactive compounds against obesity and
obesity-related metabolic dysfunction.

Concentrations of
Part of Plant Structural Class Bioactive Compounds References
Bioactive Compounds
Chlorogenic acid 10.49 mg/100 mL [43] [43–48]
Fruit Phenolic acid Gentisic acid 19.16 mg/100 mL [43] [43–45,48]
P-hydroxybenzoic acid 14.12 mg/100 mL [43] [43–45,48]
Anthocyanin
Data not shown [49]
(cyanidin-3-O-rutinoside)
Catechin 53.68 mg/g [50] [50,51]
Flavonoids Epicatechin 6.8 mg/g [51] [51]
Kaempferol 6.4 mg/g [51] [52,53]
Rutin 8.06 mg/g [50] [45,54–56]
Quercetin 7.4 mg/g [51] [49,54]
Iridoids Asperulosidic acid Data not shown [48,57]
Americanin A 17.4 mg [58] [58,59]
Americanol A 21 mg 60] [60]
Isoprincepin 14 mg [60] [60]
Lignans Lirioresinol B Data not shown [61]
Lirioresinol B dimethyl ether Data not shown [61]
Morindolin 10 mg [60] [60]
3,3’-Bisdemethypinoresinol 69 mg [60] [60]
Coumarins Scopoletin 46.1 mg [58] [49,55,58,62]
Minerals Potassium 3900 mg/L [38] [38,63–65]
Triterpenoids/ Ursolic acid Data not shown [61,66–68]
terpenes Saponin Data not shown [69]
Vitamin C Data not shown [70,71]
Vitamins
Vitamin E Data not shown [70,71]
Nutrients 2017, 9, 540 5 of 29

Table 1. Cont.

Concentrations of
Part of Plant Structural Class Bioactive Compounds References
Bioactive Compounds
Catechin 63.46 mg/g [50] [50]
Epicatechin 23.08 mg/g [50] [50]
Leaf Flavonoids
Rutin 6.83 mg/g [50] [45,50,55]
Kaempferol 21–80 mg [52] [52,66]
Triterpenoids/terpenes Ursolic acid Data not shown [61,68]
Deacetylasperulosidic acid Data not shown [73]
1,2-Dimethoxyanthraquinone 3.5 mg [72] [72]
Alizarin-2-methyl ether 11.3 mg [72] [72]
Rubiadin-1-methyl ether 15.5 mg [72] [72]
Root Anthraquinones
Lucidin 3-O-beta-D-primeveroside Data not shown [73]
Damnacanthol-3-O-beta-D-primeveroside Data not shown [73]
Morindone-6-O-beta-D-primeveroside Data not shown [73]
Asperulosidic acid Data not shown [73]
Iridoid
Principal bioactive compounds from fruits, leaves, and roots of Morinda citrifolia used for obesity and obesity-related
metabolic dysfunction.

These bioactive compounds, called phytochemicals, include phenolic acids, lignans, flavonoids,
flavones, flavans-3-ol, anthocyanins, phytosterols, alkaloids, vitamins, and minerals. In recent
decades, polyphenols have been the most important compounds shown to possess beneficial effects
against obesity and metabolic dysfunction. Polyphenols include phenolic acids, flavonoids, and
stilbenes, which are the most common compounds used in the development of natural products for
metabolism-associated disorders/diseases [13,44,45].
Phenolic acids are divided into two classes: hydroxycinnamic and hydroxybenzoic acids.
Hydroxycinnamic acids include o-coumaric acid, m-coumaric acid, caffeic acid, ferulic acid, and sinapic
acid, and are present in the form of simple esters with glucose or quinic acid. Hydroxybenzoic
acids include salicylic acid, gentisic acid, p-hydroxybenzoic acid, gallic acid, vanillic acid, and
3,4-dimethoxybenzoic acid. The most common acid derivative is chlorogenic acid [13,44,45].
Flavonoids are abundant compounds in nature and they are divided into six subgroups: flavonols,
flavanones, isoflavanoids, flavones, flavand-3-ol, and anthocyanins. Flavonoids have been widely
studied due to their therapeutic properties in the treatment of metabolic disorders due to their ability
to modulate the numbers of cell signaling pathways that affect carbohydrate digestion, fat deposition,
and the release rate of insulin or glucose uptake in insulin-responsive tissues [44,45,50,51].
Quinones are a class of organic compounds, where 9,10-anthraquinones (9,10 dioxoanthracenes)
are an important subgroup [74]. Anthraquinones in Morinda citrifolia are found especially in
the roots, and the main compounds with important effects on metabolism are alizarin, lucidin
3-O-β-D-primeveroside, damnacanthol-3-O-β-D-primeveroside, and rubiadin-1-methyl ether [72,73].
Coumarins are found in many edible plants and fruits. One of the most important coumarins
found in noni plant is scopoletin (6-methoxy-7-hydroxycoumarin), which has shown a notable
effect in the treatment of obesity and metabolic dysfunction [49,55]. Lignans and neolignans are
present in many plants, being a large group of natural products derived from the oxidative coupling
of two C6-C3 units [75]. The most important lignans isolated from noni fruit are americanin A,
americanol A, episesamin 2,6-dicatechol, isoprincepin, lirioresinol, lirioresinol B dimethyl ether,
morindolin, and 3,3’-bisdemethypinoresinol. These lignans improve parameters in obesity and
associated disorders/diseases [58,59,61,76].
Triterpenoids are the largest class of secondary metabolites produced by plants. Ursolic acid and
related triterpene compounds, such as oleanolic acid, betulinic acid, uvaol, and α- and β-amyrin are
widespread in many plants [77,78]. The most abundant triterpenoid from noni is ursolic acid, which
has been widely investigated because of its hypoglycemic property [61,67,68].
Iridoid is a monoterpene, differing from triterpenes, and it is derived from geraniol. Iridoid
glucosides and glycosides, a subclass of iridoid, are terpenes bound to glucose, or any sugar,
Nutrients 2017, 9, 540 6 of 29

respectively [79]. Asperulosidic acid is one of the most important iridoids isolated from
Morinda citrifolia, and it has been shown to improve blood fluidity, which influences the health
of obese patients and those with obesity-associated disorders, such as hypertension, diabetes
and dyslipidemia [57,80,81]. Vitamins (C, ascorbic acid, and E, α-tocopherol) are two important
non-enzymatic antioxidants that have important effects because of their free-radical scavenging
property [70,71].

2.4. Toxicity of the Noni Plant

The toxicity and low palatability could explain why noni has never been a food plant; therefore,
considerable effort is needed to extract or deactivate the toxins. Studies have reported human [41,82]
and animal [83] toxicity. In some human cases reported, Millonig et al. [41] and Stadlbauer et al. [82]
demonstrated that NJ led to signs of hepatoxicity. The first group observed that a 45-year-old man had
elevated transaminases and lactate dehydrogenase. After stopping the ingestion of NJ, transaminase
levels normalized. The second human clinical study reported that a 29-year-old man, who had
previous toxic hepatitis after small doses of paracetamol, developed sub-acute hepatic failure following
consumption of 1.5 L of NJ, while a 69-year-old woman without evidence of previous liver disease
experienced an episode of self-limited acute hepatitis following consumption of two liters of NJ.
Recently, Shalan et al. [83] compared the chronic toxicity of NJ and noni leaf aqueous extracts
(1 and 2 mg/mL, respectively) to drinking water for six months on the liver and kidneys in female
mice. This study observed that none of the doses of noni leaf extracts showed toxic effects; however,
mice that consumed noni fruit extract at 2 mg/mL showed toxicity symptoms, such as hypoactivity,
excessive grooming, sunken eyes, and hunched posture, with 40% mortality after three months of use.
The main cause of death was hepatoxicity with dose-dependent hepatocellular necrosis, though with
no effects on kidney.
One possible explanation for noni fruit toxicity can be related to the large amount of
anthraquinones. Inoue et al. [84] reported that madder dye, a food coloring extract from the roots of
Rubia tinctorium L., containing large amounts of two anthraquinones, alizarin, and rubiadin (metabolite
of lucidin-3-O-primeveroside), showed carcinogenicity in the kidney and liver of six-week-old male
F344 rats, where rubiadin had higher carcinogenic potential than did alizarin. However, this study
was not applied to noni fruit or leaves. West et al. [85] reported that NJ (Tahitian Noni Juice® , Tahitian
Noni International, American Fork, UT, USA) (TNJ) was not hepatotoxic and demonstrated that
anthraquinones did not possess the same universal biological effect and that it was not reasonable
to assume that one category of anthraquinones would have the same exact toxic action as another.
Westendorf et al. [86], using high-performance liquid chromatography (HPLC), did not detect genotoxic
hydroxyanthraquinones (HAs), such as lucidin and rubiadin in NJ.
The same study demonstrated that the treatment of liver cells in vitro (primary rat hepatocytes
and H4IIE rat hepatoma cells) with a common TNJ did not induce genotoxicity. To evaluate the possible
genotoxicity of TNJ, they used the V79-HPRT assay and ex vivo hepatocyte UDS assay. V79 cells
are Chinese hamster fibroblasts and are currently used as a mammalian cell model to determine the
mutagenic effect of natural compounds. In V79 cells treated with TNJ no mutagenicity was observed.
Moreover, when primary hepatocytes from rats treated with 10 g/kg body weight, about 700 mL of
juice for an adult human, were tested, they showed no acute toxic effects, as seen by UDS (unscheduled
DNA synthesis), which is a marker of DNA damage repair [86].
Although there are several controversial studies related to toxicity, some authors suggest a closer
evaluation of noni products in general. At the time of NJ production, manufacturers must process the
product to remove the toxic principles or deactivate them and test the resulting non-toxic preparations
for beneficial activity. Additionally, hygienic measures must be taken to ensure safety for human
consumption. Nonetheless, these toxicity studies will be irrelevant if NJ products are obtained using
inappropriate processing methods, contain microbial contaminants, or have been adulterated with
unsafe ingredients [87].
Nutrients 2017, 9, 540 7 of 29

