Introduction

Increasing awareness on the positive effect of diet on human wellbeing has brought novel natural nutraingredients and functional food products into a new extraordinary age.¹ The functional food  is commonly defined as a diet comprising more than one useful constituents that offer supplementary health benefits in addition to the rudimentary, alimentary and energetic importance that each food offers.² Functional foods have been linked with improved health and quality of life, good health promotion, and decreased threat of ailment.¹ Public awareness on healthy diet is increasing in recent times as it is important for the prevention of chronic diseases including cancer, cardiovascular problems, and osteoporosis³. Besides, the societal necessity to minimize the  prescription of pharmaceutical products due to their adverse side effects and  minimize the cost of  healthcare, has encouraged the government agencies and the industries towards the wide usage of functional foods.⁴

The utilization of microalga Nostoc to survive hunger among Chinese people has inferred that  human beings had used microalgae as a food supplement over thousands of years .⁵ Certain blue-green microalgae such as , Aphanizomenon and Spirulina  have been utilized for thousands of years by humans as food.⁶

Microalgae comprise a vast diversity of microorganisms from prokaryotic cyanobacteria to eukaryotic microalgae that can synthesize bioactive substances by using carbon dioxide, nutrients (nitrogen, phosporus, potassium)  and solar energy proficiently.⁷ The carotenoids, long-chain fatty acids, sugars, both essential and non-essential amino acids, minerals, enzymes and vitamins are the most sought after bioactive compounds produced by the microalgae that are essential for human nutrition and well being. Thus, microalgae are perceived as ideal candidates for modern “nutraceutical” or “healthy food”.⁸

Arthospira plantesis, Haematococcus pluvialis, Dunaliella salina, and Chlorella vulgaris, are the most commonly used microalgae as food supplements in human and feed additives for animals because they are the most biotechnologically relevant microalgae.⁹ In addition, microlgae products are used in cosmetic industries as skin cream pigments and in pharmaceutical applications due to their therapeutic values.¹⁰ Further, microalgae function as probiotic agents and are incorporated in traditional food products such as pasta, biscuits, salad dressings and mayonnaise to enhance the intake of nutritionally diverse foods that promotes human health outcomes.³ Interestingly, microlagae are also used as a natural food colorant or as a dietary substitute in snack foods, pasta, gums, candy bars, snacks and drink mixes.¹¹

Due to the abundance of accessible microalgae bestowed in nature, selecting the most appropriate microalgae for specific applications in food technology is extremely important for successful production of novel foods.³ Conversely, biomass manufacturing systems that are currently in use have to be modified using more advanced technologies, in operational as well as technological  levels, to enrich the bioactive compounds produced by the microalgae.^{1, 12}

To highlight the importance of the usage of the products synthesized and extracted from microalgae as an alternative source for naturally produced healthy food supplements, this review article summarizes the nutritional values and the therapeutic applications of the bioactive compounds derived from microalgae.

Bioactive Food Compounds of Microalgae

Microalgae are fascinating life forms, whose evolution is not only to survive but also to flourish in the harshest surroundings of the planet. They do this by naturally generating an outstanding collection of defensive and nourishing compounds like flavonoids, phospholipids, special carotenoids, antioxidants, oils rich in nutrients, non-digestible oligosaccharides and fatty acids.¹² The biosynthesis of the bioactive compounds including natural antioxidants and drugs from microalgae are stimulated and enhanced by manipulating the cultivation procedures like increasing or decreasing the temperature, nutrients,  growth phase, photoperiod and light intensity for optimal growth and high yield.¹²

Lipids

The oils derived from microalgae can be a good substitute for the currently used vegetable oils as the microlagal oils are rich in essential fatty acids. For example, the concentrations of linoleic and alpha-linolenic acids in microalgal oils are greater than the oils obtained from rapeseed (canola), soy or sunflower oils.¹³

The development of high concentrations of nutritionally important polyunsaturated long-chain fatty acids (PUFAs), such as docosahexaenoic acid (DHA, 22:6, ω−3 ) and eicosapentaenoic acid (EPA, 20:5, ω−3 ) can be made possible through microalgal oils. The EPA and DHA supplements are well known for their beneficial effects to enhance brain function, especially to improve children’s cognitive performance and also prevent cardiovascular diseases and inflammation.¹⁴ Interestingly, microalgal oils can be considered a natural gift to vegetarians since the oils derived from microalgae can be the best substitute for fish oils. Also, the chemical pollutants, like mercury, present in the fish supplies can contaminate the fish oils that in turn might cause health hazards to the consumers. Hence, microalgal oils can be a better alternative for fish oils available in the market.¹⁵

