Antioxidant effects of seaweeds and their active compounds on animal health and production – a review

Abstract Natural antioxidants applied as feed additives can improve not only animals’ health and overall performance but also increase their resistance to environmental stress such as heat stress, bad housing conditions, diseases, etc. Marine organisms, for example seaweeds – red, brown, and green macroalgae contain a plethora of biologically active substances, including phenolic compounds, polysaccharides, pigments, vitamins, micro- and macroelements, and proteins known for their antioxidant activity, which can help in the maintenance of appropriate redox status in animals and show pleiotropic effects for enhancing good health, and productivity. The dysregulated production of free radicals is a marked characteristic of several clinical conditions, and antioxidant machinery plays a pivotal role in scavenging the excessive free radicals, thereby preventing and treating infections in animals. Supplementation of seaweeds to animal diet can boost antioxidant activity, immunity, and the gut environment. Dietary supplementation of seaweeds can also enhance meat quality due to the deposition of marine-derived antioxidant components in muscles. The use of natural antioxidants in the meat industry is a practical approach to minimize or prevent lipid oxidation. However, overconsumption of seaweeds, especially brown macroalgae, should be avoided because of their high iodine content. An important point to consider when including seaweeds in animal feed is their variable composition which depends on the species, habitat, location, harvest time, growing conditions such as nutrient concentration in water, light intensity, temperature, etc. This review highlights the beneficial applications of seaweeds and their extracted compounds, which have antioxidant properties as feed additives and impact animal health and production.


Introduction
Seaweeds, also called macroalgae, are multicellular large-size marine organisms, which are classified into three main groups, according to their pigmentsgreen (Chlorophyta), red (Rhodophyta), and brown seaweeds (Phaeophyceae) (Makkar et al. 2016;Corino et al. 2019;Alboofetileh et al. 2021). This biomass has been used for centuries in many coastal communities and played an important role as a component of food, natural fertilizer or animal feed (Mac Monagail et al. 2017). According to the latest Food and Agriculture Organization (FAO) report (2018), in Saccharina japonica (earlier classified as Laminaria japonica), which production constitutes 33%.
Seaweeds are known to be rich in both primary and secondary metabolites. The primary metabolites, which are directly involved in processes such as growth, development, reproduction to perform physiological functions, can be divided into several classes: carbohydrates (fucoidan, alginate, laminarin in brown seaweeds, agar, carrageenan in red seaweeds, and ulvan in green seaweeds), lipids (fatty acids: saturated, mono-, di-, and polyunsaturated, waxes, acylglycerols: mono-, di-, and triacylglycerols, phospholipids, glycoglycerolipids, fat-soluble vitamins, e.g., A and E, sterols, and carotenoids), and proteins (combination of different amino acids). In addition to the primary metabolites, seaweeds can accumulate minerals (microelements, macroelements, and trace elements) that are also essential to their life (Makkar et al. 2016;Salehi et al. 2019;Matos et al. 2021). Seaweeds can also synthesize a vast number of secondary metabolites, which largely determine their bioactive potential (Øverland et al. 2019;Salehi et al. 2019). In contrast to primary metabolites, secondary metabolites are not necessary for tissue growth. They are formed in the biomass as a response to exposure to biotic (e.g., fungi, bacteria, viruses, insects, etc.) and abiotic stress (e.g., UV radiation, drought, salinity, high temperature) (Mets€ amuuronen and Sir en 2019; Matos et al. 2021). An important group of seaweeds' secondary metabolites are phenolics, which involve simple phenols like phenolic acids and polyphenols, including flavonoids and non-flavonoidse.g., tannins. Carotenoids and sterols listed above as primary metabolites are often included in the secondary metabolite class (Salehi et al. 2019). Most of the listed compounds have antioxidant activity. Seaweed antioxidants play the function of "free radical scavengers"they prevent or repair damages caused by oxidative stress and have a high potential for treating various diseases (Liu and Sun 2020). This unique composition of seaweeds results from their growth in an ever-changing environment. They are constantly exposed to stress conditions such as salinity, changes in temperature, nutrient enrichment, UV radiation exposure, presence of herbivores or pollutants. The resistance of seaweeds to biotic and abiotic stress is due to the production of physiologically active substances such as oligosaccharides, amino acids, vitamins, and phytohormones (Farvin and Jacobsen 2013;Manlusoc et al. 2019;Matos et al. 2021).