2.5. Therapeutical Use of the Noni Plant

Due to the potential bioactive compounds present in Morinda citrifolia fruit that are good for human
health, some companies add other fruit juices to provide a flavorful and enhanced product [14,88].
However, not only the fruit, but also other parts of the plant, have phytonutrients with beneficial
effects. Growing evidence suggests that noni has important antimicrobial and antibacterial activities.
Extracts of noni leaves made with three different solvents, ethyl acetate extract, n-butanol, or water,
showed a very strong antimicrobial and antibacterial activity against some microorganisms, including
Proteus vulgaris, Staphylococcus aureus, Bacillus subtilis, and Escherichia coli [17].
It has long been believed that noni leaves have a large number of phenolic compounds,
especially coumarins and flavonoids, and also acubin, L-asperulose, alizarin, scopoletin, and other
anthraquinones [29,89]. These phenolic compounds possess antimicrobial activity [18], which may,
due to their antioxidant effects, possibly involve proton exchange processes [90]. The use of noni for
esophageal reflux and gastric ulcerative disease has also produced good results, such as preventing the
occurrence of esophagitis due to acid reflux, reducing the formation of acute gastric lesions induced
by ethanol, suppressing the development of gastric lesions, and also significantly inhibiting gastric
acid secretion and pepsin activity in the pylorus-ligated rat [19]. Scopoletin is the component of noni
that is thought to have this valuable potential preventive and therapeutic action for gastro-esophageal
inflammation [19].
Palu et al. [91] reported another anti-inflammatory action of NJ, where they demonstrated
suppression of IL-4 in mice with NJ treatment in relation to water. NJ increased the production
of IFN, which is correlated with the activation of macrophages. The suppressive effects of NJ on IL-4
production in splenocytes, concomitant with increased production of IFN, indicates that NJ modulates
the immune system.
A recent study reported by Shalan et al. [92] demonstrated that noni leaf extract possessed
ergogenic effects, helping delay fatigue by enhancing energy production, regulation, and efficiency
in female mice after a swimming endurance test. Noni extract enhanced performance by improving
angiogenesis in skeletal muscle and liver (via vascular endothelial growth factor A, VEGFA),
showing antioxidant (superoxide dismutase–SOD2 and glutathione-GSH) and anti-inflammatory
(IL-4 and IL-10) properties, and ameliorating mitochondrial biogenesis (via AMP-activated protein
kinase (AMPK), uncoupling protein-3 (UCP-3), peroxisome transcriptional proliferator-activated
receptor gamma, coactivator 1 alpha (PGC-1α), and nuclear respiratory factor-2 (NRF2)) and stress
response (cortisol).
Another application of NJ was related to its anticancer properties since it reduces free radicals
which are involved in oxidative damage and lipid peroxidation. One of the main components
associated with this property is damnacanthal, a valuable anthraquinone found in the roots of the noni
plant, which is widely used for the treatment of chronic diseases, such as cancer and heart disease.
Damnacanthal is involved in the K-ras pathway, inducing actin fiber organization, which is affected
in activated ras-expressing tumors [20,21]. The noni roots also show antispasmodic, vasodilator, and
cardiodepressant activities [93].
A phase one clinical trial was conducted to determine the best dose of noni for capsule
supplementation, in which a conventional dose escalation design was used to begin, where the
subjects of the research were patients with some type of cancer. No adverse effects were found, and the
only hurdle was the number of capsules to be ingested to complete the full dose of 14 g of encapsulated
freeze-dried noni fruit per day. In addition, some quality of life factors, such as physical function
and fatigue control, were improved in patients who took a mean dose of 8 g per day, compared with
patients who took higher and lower doses [26].
Nutrients 2017, 9, 540 8 of 29

3. Effects of Bioactive Compounds from the Morinda citrifolia L. Plant on Obesity and
Obesity-Related Metabolic Dysfunction

3.1. Morinda citrifolia and Obesity

Obesity is characterized by the expansion of adipose tissue. This type of tissue can be classified as
brown, beige, and white adipose tissue (WAT). WAT is considered not only as an energy reservoir, but
also as an organ with endocrine functions. It is classified according to its localization as subcutaneous
adipose tissue or visceral adipose tissue, the latter being one of the most important fat deposits
associated with metabolic disease [94–99]. The endocrine functions that revolve around WAT are due
to their capacity to maintain, under physiological conditions, lipid metabolism, such as lipogenesis,
lipolysis, and adipogenesis processes [97–99], and releasing adipokines, which are substances with
important biological and metabolic functions, such as adipsin, tumor necrosis factor-α (TNF-α),
leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), interleukins (IL-6, IL-10, IL-1β),
plasminogen activator-1 (PAI-1), components of the renin-angiotensin-aldosterone system (RAAS),
resistin, visfatin, omentin, and many others [100–105].
In this regard, natural products, such as plants, herbal supplements, and diet-based therapies
have been widely studied because of their potential benefits in human health against obesity and
its metabolic disorders [106–109]. Nishioka et al. [110] investigated the mechanisms underlying the
beneficial effects of NJ with focus on glucose and lipid metabolism in high-fat diet (HFD) obese
C57BL/6 mice (Table 2). The animals that consumed HFD + NJ showed decreased adipose tissue
weights, plasma triglyceride levels, and improved glucose tolerance without toxicity and displayed a
lower final body weight, compared to the HFD group. These benefits in the parameters and biomarkers
of obesity demonstrated the anti-obesity effects of NJ.
Accordingly, the benefits of NJ in HFD mice have also been reported by others. The reduction
of weight gain and improvement of metabolic parameters, such as total cholesterol, low-density
lipoprotein-cholesterol, glucose and insulin tolerance, fasting glucose levels, and hepatic insulin
resistance has been seen in rats [111], mice [49], and hamsters [43] (Table 2). No liver damage was
observed. One explanation for the effectiveness of NJ is the large amount of phenolic acids present in
its composition, including gentisic acid, p-hydroxybenzoic acid, and chlorogenic acid (Table 2).
A recent study demonstrated positive effects of Morinda citrifolia leaves (MLE) as dried plant
material that were extracted with 60% ethanol (MLE 60) in HFD obese Sprague-Dawley male rats.
They tested two different doses of MLE and compared those groups receiving MLE with the group
receiving a synthetic anti-obesity drug (Orlistat 30 mg/kg). The parameters adiposity, fecal fat content
and plasma lipids, insulin, and leptin with the higher dose of MLE (500 mg/kg) group were similar as
that in the Orlistat group, except the ghrelin levels, which showed better results with the lower dose of
MLE (250 mg/kg). Some metabolic pathways, including glucose metabolism and TCA (tricarboxylic
acid) cycle, amino acid metabolism, choline metabolism, creatinine metabolism, and gut microbiome,
were analyzed using a 1 H nuclear magnetic resonance (1 HNMR)-based metabolomics approaches.
Both doses of the extract showed improvement in certain metabolic pathways that were impaired by
HFD-induced obesity [112] (Table 2).
Under physiological conditions, lipogenesis and lipolysis are the two primary metabolic events
in adipose tissue, and they are orchestrated to maintain lipid homeostasis. Non-esterified fatty acids
accumulate in WAT and are esterified into triacylglycerol by lipoprotein lipase (LPL). This process
of synthesis of esterified fatty acids (FAs) is called lipogenesis. On the other hand, lipolysis is the
mobilization or hydrolysis of triglycerides. The availability of FAs and glycerol are necessary for
energy storage. Glycerol is an important substrate for hepatic gluconeogenesis and FAs are important
energy substrates for peripheral tissues [97–99]. Therefore, LPL is an important biomarker in obesity
and it has been reported to be consistently augmented in the adipose tissue of obese subjects [50].
Nutrients 2017, 9, 540 9 of 29

Table 2. The effects of administration of the Morinda citrifolia L. plant on obesity.