Initially, the primary objective of the research development on algal lipids was targeted towards the synthesis of biodiesel. However,  the wider usage of microlagal omega fatty acids in infant formulations and also as nutraceutical agents have attracted the current market considerably.¹⁶ Numerous microalgae strains have been analyzed for fatty acid content and great accumulations of DHA and EPA have been found in the strains of the genera Nannochloropsis, Phaeodactylum, and Koliella. Notably, the arachidonic acid of Porphyridium cruentum helps to improve normal growth,  improve visual and functional development in infants. Similarly, the eicosapent aenoic acid present in Nannochloropsis sp. has beneficial effects on cardiovascular system as it offers protection against atherosclerosis and nervous sytem towards mental development and support.¹⁶

Proteins

In the 1950s itself, microalgae were proposed as a novel protein source¹⁷ due to their high protein content and rich amino acid profile.¹⁸ The hydrolysates or peptides of microlagal proteins can be produced by various enzymatic processes and fermentation.¹⁹ The protein constituents of microlage provide numerous health benefits such as antihypertensive, antioxidant, anticancer, immune-modulatory, anticoagulant, and hepato-protective.²⁰

The microalgae commonly used in the formulation of protein products are Spirulina (65% protein), Dunaliella (57% protein) and Chlorella (55% protein).²¹ Special attention has been given to Spirulina among all the studied microalgae species due to its supreme quality and protein quantity (60–70 percent of dry weight) with easy digestability.²² Phycobiliproteins are a curious category of microalgae proteins, which are the accessory photosynthetic pigments, including phycocyanin, phycoerythrin, phycoerythrocyanin, and allophycocyanin. The Synechococcus sp. and Arthrospira sp. are the most important algae currently used to extract phycobiliproteins. The phycobiliproteins are used in dairy products, chewing gums, sweets and ice creams as natural colorants and also find application in several nutraceutical products including tablets and, capsules.²³  Numerous beneficial health effects of phycobiliproteins including neuroprotective, antioxidant, hepatoprotective, anti-inflammatory, anticancer and hypocholesterolemic have been reported.²⁴

Solvent extraction, enzyme hydrolysis and microbial fermentation techniques are utilized to produce bioactive microalgae peptides. Enzymatic hydrolysis are preferred in food and pharmaceutical industries due to the absence of residual organic solvents or potentially harmful compounds in food.²⁵ Advanced high throughput analysis and molecular studies of algal peptides are required to fully benefit the superior novel proteins from the microalgae.

Carbohydrates

A relatively low photoconversion efficiency of algae enables them to build up large carbon concentrations  (greater than 50% by dry weight) with substantial biofuels in microalgae, which in particular act as protective, storage and structural molecules.²⁶ The use of microalgae as a sustainable source of carbohydrates is a potential area that should be explored further.²⁷ The glycogen (α1,4-based glucan), hybrid starch and amylopectin-like polysaccharides (starch) that are closely related to the plant are present in cyanobacteria, red algae and green algae respectively.²⁸ Microalgae contain both prominent sugars like mannose, galactose, xylose, arabinose and glucose, and also less frequent sugars, including rhamnoses, fucose and uronic acids.²⁹ Cultivation and environmental factors can modulate nearly 33 – 64% on the content of microalgae carbohydrates as they relate to the carbon source and metabolism (e.g. autotrophy, heterotrophy and mixotrophy).³⁰

Some microalgae polysaccharides can be used in industries commercially, taking into account the rapid growth by crop control.³¹ Isolated polysaccharides from microalgae, such as P.cruentum, S.platensis, D. Salina, Rhodella reticulate and Schizochytrium sp., displayed useful antioxidant properties and efficient scavenging capabilities on superoxide radicals, hydroxyl radicals and hydroxyl peroxide.³² Recent research disclosed the occurance of high content polysaccharides in Isochrysis galbana (up to 25% dry cell weight).³³ The rich carbohydrate content of microalgae can serve as an alternative source of sustainable energy that can be supplemented to alleviate hunger and poverty.