Seaweed-based antioxidants are discussed mainly in terms of cosmetic, pharmaceutical, and biomedical applications, food applications (stabilizer and preservative), and agriculture (biostimulants of plant growth) , but less in terms of feed and animal health and production. Antioxidants derived from seaweeds can have many beneficial effects on animal health (de Quiros et al. 2010;Liu and Sun 2020), such as antioxidant, anti-inflammatory, antimicrobial, immunomodulatory, and prebiotic effects (Corino et al. 2019;Liu and Sun 2020). The supplementation of animal feed with prebiotics based on seaweed biomass has recently gained much attention due to their positive effect on gut health and immune system (Ruiz et al. 2018). The general scheme showing the seaweed antioxidants and their effect on animal health and performance is presented in Figure 1.
This review focuses on the application of seaweeds, seaweed extracts, and extracted compounds in animal feed. Special attention has been paid to antioxidants and their effects on animal health and production performance. Furthermore, the significance of seaweeds' antioxidants, their different forms and use in animal nutrition, and their influence on the quality of animal-derived products have been discussed.
Furthermore, seaweeds are known to contain unique polysaccharides, which are specific to a given algal group. The content of carbohydrates in all seaweeds is recognized as high (Ford et al. 2020a;Matos et al. 2021). Øverland et al. (2019) presented the ranges of their contentbrown seaweeds 380-610 g/kg of dry mass (d.m.); green seaweeds 150-650 g/kg d.m. and red seaweeds 360-660 g/kg d.m. Polysaccharides like fucoidan, alginate, laminarin are found in brown seaweeds, agar and carrageenan in red seaweeds, and ulvan in green seaweeds (Kraan 2012;Corino et al. 2019;Øverland et al. 2019;Liu and Sun 2020;Morais et al. 2020). Sulfated polysaccharides from marine algae such as fucoindan, carragenan, and ulvan possess antioxidative activity and can enhance the antioxidant status in animals (Salehi et al. 2019;Liu and Sun 2020). Seaweeds are rich not only in polysaccharides acting as antioxidants but also in the undigestible polysaccharides, thereby serving as a potential source of dietary fibers . The dietary fibers are classified into two groups (1) insoluble such as cellulose, mannan, and xylan, and (2) watersoluble such as alginic acid, furonan, laminarin, agar, and porphyran (Kraan 2012). Polysaccharides applied as prebiotics in animal feed positively affect the cellulolytic and lactic acid bacteria present in the gastrointestinal tract (GIT) and inhibit the occurrence of pathogenic bacteria such as Escherichia coli and Clostridium difficile. Maintenance of the adequate gut microbiome and reduced risk of inflammation enhance gut morphology and nutrient absorption from the feed (Lynch et al. 2010;Kraan 2012). Polysaccharides, especially laminarin and fucoidan, have a positive effect on animal healthmodulate the gut environment, stimulate the innate immune system, reduce the risk of diarrhea, enhance growth performance and promote productivity (also in the absence of in-feed antibiotics) (Lynch et al. 2010;Kraan 2012;Del Tuffo et al. 2019).
Micro-and macroelements (e.g., iodine, zinc, iron, manganese, selenium, sodium, calcium, potassium, and magnesium) are other seaweed constituents important for the proper development and health of animals. Seaweeds easily bioaccumulate minerals from seawater and contain 10-20 times more minerals than land plants (Makkar et al. 2016;Matos et al. 2021). Micro-and macroelements are present in a form, which is highly bioavailable to animals. Some microelementse.g., selenium, zinc, and manganese demonstrate strong antioxidant properties (Corino et al. 2019;Øverland et al. 2019;Liu and Sun 2020;Morais et al. 2020). Feed for animals containing seaweeds are usually higher in ash than the feed/concentrates used in the control group (Rjiba et al. 2010). Seaweeds possess the ability to accumulate micro-and macroelements and toxic metal ions such as arsenic, cadmium, and lead, which can limit their use as a component of animal feed (Corino et al. 2019;Øverland et al. 2019). The same is the case of high iodine content (Øverland et al. 2019).
Seaweeds constitute a valuable source of proteins (Farvin and Jacobsen 2013;Makkar et al. 2016;Corino et al. 2019;Morais et al. 2020;Matos et al. 2021) with red seaweeds as the richest source of protein À 64-376 g/kg d.m. (crude protein), then green seaweeds 32-352 g/kg d.m. and finally brown seaweeds 24-168 g/kg d.m. (Øverland et al. 2019). Seaweeds can provide animals with all essential and many non-essential amino acids. Therefore, a detailed amino acid analysis of seaweeds should be performed for nutritional purposes (Øverland et al. 2019). Essential amino acids in Sargassum latifolium represent 42% of the total amino acids content (12 mg/g d.m.). Therefore, they are suggested as a complementary source of proteins for animal nutrition ).