Host Part of Plant Dose/Time Effects Reference

−Reduced body weight by 40% in mice fed
control, while reduced body weight by 25% in
1.5 µL/g body weight Nishioka et al.
Mice Fruit Noni Juice HFD mice.
(twice daily)/5 weeks [110]
−Reduced adipose tissue weights, plasma
triglycerides and improved glucose tolerance.
−Reduced body weight (better at
50 mg/kg/day dose).
50 mg/kg/day/30 days −Reduced serum total cholesterol,
Rats Fruit Noni Juice Shoeb et al. [111]
triglycerides and lipid fractions: LDL and
VLDL (all doses).
100 mg/kg/day/30 days −Increased lipid fraction HDL (all doses).
−Inhibited weight gain after 12 weeks.
−Improved glucose and insulin tolerance and
Fruit 1.5 µL/g body
fasting glucose in HFD-fed C57Bl/6 mice.
Mice Fermented weight/twice Nerurkar et al. [49]
Noni Juice daily/12 weeks −Improved hepatic insulin resistance by
FOXO-1 and inhibition of PEPCK and G6P
(gluconeogenic enzymes).

−3 mL (containing −Decreased visceral fat in HFD-hamsters

64.23 mg crude (all doses).
polysaccharides/kg body −Decreased serum and liver lipids: total
weight/6 weeks. cholesterol and triglycerides in HFD hamsters
(all doses).

−6 mL (containing −Beneficial effects on liver and hepatic

128.46 mg crude enzymes (ALT) in HFD hamsters (all doses).
Hamster Fruit Noni Juice Lin et al. [43]
polysaccharides/kg body −Increased antioxidant capacity in the liver in
weight/6 weeks. HFD hamsters (all doses).
−Decreased inflammatory biomarkers in the
−9 mL (containing liver (TNF-α, MCP-1, IL-1β) in HFD hamsters
192.69 mg crude (all doses).
polysaccharides/kg body
−Decreased gelatinolytic levels of MMP9 in
weight/6 weeks)
HFD hamsters (all doses).
−Prevented weight gain, especially MLE 60
500 mg/kg.
−250 mg/mL/9 weeks. −Positive effects on adiposity, fecal fat content,
plasm lipids, insulin and leptin levels,
Ethanolic especially MLE 60 500 mg/kg. Jambocus et al.
Rats Extract of
−Improved ghreline levels, especially MLE [112]
Leaves
250 mg/kg.
−500 mg/mL/9 weeks. −Improvement in metabolic perturbations
caused by obesity, both concentrations
of extract.
Ethanolic
In vitro Extract of Fruit 0.2 mg/mL in vitro −Inhibited LPL activity. Pak-Dek et al. [50]
and Leaves
Ethanolic
In vitro 1 mg/mL in vitro −Inhibited LPL activity. Sahib et al. [51]
Extract of Fruit
Effects of administration of different doses and parts of the Morinda citrifolia plant on obesity in in vivo and
in vitro studies.

The influence of Morinda citrifolia fruit (MFE) and leaf (MLE) extracts on LPL activity were
evaluated in vitro by two independent research groups [50,51]. Pak-Dek et al. [50] studied MFE
and MLE with green tea (GTE) and catechin extracts on the enzymatic activity of LPL. The data
demonstrated that all extracts tested inhibited LPL activity substantially after 30 min of incubation.
However, the greatest inhibition of LPL activity was seen with 0.2 mg/mL MLE in a dose-dependent
manner when compared to MFE, GTE and catechin.
Sahib et al. [51] evaluated MFE, Momordica charantia (MCE) and Centella asiatica (CAE) extracts in
LPL inhibition and the effects of the extracts in proliferation and differentiation of 3T3-L1 preadipocytes
Nutrients 2017, 9, 540 10 of 29

(Table 2). The results showed that 1 mg/mL MFE exerted the most significant inhibitory effect on LPL,
and in a dose-dependent manner. On the other hand, after 24, 48, and 72 hours of extract incubation,
only MCE inhibited adipogenesis in the concentration range of 0–5 mg/mL and differentiation at the
highest concentration of 0.5 mg/mL at 48 h. Interestingly, the data revealed that all of the extracts
contained high concentrations of phenolic compounds, including catechin and epicatechin, which may
be the responsible agents for these effects [51].
Several studies attributed these effects on lipid metabolism to the phenolic compounds, especially
catechins present in the extracts [113,114]. However, due to the fact that catechins in MFE and MLE
were lower than in GTE [50], one explanation about the inhibition of LPL may be the synergistic effect of
catechin with other components present in the extracts since synergism between flavonoids is believed
to be better than with one alone. In fact, low-processed whole plant extracts supply multiple chemicals,
as much as food does, and depends on synergistic metabolic effects to confer health. In conclusion, the
groups suggested that MLE and MFE may be used as anti-obesity agents [50,115].
Polyphenols have been intensively used in studies of obesity and weight management, as well as
in other metabolic conditions [13,44,45]. The most used polyphenols include phenolic acids (gentisic
acid, p-hydroxybenzoic acid, and the derivative chlorogenic acid) and flavonoids (epicatechin, catechin,
rutin, quercetin, and kaempferol). Several transcriptional factors, such as proliferator-activated
receptor (PPAR)-γ and CCAAT/enhancer-binding proteins (C/EBPs), are involved in the early stage
of adipocyte differentiation [116]. PPAR-γ, for instance, influences glucose homeostasis and insulin
sensitivity [117].
Flavonoids and phenol acids were able to inhibit adipogenesis in 3T3-L1 adipocytes [45]. The
polyphenols rutin (flavonoid) and o-coumaric acid (phenol acid) showed the best results in the
inhibition of differentiation with lower levels. Moreover, these compounds were able to inhibit the
expression of PPAR-γ and C/EBPα protein levels, demonstrating that these polyphenols inhibit
adipogenesis by affecting the transcriptional factor cascade upstream of PPAR-γ expression and also
inhibiting the expression of leptin and upregulating adiponectin protein levels [45].
Chlorogenic acid has been claimed to modulate lipid and glucose metabolism in vivo in healthy,
as well as in metabolic disorder conditions [46,47]. Eight weeks of treatment with chlorogenic acid
exhibited important alterations in a model of HFD-obese male golden hamsters, decreasing body
weight gain and visceral adiposity, and ameliorating several metabolic parameters. Furthermore,
chlorogenic acid modified lipid and glucose metabolism due to (PPAR)-α action which, in turn,
regulated binding, transport, oxidation, and synthesis of free fatty acids (FFAs) [46]. Thus,
after activation of PPAR-α, the activity of FFA oxidation enzymes may increase elevating fat
energy utilization in the liver and muscle, ameliorating insulin tolerance, and decreasing insulin
resistance [118,119].
Additionally, another flavonoid that was isolated from the fruit and leaves of Morinda citrifolia
is kaempferol [52,66,120]. This flavonoid is the major component of soy leaves (SLE), and a recent
study evaluated the anti-obesity effects of SLE extracts in HFD-obese male C57BL/6 mice. Ten weeks
of treatment suppressed body weight gain and fat accumulation of WAT. Furthermore, kaempferol
supplementation (50 mg/kg/day) induced (i) a decrease in pro-inflammatory cytokine (TNFα and
IL-6) gene expression; (ii) a downregulation of adipogenesis-related genes, such as C/EBP-α, sterol
regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS); and (iii) an upregulation
of fat oxidation-related genes, such as hormone-sensitive lipase (HSL), carnitine palmitoyl transferase 1
(CPT-1), and uncoupling protein-2 (UCP-2), in WAT from HFD-obese mice. Similar results were
observed in 3T3-L1 adipocytes, as well [121].