Phytochemicals

Phytochemicals are a group of bioactive compounds available in microalgae with diverse biological features including antioxidant, anti-inflammatory and antimicrobial activities. Phenolics are the most abundant phytochemicals that exist in microalgae and are well known for their antioxidant properties.³⁴ The phenolic compounds are generally divided into 10 categories, namely phenolic acid, hydroxycinnamic acid, basic phenol, xanthone, flavonoid, stilbene acid, anthraquinone, coumarins, naphthoquinones and lignins.³⁵ Flavonoids are the active scavengers for various forms of reactive oxygen species (ROS) and lipid peroxyl radicals to prevent lipid peroxidation and oxidative stress.³⁴

Arthrospira extracts exhibited antioxidant activities by preventing the peroxidation of LDL cholesterol which leads to constraining atherosclerotic plaques and strokes.³⁵ Antioxidant effects evaluated by testing oxidation stability demonstrated that chlorogenic and caffeic acids found in this microalgae  have greater antioxidant activity than other phenolic acids ³⁶. The combined effects of these phenolics and 13-cis-retinoic acid have been documented to not only prevent lipid peroxidation but also protect against various cancer.³⁶ Numerous earlier  findings have confirmed the antioxidant potential of phenolic compounds obtained from Chlorella and Dunaliella.³⁷ The presence of these phytonutrients and bioactive substances make the microalgae a potent source of nutritional ingredients, nutraceuticals and dietary supplements.

Vitamins and Minerals

Microalgae also produce large amount of essential micronutrients such as  vitamins and minerals.³⁸ Microalgal biomass have been reported to constitute important vitamins (e.g., Thiamin, (B1), Riboflavin (B2), Pyridoxine (B6), Cyanocobalamine (B12), vit C and vit E) and sufficient mineral content ( e.g., sodium, potassium, copper, magnesium, iron and zinc). The cobalamin (vitamin B12) is commonly present in the green and red algae at high concentrations³⁴ that makes microalgae as an alternative source  of B12 especially for vegans and vegetarians.

Fabregas and Herrero performed a research in 1990 to find out the vitamin content of different strains of microalgae. They observed that, relative to traditional food sources, microalgae consist of a greater concentration of four vitamins; provitamin A, vitamin B1, vitamin E and folic acid. Dunaliella tertiolecta has been confirmed to have the capacity to synthesize vitamin B12 (cobalamin), vitamin B2 (riboflavin), vitamin E (tocopherol) and provitamin a (β-carotene). Tetraselmis suecica has also been an outstanding source of vitamin B1 (thiamin), vitamin B3 (nicotinic acid), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine) and vitamin C (ascorbic acid), and Chlorella sp contains a high concentration of vitamin B7 (biotin). A research by Shim et al. found that about 9-18% of Chlorella species are a plentiful source of vitamin B12.³⁹

There are several bioactive food compounds derived from microalgae that can be employed in therapeutic applications. For instance, γ-linolenic acid (GLA) and vitamins from S. platensis are utilized as immunity boosters.^{40, 41} Proteins from S. platensis and D. salina, short-chain fatty acids from H. pluvialis, proteins and dietary fibers from Chlorella and phenylethylamine from Aphanizomenon are used as health food supplements.^{41,42.43,44,45} Besides, eicosapentaenoic acid (EPA), arachidonic acid (ARA) and vitamins derived from P. cruentum are consumed as nutraceuticals to enhance the blood clotting and immune system.^46,47 Table 1 outlines the therapeutic applications of bioactive food compounds obtained from microalgae. These bioactive compounds are extensively used for various physiological functions and play a vital role in ensuring good health and well being.

Table 1:  Therapeutic Applications of Bioactive Food Compounds from Microalgae.

Pigments

The presence of different pigments and colors in each phylum is one of the most noticeable characteristics of microalgae.⁴⁸ Given their phylogenetic age, it is self-evident that they have evolved to produce pigments that are unique to them.⁴⁹ The different types of pigments isolated from microalgae have been proven to have numerous health benefits and hence have attracted the industries in producing various food and pharmaceuticals products in recent years using microlgal pigments as an active food additive.  Table 2 summarizes the pigments of microalgae and their potential applications. These pigments are natural with zero toxicity and better health outcomes that make them a healthier choice compared to synthetic food additives and colorants.