An important point to consider when including seaweeds in animal feed is their variable composition which depends on the species, habitat, location, time of harvest, growing conditions such as nutrient concentration in water, light intensity, temperature, etc. (Makkar et al. 2016;Del Tuffo et al. 2019). It is recommended to harvest seaweeds when active compounds are the most abundant to reduce the amount of algal biomass supplemented to the feed (Ford et al. 2020a). Therefore, the use of seaweeds in animal nutrition as a source of antioxidants should be preceded by a detailed analysis of the algae composition, depending on the species, location, harvest date, etc.

Significance of antioxidants to animals
Oxidative stress and increased production of reactive oxygen species (ROS) regulate several organs and tissues' metabolic activities under diverse veterinary conditions and play a significant role in the productive output of livestock. The oxidative damage caused by the increased generation of unnecessary ROS due to the activity of NADPH-oxidases results from the exposure to multiple stress factors, including biotic and abiotic factors (Kaur et al. 2014). In the pathophysiology of various infections and diseases, such as foot and mouth viral infection and interdigital dermatitis, the weakening of antioxidant defense has an essential role in the prognosis of the disease (Khoshvaghti et al. 2014;Hayat et al. 2020).
Enzymatic antioxidant machinery comprises catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD), and other enzymes (Kaur et al. 2016). At the same time, the non-enzymatic antioxidants include vitamins A, C, and E, thiol antioxidants (thioredoxin, glutathione (GSH) and lipoic acid), carotenoids, melatonin, natural flavonoids, etc. (Rahman 2007;Valko et al. 2007;Kurutas 2016;Changxing et al. 2018aChangxing et al. , 2018b. Several biotic and abiotic stress factors (e.g., bacteria, environmental pollutants, radiation, chemicals, medications, food, diseases, and temperature) may influence the concentration of multiple antioxidant enzymes like CAT, GPX, SOD, and GSH, MDA (malondialdehydea product of lipid peroxidation in animal blood), as well as their activities. The reduction in the concentration of antioxidant enzymes and their activities increases free radical's generation levels. The virulence effect of pathogenic microorganisms is heightened by the presence of elevated amounts of free radicals in macrophages, which are released in large numbers when bacterial infections arise. CAT, GPX, and GSH are essential components of the cell's mechanism of protection against oxidative stress, which help sustain the immune cells' functions against infectious diseases (Rahman 2007;Valko et al. 2007;Rahal et al. 2014).
Several studies in various clinical manifestations have explored the role of antioxidant enzymes and their functioning. A study was conducted to evaluate the relationship between antioxidant enzymes such as SOD, GPX, MDA, CAT, and foot and mouth disease (FMD) in cattle. Forty diseased cows affected with FMD virus were compared with ten healthy adult cattle as a control. SOD and GPX activities were significantly reduced by FMD virus infection as compared to the control group. MDA activity was significantly higher in infected animals compared with healthy cows. It has been reported that the antioxidant enzymatic machinery significantly reduced its functioning in viral infection in cattle, which postulates the possible roles of oxidative stress in clinical manifestation (Khoshvaghti et al. 2014). In another study, the correlation between acute bovine laminitis and antioxidant enzymatic activities of MDA, CAT, GSH, and SOD was measured in dairy heifers. A significant reduction in SOD concentration was recorded when compared to the control group, whereas MDA activities were significantly higher in treated heifers than in the healthy heifers. Non-significant differences were recorded in GSH and CAT activities between the control and experimental group. It has been postulated that inadequate levels of antioxidants (enzymatic and nonenzymatic) may be linked to oxidative stress in sick heifers. Antioxidant enzymes such as SOD, GSH, CAT, and MDA activity might play a crucial role in the pathogenesis of acute laminitis in dairy heifers (Hayat et al. 2020). Further, another study reported that the enhanced production of MDA and NO in the case of interdigital dermatitis infection. CAT levels were significantly lower in serum compared to the control group in several conditions, including interdigital dermatitis, footrot, and interdigital pouch infections. GPX and GSH concentrations in serum were also reported significantly lower in interdigital dermatitis infections. Further, it has been recorded that MDA and NO concentrations were significantly higher in sheep with foot disease whereas, CAT concentrations were significantly lower in serum. It has been postulated that there is a strong correlation between foot infectious diseases and antioxidant machinery in animals. Hence, oxidative stress and increased ROS levels lead to lipid peroxidation and protein and DNA damage, which enhance the severity of the infection (Yurdakul and Yildirim 2018).