3.2. Morinda citrifolia L. and Insulin Resistance/Type 2 Diabetes Mellitus (T2DM)

Obesity can lead to insulin resistance, which is a condition in which a cell, tissue, or organism fails
to respond appropriately to a given dose of insulin. To understand the mechanisms of insulin resistance,
investigators have developed numerous models of insulin resistance using various chemicals, drugs,
Nutrients 2017, 9, 540 11 of 29

and nutritional challenges [122]. T2DM is a difficult problem that has been increasing rapidly, and
insulin resistance has an important role in the pathogenesis of T2DM. The reconstitution of insulin
sensitivity is an important strategy for the treatment of T2DM. Thus, Morinda citrifolia has been widely
studied as an alternative treatment for these complications.
Intensive research efforts have evaluated the positive effects of Morinda citrifolia on glucose
homeostasis in models of T2DM [49,61,73,76]. Nguyen et al. [61] observed that methanolic
Morinda citrifolia extract (part not identified) showed an anti-diabetic effect in vitro. The extract
exhibited stimulatory effects on glucose uptake using a fluorescent-tagged glucose probe (2-NBDG) in
3T3-L1 adipocyte cells. The group identified two new lignans, three new neolignans, and 10 known
compounds, where the lignans and ursolic acid were the bioactive compounds that confirmed the
inhibitory effects on protein tyrosine phosphatase 1B-gene (PTP1B) and stimulatory effects on 2-NBDG.
In this study, lignans, such as episesamin 2,6-dicatechol, lirioresinol B, lirioresinol B dimethyl ether,
and ursolic acid, were considered the anti-diabetic effectors for the inhibition of PTP1B (Table 3).
Protein tyrosine phosphatases (PTPs) are a group of proteins that participate in intracellular signaling
and metabolism by dephosphorylating tyrosine residues. There are several PTPs, where PTP1b
has important roles in insulin receptor signaling [123] and is a key regulator of the leptin signaling
pathway [124].

Table 3. The effects of administration of the Morinda citrifolia L. plant on insulin resistance/type 2
diabetes mellitus (T2DM).

Host Part of Plant Dose/Time Effects Reference

−Stimulatory effects on glucose uptake
−Isolation of through a fluorescent-tagged glucose
Morinda citrifolia powder compounds (two new probe (2-NBDG) in 3T3-L1
In vitro (plant part not identified) adipocyte cells. Nguyen et al. [61]
lignans, three new
Methanol extract. neolignans, and 10 −Inhibitory effects on protein tyrosine
known acid phosphatase 1B gene (PTP1B), which is
compounds). overexpressed in insulin resistance.
−Inhibited weight gain after 12 weeks.
−Improved glucose and insulin tolerance
−1.5 µL/g body and fasting glucose in HFD-fed
Fruit (Fermented noni
Mice weight/twice C57Bl/6 mice. Nerurkar et al. [49]
juice).
daily/12 weeks −Improved hepatic insulin resistance by
FOXO-1 and inhibition of PEPCK and
G6P (gluconeogenic enzymes)
−Reduced fasting glucose levels,
−Fruit (15 kg dried noni −fermented noni glycosylated hemoglobin (HbA1) in
Mice fruit powder fermented juice/90 days. KK-Aγ diabetic-mice.
by Cheonggukjang and
−Improved insulin sensitivity in KK-Aγ
bacteria).
diabetic-mice.
−Diminished lipid fraction LDL and Lee et al. [76]
triglycerides in KK-Aγ diabetic-mice.
−Fruit (70% methanol −200 and 400 µg/mL
In vitro −70% methanol extract in culture cells
extract). in vitro. (C2C12 cells) activated PPAR-γ and
stimulated AMPK pathway.
−Roots (methanol −n-BuOH fraction significantly reduced
extract—soluble phases: −3 g/kg/single blood glucose levels after five hours of
Mice Kamiya et al. [73]
CHCl3 , EtOAc, n-BuOH, administration. administration in streptozotocin-diabetic
H2 O). ddY mice.
Effects of administration of different doses and parts of the Morinda citrifolia plant on insulin resistance/T2DM in
in vivo and in vitro studies.

In other studies, lignans from Myristica fragrans Houtt. (nutmeg) demonstrated strong stimulation
AMPK activity in differentiated C2C12 cells. AMPK has been considered as a potential therapeutic
target for the treatment of metabolic syndrome, including obesity and T2DM [125]. Ursolic acid is one
of the most important triterpenoids isolated from various natural products, including Morinda citrifolia.
Nutrients 2017, 9, 540 12 of 29

Jayaprakasam et al. [67] isolated ursolic acid, as well as anthocyanins from Cornus mas (cornelian
cherry), and added them to the HFD for an additional eight weeks. The compounds diminished
obesity and glucose intolerance in HFD-obese C57Bl/6 mice to some extent [67]. Indeed, the beneficial
effects of acute (three days) and chronic (six weeks) treatment with ursolic acid was also reported by
others. These treatments increased skeletal muscle and brown fat metabolism which, in turn, increased
energy expenditure. These data were confirmed by the reduction of obesity, glucose intolerance, and
fatty liver in HFD-obese C57Bl/6 mice [68].
Another important study demonstrated that fermented noni juice (fNJ) administered to
HFD-fed C57Bl/6 male mice reduced body weight and improved glucose and insulin tolerance,
as well as fasting blood glucose. These authors detected scopoletin, quercetin, and anthocyanin
(cyanidin-3-O-rutinoside) in methanolic extracts of fNJ using HPLC. They suggested that the
anti-diabetic effects of fNJ may be associated with quercetin and anthocyanin [49] (Table 3).
Kampkotter et al. [54,126] demonstrated the properties of quercetin in resistance to oxidative stress in
an established model of Caenorhabditis elegans, which is an in vivo model that has become increasingly
popular to evaluate pharmacologically-active compounds of herbal origin. Quercetin not only had a
strong antioxidant capacity, but also prolonged the lifespan of Caenorhabditis elegans and was considered
a modulator of cell signaling processes to exert its protective properties.
Anthocyanins present in bilberry fruit extract ameliorated hyperglycemia and insulin sensitivity
in male KK-Aγ mice, a genetic model of T2DM. Anthocyanins activate AMPK, a signaling pathway
important because of its role in the control of hepatic glucose and lipid metabolism [127,128]. These
data corroborated with another study [67] that isolated anthocyanins (cyanidin 3-O-galactoside,
pelargonidin 3-O-galactoside, and delphinidin 3-O-galactoside) from Cornus mas (cornelian cherry).
HFD-obese mice that received anthocyanins exhibited a non-obese pattern in the glucose tolerance test
while HFD-obese mice showed substantial glucose intolerance [67]. Kaempferol and quercetin isolated
from Euonymus alatus were shown to improve insulin-stimulated glucose uptake in 3T3-L1 mature
adipocytes [53].
In addition, Zhang et al. [62] showed that scopoletin, a phenolic coumarin, had beneficial
effects on insulin-resistant HepG2 cells. Insulin resistance was evaluated by measuring PI3K-linked
protein kinase B/Akt (Akt/PKB). Thereafter, scopoletin was able to stimulate the reactivation of
insulin-mediated Akt/PKB phosphorylation, which was greater compared to the positive control
rosiglitazone, a thiazolidinedione and activator of PPARγ that markedly improves insulin and glucose
parameters in T2DM patients [129]. In 3T3-L1 adipocytes, scopoletin upregulated the expression of
PPARγ2, an isoform of PPARγ that has critical functions in adipocyte differentiation, lipid storage,
and glucose metabolism [130].
Accordingly, Lee et al. [76] also reported the beneficial effects of noni fruit in diabetes. They
used noni fruit powder fermented by Cheonggukjang, which is a fast-fermented soybean paste, and
bacteria, such as Bacillus subtilis (KCTC11352BP), Bacillus sonolensis (KCTC11354BP), Bacillus sp. (KCTC
11351BP) and Bacillus circulans (KCTC 11355BP). The data showed that a fNJ (FMC)-based diet, for
90 days was effective in reducing fasting glucose and glycosylated hemoglobin (HBA1c), enhancing
insulin sensitivity and decreasing LDL, triglycerides and cholesterol in KK-Aγ diabetic mice. These
responses are believed to be due to the activation of PPAR-γ and AMPK phosphorylation (Table 3).
In fact, when HEK293 cells were transfected with a plasmid containing the PPAR-γ
response-element-driven luciferase reporter gene, fermented noni extract activated the
PPAR-γ-dependent luciferase activity. In addition, this compound stimulated glucose uptake
in C2C12 culture cells via activation of the AMPK pathway. These effects could be due to the presence
of anthraquinones, flavonoids and terpenoids [76].
The evaluation of dried roots of Morinda citrifolia were extracted with methanol, suspended
in water (H2 O), and partitioned in different parts of chloroform (CHCl3 ), ethyl acetate (EtOAc),
and n-butanol (n-BuOH). Sequentially, the solvents were removed from these different parts in
order to generate the soluble phases: CHCl3 , EtOAc, n-BuOH, and H2 O. Therefore, the fractions
Nutrients 2017, 9, 540 13 of 29