Chlorophyll

Chlorophylls are green in colour, which are non-polar pigments with a porphyrin chain and are present in cyanobacteria, algae, and superior plants.⁴⁹ Chlorophylls contain tetrapyrrole with  tightly bound magnesium atom. Chlorophylls are dimonant pigments in green algae (Chlorophyta) .¹⁰ Microalgae contain 0.5 to 1.0 % of chlorophyll per gram.⁵⁰ Chlorophyllin is a chlorophyll derivative in which sodium or copper replaces magnesium and the phytol chains are lost. Chlorophyllins are used in dietary supplements to control geriatric patients’ body odor and studies have reported the antimutagenic and anticarcinogenic effects of chlorophyll and chlorophyllin.⁵⁰

Carotenoids

Among the lipid components of the microalgae, some lipophilic components are especially important in the health industry.⁵¹ Because of easy growing, non-competitive food production processes, and adaptation to the changing environmental conditions which in turn results in the production of a wide range of secondary metabolites, microalgae have recently generated a high level of interest for different natural sources of carotenoids.⁵¹ Carotenoid biosynthesis can be induced by the regulation of crop circumstances or genetic engineering approaches.⁵² In microalgae, carotenoids appear to be mainly photo-protective and light-processing pigments. Carotenoids have high potential antioxidant properties, and hence protect  the harmful effects of excessive UV solar radiation and oxidative stress  by scavenging free radicals .^{10, 53}

Several groups of carotenoids are found to be effective against more than 60 diseases that are life-threatening including cancers, cardiovascular problems, premature aging, and arthritis.⁵⁴ The microalgae H.pluvialis is the primary source of carotenoid (β-carotene). Dunaliella extract has been sold as dietary supplements in numerous places since 1980.⁵⁵ The highest level of 9-cis-beta-carotene is found in Dunaliella amongst all the natural sources. Healthcare and consumer industries prefer natural beta-carotenes from microalgae as they are better absorbed in living organisms by a combination of trans and cis isomers than the beta carotenes synthesized by chemical processes.⁵⁶ Fortification of beta-carotene in soft drinks, cheese, butter and margarine is becoming popular in recent times. In addition, most cyanobacteria are α- carotene generators.⁵⁶

The carotenoids are proven to have anticancer actions through activation of cell apoptosis and suppression of cell proliferation. In particular, beta-carotenes such as astaxanthin, canthaxanthin, and zeaxanthin help to reduce the size and number of liver neoplasms.⁵⁷Astaxanthin has benefited humans through improved eye protection, strength and endurance, and also by preventing premature aging, inflammation and UV-A damages.⁵⁸ Several positive effects of astaxanthin on vision, growth, immune function, reproduction, and regeneration have brought in the usage of this pigment in human nutrition and animal feed.⁴³ Astaxanthin was approved in 1987 as a food preservative for utilization in aquaculture.⁵⁹

H. pluvialis is a green freshwater microalga that can produce significant amounts of astaxanthin under oxidative stress. Currently, several companies grow algae on a wide scale using different methods to produce cysts with enriched astaxanthin. Using various methods of extraction, the H.pluvialis can yield about 70–94% of astaxanthin which is a boon to promote blue economy.⁶⁰

Natural pigments isolated from microalgae have been proven to have numerous health benefits and have been utilized in many industrial products. Chlorophyll and phycocyanin from S. platensis, α-tocopherol and chlorophyll from C. vulgaris as well as phycocyanin from Aphanizomenon are vastly applied in food, cosmetics and pharmaceutical sectors.^10,61,62,63 Besides, D. salina contains pigments like β-carotene, bixin, and lutein. They are mostly yellow to orange in colour and are used in food additives and cosmetics, and also for animal tissue pigmentation.^10,61,64 Other than that, the reddish and golden orange pigments of H. pluvialis such as astaxanthin and cantaxathin are widely as livestock additive for salmon and trout farming to produce coloured fish with enhanced antioxidant and immune properties.^65,66 Futher, the phycoerythrin derived from P. cruentum has proven to have antiviral properties to be utilized as a neutraceutical agent.⁶⁷

Table 2: Microalgal Pigments and their Potential Applications.

Conclusion

Currently, the industrialized microalgae are primarily used as food, food additives, aquaculture feed, dyes, cosmetics, pharmaceuticals, and nutraceuticals. For human usage, only a small fraction of the total number of algal organisms are cultivated. There exist possibly numerous species of microalgae that nature has bestowed with good nutritional values and health benefits which remain underexplored for their potential usage. Therefore, in the forthcoming years, the potential of microalgal use in food intake, nutritional supplements, energy production, and much more is likely to intensify. Geographical use of microalgae for human nutrition will offer economically manageable and naturally produced healthy food for sustainable supply of food to meet the demand of the growing population of the world.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Funding Sources

The authors wish to acknowledge the financial support provided through the UTAR  Research Fund 2020, [Project no.:IPSR/RMC/UTARRF/2020-C1/A05], by Universiti Tunku Abdul Rahman, Malaysia.

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