of soluble phases of methanol extract from Morinda citrifolia roots (MRE) were administrated
orally to streptozotocin-induced ddY diabetic male mice (single administration). Only n-BuOH
exhibited a significant reduction of blood glucose levels after five hours of administration,
whereas methanol extract and other soluble phases did not display any hypoglycemic effects.
Hence, after isolation of compounds from the n-BuOH fraction, two iridoids and three
anthraquinones were identified, where two anthraquinones, lucidin (lucidin 3-O-β-D-primeveroside),
and damnacanthol-3-O-β-D-primeveroside, were responsible for the hypoglycemic effects [73]
(Table 3).
Likewise, anthraquinones are important agents in the treatment of diabetes [72]. Three
anthraquinones (1,2-dimethoxyanthraquinone, alizarin-2-methyl ether and rubiadin-1-methyl ether)
were isolated from the n-hexane and CHCl3 fractions of Morinda officinalis roots and used to investigate
fat accumulation in 3T3-L1 pre-adipocytes using the oil red O staining method. Alizarin-2-methyl
ether was the compound that produced the highest increase in adipocyte differentiation followed by
rubiadin-1-methyl ether and 1,2-dimethoxyanthraquinone [72].
Morinda citrifolia also displayed positive effects in streptozotocin (STPZ)-diabetic
rats [70,71,131,132]. In diabetic patients, wounds are very complex to manage due to impaired
wound-healing. Nayak et al. [131] evaluated the wound-healing effects of NJ on an excision wound
model in induced diabetic rats. These animals exhibited improvement in wound-healing after
consuming NJ. The wound area was reduced earlier and had less dead tissue at the wound site in
NJ-treated rats than in their respective controls. The authors correlated wound-healing improvement
with low fasting glucose, which was also found to be reduced. Triterpenoids and tannins are bioactive
compounds that promote wound-healing due to their astringent and antimicrobial properties,
promoting wound contraction and increasing the rate of epithelialization. Furthermore, these
substances, especially triterpenoids, may have hypoglycemic effects [133].
The anti-diabetic effects of fNJ could be seen in another STPZ-diabetic rat model [132]. A possible
explanation for these effects was the presence of saponins, triterpenes, steroids, flavonoids (rutin),
and cardiac glycosides in the extract. However, the group attributed these effects to triterpenes and
saponins, the principal compounds that show the highest specific actions on glucose metabolism.
Norberg et al. [69] reported that saponins may have a glucagon decreasing effect and may enhance
glucose utilization, thereby lowering blood glucose. Moreover, saponins stimulate insulin release
from the pancreas due to diminishing degradation of glucagon-like peptide (GLP). Triterpenoids have
already been indicated as beneficial agents in diabetes mellitus, especially in alloxan-induced mice,
improving symptoms of glycosuria and elevated blood sugar [134,135].
These data corroborate another study [70] in which aqueous and methanol MFE were administered
to STPZ-diabetic rats for one week before diabetes induction, three days during induction, and
five weeks afterwards. Both MFE reduced blood glucose, glycosylated hemoglobin, blood urea,
and creatinine levels, which were explained by the possible prevalence of antioxidants (vitamin C,
vitamin E, flavonoids, terpenoids, and anthraquinones) in these extracts. In the same animal model,
an antihyperglycemic effect and antioxidant activity were observed for ethanolic MFE given for
30 days [71].
These antioxidant properties were demonstrated by thiobarbituric acid reactive substance
(TBARS), hydroperoxidose, and enzymatic and non-enzymatic antioxidants, such as catalase (CAT),
glutathione, superoxide dismutase (SOD), and vitamins C and E, respectively. It is believed that these
beneficial effects of noni were due to the synergistic effect of several biologically-active ingredients in
the extract, which provides for the antioxidant nature of the extract [71]. Another synergistic effect of
components of NJ was observed in alloxan-diabetic Sprague-Dawley rats, whereas NJ given for four
weeks combined with insulin was more effective in lowering fasting glucose levels compared to the
use of NJ or insulin alone [136].
Nutrients 2017, 9, 540 14 of 29

3.3. Morinda citrifolia and Non-Alcoholic Fatty Liver Disease (NAFLD)

The liver is an important organ that possesses a fundamental role in metabolic homeostasis, such
as in the process of lipogenesis, gluconeogenesis, and cholesterol metabolism. In recent decades,
a variety of pathological conditions emphasize the importance of metabolic functions that occur in the
liver. The increased prevalence of obesity and metabolic syndrome lead to pathophysiological changes
that may result in the development of non-alcoholic fatty liver disease (NAFLD) [137].
NAFLD is considered one of the modern diseases of the new era, being the major cause of
mortality and morbimortality related to chronic liver diseases. Most of the time, this pathology occurs
in 25% of the population, increasing to 70% in obese and T2DM patients [138–140]. NAFLD is a liver
disease that may progress from hepatic steatosis alone, without inflammation and hepatocellular
damage, to steatohepatitis with lobular inflammation, and with evidence of hepatocyte injury called
non-alcoholic steatohepatitis (NASH). Many patients that have NASH develop liver fibrosis, which
may result in hepatocyte death, cirrhosis, and hepatocellular carcinoma, with high chances for the
need of liver transplantation [141].
Despite some studies having demonstrated hepatotoxic effects of noni in humans and
animals [41,82,83], a few others have reported hepatoprotective effects of noni, but it has only been
explored in obese animals [43,51]. The effects of Morinda citrifolia in NAFLD was performed by
Lin et al. [43]. They reported that HFD-induced obese male Golden Syrian hamsters supplemented with
different doses of NJ showed diminished biomarkers of liver damage, namely alanine transaminase
(ALT), along with diminished TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), cyclooxygenase
2 (COX-2), and metalloproteinase 9 (MMP9) levels, and improved morphological characteristics
of hepatic steatosis, such as a decrease in microvesicular steatosis and blurred cellular boundaries.
In addition, NJ supplementation in HFD-obese hamsters decreased serum and liver total cholesterol
and triglycerides, improved liver antioxidative capacity (CAT, SOD, glutathione peroxidase (GSH-Px),
GSH, trolox equivalent anti-oxidative capacity (TEAC)) and lowered liver lipid peroxidation (TBARS)
(Table 4).

Table 4. Effects of the administration of the Morinda citrifolia L. plant on non-alcoholic fatty liver disease
(NAFLD).

Host Part of Plant Dose/Time Effects Reference

−3 mL (including −Diminished visceral fat in

64.23 mg crude HFD-hamsters (all doses).
polysaccharides/kg −Lowered serum and liver lipids: total
body weight/6 weeks. cholesterol and triglycerides in HFD
hamsters (all doses).
Fruit noni juice (2.14 g −Beneficial effects on the liver and
Hamster crude −6 mL (including hepatic enzymes (ALT) in HFD hamsters Lin et al. [43]
polysaccharides/100 mL) 128.46 mg crude (all doses).
polysaccharides/kg
−Increased antioxidant capacity in the
body weight/6 weeks.
liver in HFD hamsters (all doses).
−Diminished inflammatory biomarkers
−9 mL (including in the liver (TNF-α, MCP-1, IL-1β) in
192.69 mg crude HFD hamsters (all doses).
polysaccharides/kg
−Lowered gelatinolytic levels of MMP9
body weight/6 weeks).
in HFD hamsters (all doses).
−Inhibited weight gain after 12 weeks.
−Improved glucose and insulin tolerance
−1.5 µL/g body and fasting glucose in HFD-fed
Fruit fermented noni
Mice weight/twice C57Bl/6 mice. Nerurkar et al. [49]
juice
daily/12 weeks. −Improved hepatic insulin resistance by
FOXO-1 and inhibition of PEPCK and
G6P (gluconeogenic enzymes).
Effects of administration of different doses and parts of the Morinda citrifolia plant on NAFLD in in vivo studies.
Nutrients 2017, 9, 540 15 of 29

All of these beneficial effects are possibly due to the large amount of phenolic acids present in
NJ. Large amounts of phenolic acids, such as gentisic acid, p-hydroxybenzoic acid, and chlorogenic
acid, are the dominant compounds in this juice [43]. Many studies have demonstrated that phenolic
compounds act as reactive oxygen species (ROS) scavengers, reducing lipid peroxidation, as well.
In vitro studies conducted by Joshi et al. [142] pointed to gentisic acid as the antioxidative and ROS
scavenging agent. If those effects are also beneficial to humans it remains unknown and further study
is necessary.
The effects of noni juice compounds have been extensively studied in animals. Chlorogenic
acid was able to enhance the activity of the important antioxidant enzymes SOD, CAT and GSH-Px
in STPZ-nicotinamide-induced type 2 diabetic rats [143]. Complementary studies reported that
aqueous extract of Mesona procumbens, which has chlorogenic acid as a major compound, has
anti-inflammatory action via the upregulation of antioxidants and downregulation of pro-inflammatory
biomarkers (TNF-α, iNOS and COX-2) [144], and it exhibits anti-obesity effects and improves lipid
metabolism [145].
In corroboration of the hepatic benefits of fNJ supplementation in an obese model,
Nerurkar et al. [49] demonstrated that fNJ produced positive effects on plasma glucose
levels by modulating hepatic gene expression of phosphoenolpyruvate carboxykinase (PEPCK),
glucose-6-phosphatase (G6P) and glucokinase (GCK). PEPCK and G6P are important gluconeogenic
enzymes regulated by insulin. They were inhibited after fNJ supplementation, which was confirmed
with HepG2 culture cells treated with FOXO1 siRNA and fNJ. GCK was upregulated by fNJ via
forkhead box O1 (FOXO1) transcription factor phosphorylation. The hypoglycemic properties of fNJ
were associated with the inhibition of hepatic FOXO1 mRNA with concomitant increase in FOXO1
phosphorylation. Consequently, fNJ improved hepatic insulin resistance indicated by homeostatic
model assessment-insulin resistance (HOMA-IR) (Table 4).
Those effects may be attributed to flavonoids, quercetin, and anthocyanins, specifically
cyanidin-3-O-rutinoside, which were isolated from methanolic extracts of fNJ. Some studies
demonstrated the inhibitory effect of anthocyanins on oxidative stress via FOXO transcription factor
regulation in Caenorhabiditis elegans [54,126]. In support of these studies, fNJ promoted the reduction of
hepatocyte fatty degeneration (smaller fatty globules and less numerous) in a model of STPZ-diabetic
rats. It was suggested that the hepatoprotective activity of Morinda citrifolia was due to the antioxidant
activity of flavonoid constituents [132].
Anthocyanins (delphinidin and cyanidin) isolated from Hibiscus sabdafera extract (HSE) also
showed positive effects against obesity and liver damage in HFD-obese hamsters. HSE and
anthocyanins regulated total body weight and visceral fat, reduced serum cholesterol and triglyceride
levels, protected against oxidation-associated damage in liver by regulating a liver antioxidant enzyme
(paraoxonase 1), and also reduced liver damage biomarkers ALT and AST [146].
Another study evaluated the benefits of scopoletin in reducing obesity and liver damage by
supplementing the diet with two doses of scopoletin in a HFD model of obese mice. Supplementation
resulted in reduced body weight, visceral fat, pro-inflammatory adipokine serum levels (leptin, MCP-1,
TNF-α, IL-6, IFNγ), insulin resistance, and hepatic lipid accumulation and, on the other hand, increased
serum adiponectin and fecal lipid levels. Moreover, supplementation was able to downregulate genes,
such as CIDEA (cell death-inducing DFFA-like effector A) and Apoa4 (apolipoprotein A-IV), which
are known to be related to hepatic steatosis and inflammation [147].

3.4. Morinda citrifolia and Dyslipidemia/Hypertension

Atherosclerosis is the primary cause of heart disease and stroke. This problem is most common in
obese, hypertensive, dyslipidemic, and diabetic patients leading to vascular damage [148]. Although
hypertension and dyslipidemia are independent risk factors that lead to atherosclerosis, the latter is
also a risk factor for CVDs, such as stroke and myocardial infarction and hypertension. In this way,
both dyslipidemia and hypertension are important risk factors for the progression and development of
Nutrients 2017, 9, 540 16 of 29

atherosclerosis [149–151]. Moreover, these factors are serious pathological conditions for endothelium
damage, causing cell proliferation, vascular remodeling, apoptosis, and enhancement of cellular
permeability with adhesion molecules that bind monocytes and T lymphocytes. The latter cells are
redirected into the intima vasculature by pro-inflammatory and chemoattractant cytokines. Hence,
monocytes differentiate into macrophages which overloaded excessive oxidized LDL, become foam
cells, elaborate cytokines, and then form atherosclerotic plaques [148].
The atherogenic dyslipidemic phenotype is characterized by high plasma triglycerides, low
levels of high-density lipoprotein cholesterol (HDL), and excessive LDL. Additionally, postprandial
(non-fasting) triglycerides (postprandial hyperlipidemia) are also an important component of
atherosclerosis [152]. The modern synthetic drugs that have been used as treatment for lipid
abnormalities are effective at reversing the measured signs, such as decreased LDL levels, but are
difficult to afford for many patients and are associated with several side-effects [153]. Morinda citrifolia
has been demonstrated to be an alternative therapy for this problem. A current study evaluated the
effects of NJ on serum lipid profiles in 132 heavy smokers (drinking 29.5 mL to 188 mL of NJ per day).
Heavy smoker volunteers who drank NJ displayed a reduction in cholesterol levels, triglycerides, and
high-sensitivity C-reactive protein (hs-CRP), a decrease in LDL and homocysteine, and an increase in
HDL fraction [25].
However, the few human studies available did not address this issue. Thus, clinical trials are
necessary to validate the beneficial qualities of Morinda citrifolia bioactive compounds in human
metabolic diseases.
In animals, a recent study performed by Shoeb et al. [111] demonstrated that supplementation with
two doses of fNJ in cholesterol-rich HFD-induced hyperlipidemia rats showed a significant decrease
in total cholesterol, triglycerides, and LDL at both doses when compared to the hyperlipidemic group.
The decrease in total cholesterol was observed with the lower dose of fNJ reaching similar values
as the positive control atorvastatin (10 mg/kg). Furthermore, the lower dose reduced body weight
compared to the hyperlipidemic group and it was also comparable to the hyperlipidemic group
receiving atorvastatin (Table 5).
These data corroborate the hypolipidemic effects of noni in a work done by Mandukhail et al. [154].
These authors compared ethanolic extracts of different parts of Morinda citrifolia and evaluated different
doses of MFE, MLE, and MRE extracts in tyloxapol (Triton WR 1339)-induced hyperlipidemia and
HFD-induced dyslipidemia models, both in rats. The highest dose of all extracts produced a significant
reduction in total cholesterol and triglyceride levels in the WR 1339 rat group. In contrast, the
HFD-induced dyslipidemia group showed different results depending on the extracts at the highest
dose of each. Both MFE and MLE prevented the rise in total cholesterol, LDL, total cholesterol/HDL
ratio, and atherogenic index without significant effects on HDL. However, MLE prevented the increase
in glucose levels and body weight in these animals, while MRE was the best extract in this study,
which proved to prevent the rise in all lipid and glucose levels and, at the same time, increasing HDL
and preventing weight gain, suggesting antidyslipidemic mechanisms for various parts of the noni
plant (Table 5).
Hypolipidemic and other positive effects of Morinda citrifolia were suggested in two
studies [111,154] that demonstrated the presence of strong antioxidant activity in the noni plant.
According to previous studies, Kamiya et al. [60] demonstrated the effects of fruits of Morinda citrifolia
in preventing atherosclerosis. MFE and its soluble phases (CHCl3 , EtOAc, n-BuOH, H2 O) inhibited
copper-induced LDL oxidation according to the TBARS method. Lignans were isolated in
the EtOAc-soluble phase, including 3,30 -bisdemethypinoresinol, americanol A, morindolin, and
isoprincepin, which showed remarkable or strong antioxidant activity. Thus, lignan compounds
of noni fruit are involved in the prevention of atherosclerosis, likely due to their numerous phenolic
hydroxyl groups (Table 5).
Nutrients 2017, 9, 540 17 of 29

Table 5. The effects of administration of the Morinda citrifolia L. plant on dyslipidemia.

Host Part of Plant Dose/Time Effects Reference

−50 mg/kg/day/ −Reduced body weight (better at
30 days. 50 mg/kg/day dose).
Rats Fruit (Noni juice) −Reduced serum total cholesterol, Shoeb et al. [111]
−100 mg/kg/day/ triglycerides, and lipids fractions: LDL and
30 days. VLDL (all doses).
−Increased lipid fraction HDL (all doses).
−Fruit ethanol extract −All of the extracts on tyloxapol-induced
(1000 and hyperlipidemia: reduced total cholesterol
500 mg/kg/day). and triglyceride levels.
−MFE in HFD-induced dyslipidemia
(1000 mg/kg/day): prevented the rise of
−Leaf ethanol extract
serum total cholesterol, LDL, total
(1000 and
cholesterol/HDL ratio, and atherogenic
500 mg/kg/day).
index. No significant effects on HDL and
glucose levels. No effect on body weight.
Fruits, leaves and roots −MLE in HFD-induced dyslipidemia Mandukhail et al.
Rats Mice (70% ethanolic aqueous (1000 mg/kg/day): prevented the rise in [154]
extract). serum total cholesterol, LDL, total
cholesterol/HDL ratio, atherogenic index,
and glucose levels. No significant effects on
−Root ethanol extract
HDL. Significantly prevented the gain in
(500 and
average body weight.
300 mg/kg/day)
−MRE in HFD-induced dyslipidemia (500
mg/kg/day): prevented the rise in serum
total cholesterol, LDL, total cholesterol/HDL
ratio, atherogenic index, and glucose levels.
Increased HDL. Significantly prevented the
gain in average body weight.
Fruit (methanolic −Lignans isolated from EtOAc fraction of
−Effective EtOAc
extract-soluble phases: methanol extract inhibited activity against
In vitro purified and isolated Kamiya et al. [60]
CHCl3 , EtOAc, nBuOH, copper-induced LDL oxidation by measuring
lignans
H2 O). the decrease in TBARS.
−3 mL NJ (containing
−Reduced sizes of heart, liver and visceral
0.20 g solids/kg body
fat in HFD-cholesterol hamsters.
weight)/day/6 weeks.
−Decreased serum triglycerides, total
−6 mL NJ (containing
cholesterol, atherogenic index,
0.40 g solids/kg body
malondialdehyde levels and hepatic lipids in
weight)/day/6 weeks
HFD-cholesterol hamsters.
Fruit (Fermented Noni
Hamster −Increased trolox equivalent antioxidant Lin et al. [48]
Juice).
capacity (TEAC), glutathione (GSH), fecal
lipids in HFD-cholesterol hamsters.
−9 mL NJ (containing
−Downregulated sterol regulator element
0.60 g solids/kg body
binding protein-1c (SREBP-1c) and
weight) /day/6 weeks.
upregulated hepatic peroxisome
proliferator-activated receptor-alpha
(PPAR-α) and uncoupling protein 2 (UCP-2)
mRNA in HFD-cholesterol hamsters.
Effects of the administration of different doses and parts of the Morinda citrifolia plant on dyslipidemia in in vivo
and in vitro studies.

Furthermore, Lin et al. [48] evaluated supplementation with fNJ at different concentrations
in HFD-cholesterol hamsters. They found that the group supplemented with fNJ displayed
hypolipidemic and antioxidative effects, demonstrated by decreases in serum triglyceride, total
cholesterol, atherogenic index, malondialdehyde levels, and hepatic lipids, while antioxidant activity
(TEAC and GSH) and fecal lipids were increased (Table 5).
To evaluate the effect of fNJ on lipid metabolism and mechanisms of actions, important genes
related to lipid homeostasis were evaluated in the liver, which is the major organ in the regulation
of lipid homeostasis. The data showed that SREBP-1c was upregulated after fNJ treatment; this is an
important transcription factor that stimulates the expression of lipogenic genes, such as that of fatty
acid synthase (FAS). This enzyme is responsible for the biosynthesis of FA. In energy expenditure,
Nutrients 2017, 9, 540 18 of 29

peroxisome proliferator-activated receptor-alpha (PPAR-α) upregulates uncoupling protein 2 (UCP2),

which increases thermogenesis, while reducing the efficiency of ATP synthesis. In this regard, the gene
expression of PPAR-α, as well as UCP-2, was upregulated in the liver after fNJ supplementation. The
bioactive compounds responsible for the effects of fNJ were gentisic acid, which was the phenolic in
the highest amount, followed by p-hydroxybenzoic acid and chlorogenic acid [48].
Many alternatives of anti-hypertensive therapies have been widely studied. Accordingly, some
authors have focused on Morinda citrifolia as an alternative therapy for hypertension. Using an animal
model of hypertension, Wigati et al. [55] investigated the action of ethanolic MLE, MFE, and the
combination of both on blood pressure in dexamethasone-induced hypertensive rats, where this model
is characterized by nitric oxide deficiency and oxidative stress. All extracts decreased blood pressure,
but were not able to repair or inhibit renal damage caused by dexamethasone induction. However,
the combination of the two extracts had the highest hypotensive activity. According to the study,
the phenolic compounds, such as rutin as a marker in MLE and scopoletin in MFE, were the agents
responsible for the hypotensive effects (Table 6).

Table 6. The effects of the Morinda citrifolia plant on hypertension.

Host Part of Plant Doses/Time Effects Reference

−Reduced blood pressure in
−Ethanolic extract of leaves
dexamethasone-induced hypertensive
(500 mg/kg body weight)/14 days
rats (all doses and extracts).
Fruit and leaf
Rats −Ethanolic extract of fruit Wigati et al. [55]
(ethanolic extract)
(500 mg/kg body weight)/14 days
−The highest hypotensive effect was
−Ethanolic extract of leaves + with the combination of the extracts.
fruit (1:1, 500 mg/kg body
weight)/14 days
−Different concentrations on −Rabbit jejunum: produced
rabbit jejunum, thoracic aorta of concentration-dependent relaxation
rats, guinea pig atria of spontaneous and high K+ -induced
in vitro * study. concentrations (antispasmodic effect).
−Guinea pig atria: caused inhibition
−Positive control: verapamil
of both atrial force and rate of
(different concentrations
spontaneous contractions
in vitro * study).
(cardiopressant activity).
Rabbit, Roots (70%
Rat and ethanolic- aqueous −Rabbit thoracic aorta: suppressed Gilani et al. [93]
Guinea-pig extract) contractions induced by
phenylephrine (1.0 µM) in normal
–Ca+2 and Ca+2 - free Krebs solution-
and by high K+ , like the positive
−* Concentration-response curve.
control (verapamil).
−Rat thoracic aorta: also caused
relaxation of the phenylephrine
(1.0 µM)-induced contractions
(vasodilatory activity).
−Increased urine volume in a
−5 mg/kg (single administration
dose-dependent manner (10 mg/kg
after 24 h).
higher than 5 mg/kg)
Fruit (noni fruit
Rats Shenoy et al. [63]
juice) −Decreased ion excretion (sodium
−10 mg/kg (single administration
and potassium)
after 24 h).
−Aquaretic action.
Effects of administration of different doses and parts of Morinda citrifolia plant on hypertension in in vivo studies.
* Studies involving animal tissues in an in vitro assay.

Previous studies have demonstrated that rutin and scopoletin are important phenolic compounds
that affect the cardiovascular system, including blood pressure regulation. Rutin possesses
renal-protective activity probably by inhibiting ROS production and through antioxidant activities,
reducing elevated malondialdehyde levels and restoring depleted manganese-superoxide dismutase
(MnSOD) and GSH, with positive effects on biochemical parameters, as well as on the histopathological
morphology of the kidneys [56]. Scopoletin also demonstrated hypotensive effects and relaxation
Nutrients 2017, 9, 540 19 of 29

of rat aorta. In addition, a possible inhibitory activity of angiotensin converting enzyme-1 (ACE1)
was suggested as a property of this phenolic compound [155,156]. Asperulosidic acid, an iridoid
glycoside present in MFE, showed substantial positive effects on blood fluidity and improved certain
lifestyle-related diseases, such as hypertension, dyslipidemia, and diabetes [80].
MRE showed antispasmodic and vasodilator activities mediated through blockade of
voltage-dependent calcium channels in isolated tissues of rats, guinea pigs, and rabbits [93] (Table 6).
These effects were mediated by alkaloids, phenolic compounds, sterols, flavonoids, tannins, coumarins,
and anthraquinones, which corroborate a study on Zingiber officinale Roscoe (ginger) that evaluated its
hypotensive effects [157]. The same bioactive compounds that were found in the noni plant were also
detected in ginger and could affect isolated tissues of rats, rabbits, and guinea pigs. The crude extract
of ginger decreased blood pressure and exhibited a cardiodepressant activity, with the activity being
mediated by Ca+2 channel-blocking, which was demonstrated when crude ginger extract shifted the
Ca+2 dose-response curve to the right, mimicking the effect of the positive control verapamil.
Considering that diuretics are used in the treatment of hypertension, Shenoy et al. [63] evaluated
the diuretic potential of NJ in normal rats. The effects observed were an increase in urine volume
in a dose-dependent manner with augmentation of the diuretic index accompanied by a significant
decrease in sodium and potassium ion excretion. The authors demonstrated that the noni plant had
aquaretic, instead of diuretic, actions (Table 6). Some authors believe that herbs act only as aquaretic
agents, which increase water excretion without affecting renal handling of electrolytes. In other words,
aquaretics only increase urine output, acting on the glomerulus, unlike conventional diuretic drugs
that act further along the nephron [63,64].
Herbs often contain large amounts of minerals (electrolytes) and noni fruit has a high content
of potassium. Hook et al. [65] evaluated the diuretic effect of Taraxacum officinale Weber (dandelion)
in normal mice and did not observe any significant variation in electrolytes (Na+ , K+ , Ca+2 ), but the
final volume of urine produced after five hours was greater than with the positive control, furosemide.
That study concluded that the high potassium content of dandelion was responsible for any diuretic
activity, where dandelion was similar in action to noni fruit and, thus, the increased urinary volume
could be suggestive of an osmotic effect [63,65].

3.5. Morinda citrifolia and the Effect on Gut Microbiota

There is a vast community of gut microbes [158]. Much has been invested in the search for
nutrients that are selective for a favorable modification of intestinal microbiota, especially those able
to increase the amount of Bifidobacterium and Lactobacillus. The dysbiosis of the gut microbiota has
been associated with the development and progression of many human diseases. The ratio of some
microbiota species are greater in obese, rather than in lean, individuals [159,160]. Noni, and its juice,
exhibit antimicrobial properties and high antioxidant activity, which would be beneficial for a healthy
intestinal microbiota [161,162].
As observed in Table 7, fNJ showed a probiotic character by allowing a greater growth of
Lactobacillus, as well as Bifidobacterium, species. This is possible because NJ (as a raw substrate)
has a fermentative process with lactic acid bacteria (Lactobacillus casei and Lactobacillus plantarum) or
Bifidobacterium (Bifidobacterium longum) [161,162].
Nutrients 2017, 9, 540 20 of 29

Table 7. Effects of administration of Morinda citrifolia L. on gut microbiota.

Host Methods Effects Reference

Time courses of lactic acid
−All reached almost 10 × 108
fermentation of noni juice by
In vitro CFU/mL after 48 h of Wang et al. [161]
Lactobacillus casei, Bifidobacterium
fermentation at 30 ◦ C
longum and Lactobacillus plantarum
−Bifidobacterium and Lactobacillus
Human stool sample from a species, presented growth
healthy volunteer (10 g) with (0.16–0.63 mg/mL for
In vitro Huang et al. [162]
ethanolic extracts of fermented Bifidobacterium and Lactobacillus
noni fruit spp.) compared with negative
control (0 mg/mL)
−Increased amount of lactic acid
bacteria with supplementation
Supplementation with noni fruit Kurniawan, Widodo,
with 2% noni fruit powder;
Hybrid duck powder using different Djunaidi [163]
concentrations −Decreased Escherichia coli with
supplementation with 3% noni
fruit powder.
Effects of administration of Morinda citrifolia on gut microbiota in in vivo and in vitro studies.

In addition, noni powder also has a prebiotic action. One of the reasons may be the high amount
of polysaccharides in the fruit, since carbohydrates, except for starch, act as dietary fiber, coming
intact with the gut and contacting the bacterial community present in the intestinal microbiota [164].
The high molecular weight fraction of NJ is mostly composed of pectic polysaccharides, including
rhamnogalacturonan, homogalacturonan, and the neutral side chains of (arabino) galactan and
arabinan [165].
Another reason may be the high phenolic composition of the fruit, which may also have a
prebiotic function [162], such as quercetin and proanthocyanidin [166,167]. Previous studies have also
indicated that phenolic compounds can inhibit the growth of pathogens such as Escherichia coli and
Helicobacter pylori [166].
In addition to the microbiota, the size and height of the villi are important for intestinal function.
Diet plays an important role in intestinal morphology [163]. The mucus layer in the small intestine
protects the epithelial cells of the small intestine and mediates nutrient transport between the lumen
and the membrane of the brush border. The ontogeny of the whole gut has extensive implications for
intestinal function [168].
Supplementation with 1% noni fruit powder caused an increase in villus height, villus surface
area, and crypt depth when compared with control [163]. Although few studies have evaluated noni
fruit with regard to the microbiota and intestinal function, the in vitro and in vivo results presented in
Table 7 show that noni fruit shows prebiotic activity, when administered alone, and probiotic activity,
when used in fNJ, improving bacterial colonization and intestinal morphology.

4. Conclusions
Bioactive compounds from natural resources are a promising field of study for alternative
medicines, where Morinda citrifolia Linn. (noni) is one of these important options. Noni has
demonstrated positive effects in metabolic dysfunction, including the regulation of body weight
and fat deposits, lipid and glucose metabolism and blood pressure, hepatoprotective effects, and
improvement in bacterial colonization of the gut and intestinal morphology. However, Morinda citrifolia
has never been an important food plant, probably due to its poor palatability and toxicity, in its
natural homeland. This review reports the influence of the noni plant and its bioactive compounds,
emphasizing the potential mechanisms of action and effects on cell signaling pathways involved in
obesity and obesity-related metabolic dysfunction. The noni plant may be processed for some possible
medicinal properties after the management of toxicity, or some parts of the plant may be mixed with
Nutrients 2017, 9, 540 21 of 29

less nutritional, but appetizing, food for health benefits. Therefore, doses and the time of treatment or
long-term supplementation, and also new alternatives in the near future to improve the bioavailability
of the product, are very important issues to be evaluated. Finally, since Morinda citrifolia contains
important bioactive compounds for health, it may be an alternative therapeutic resource with great
potential in the treatment of obesity and obesity-related metabolic dysfunction.

Acknowledgments: We thank the post-graduate program in health and development in the Central-West Region
of Brazil, Federal University of Mato Grosso do Sul-UFMS, and the post-graduate program in biotechnology,
Catholic University Dom Bosco for their support. A. Leyva provided English editing of the manuscript.
Author Contributions: Aline Carla Inada, Priscila Silva Figueiredo, Rosângela Aparecida dos Santos-Eichler,
Alline Pereira de Castro, and Rita de Cássia Avellaneda Guimarães: assistance with structuring of the review,
writing, and literature review; Priscila Aiko Hiane and Karine de Cássia Freitas: assistance with structuring of
the review.
Conflicts of Interest: The authors report no conflict of interest.

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