Antioxidants in the body cells are present in small amounts, which positively limit the oxidation of important cellular components such as proteins, DNA or RNA. Additionally, natural or synthetic antioxidants may be used either endogenously or exogenously as a component in livestock diet or as a feed additive. Ascorbic acid, among other vitamins and nutrients, has been believed to be an antioxidant agent, which can reduce and neutralize reactive oxygen species. This vitamin, being a cofactor for several enzymes, is required for normal growth and development (Eryilmaz 2017;Nielsen et al. 2021). Seaweeds can serve as a source of vitamin Cthe average content is 0.773 mg/g d.m. The highest mean value of this vitamin was observed in brown seaweeds À 0.815 mg/g, then green seaweeds À 0.781 mg/g, and finally in red seaweeds À 0.720 mg/ g d.m. (Nielsen et al. 2021). Physiologically, strong antioxidants can be readily absorbed and effectively remove free radicals while also removing redox metals at appropriate amounts. The endogenous antioxidant serves a key role in helping the cells work more efficiently (Arain et al. , 2018bWaheed Janabi et al. 2020;Naiel et al. 2021). Recently, it has been suggested that persistent oxidative stress may contribute to chronic inflammation, which in turn mediate a variety of chronic diseases in animals (Ju arez-Portilla et al. 2019). For example, a link between tumor initiation and progression and oxidative stress has been demonstrated either by genetic mutations or DNA injury (Visconti and Grieco 2009). In comparison, the release of histamine or other inflammatory molecules and the increase in the inflammation-inducing white blood cells, like mast cells and neutrophils, resulting in a rise of the blood supply to the affected region, thereby enhancing the oxygen influx, which in turn leads to oxidative stress at the site of infection. Therefore, increased development and concentration of oxidative stress leads to the infection's severity in various clinical manifestations. Proinflammatory cytokines, as well as specific mediators of inflammatory cells, including the derivatives of fatty acids, cytokines, and chemokines, can also respond through growing the number of immune cells present at the injury or disease site and thereby augmenting the output of ROS (Coussens and Werb 2002;Hussain et al. 2003).
Besides, free radicals are frequently found in animals' neuropathological conditions. Hence, the defense against oxidative damage could serve as a means of preventing disease progression such as neurodegeneration in animals. Among other aspects, researchers found that ROS production is closely linked to inflammation, and marine algae compounds containing both antioxidant and anti-inflammatory properties may be excellent choices for treating hyperinflammatory responses in several animal diseases due to their complex and multifaceted properties (Barbalace et al. 2019). Barbalace et al. (2019), in their comprehensive literature survey, showed that seaweed chemical components such as antioxidants, fatty acids, polysaccharides, sterols, carotenoids, phycobilins, phycocolloids, etc. possess the potential in reducing proinflammatory cytokines such as NO, TNF-a, IL-6, and IL-1b and in downregulating the inflammatory enzymes such as iNOS and COX-2. Further, the antioxidant properties of several seaweed extracts have been reported to attenuate the signaling mechanisms contributing to inflammatory enzymes activation (Barbalace et al. 2019).

Forms of seaweeds' antioxidants in animal nutrition
Seaweeds as a feed/feed additive can be used in the form of intact natural biomass (fresh or dried) or in the form of extract (Dierick et al. 2009;Michiels et al. 2012;Michalak and Mahrose 2020). The intact seaweeds are usually incorporated into feed pellets, whereas extracts into solutions (drinking water) (Abbott et al. 2020). The biomass after collection from the coastal zone is, in most cases, washed with tap water to remove sodium and impurities, dried, grounded, and finally used as a seaweed powder in animal diet (Abdoun et al. 2014;Ramadan et al. 2020). In this case, not only antioxidants but also other seaweed bioactive compounds are supplemented to animals. Campbell et al. (2020) proposed ensiling of seaweeds before application in livestock feeding, which is a suitable method of biomass preservation. Ensiling of brown seaweeds -Saccharina latissimi and Fucus vesiculosus with or without lactic acid bacteria inoculant (Lactobacillus plantarum) had a limited effect on the phenolic content. Fermentation for 90-days did not influence the chemical composition of F. vesiculosus, but for S. latissimi the content of crude protein, ash, and fiber was decreased.
To make seaweeds' biomass a valuable source of antioxidants for animals, it should be subjected to the extraction process (Table 1). Before extraction, this biomass is usually pretreated (washing, drying, milling or grinding, pre-extraction) to obtain a higher yield of seaweed antioxidants . The content of antioxidants in the produced extract depends on different extraction methods, as well as on the tested seaweed species (Farvin and Jacobsen 2013). Usually, seaweed extracts are a concentrate of many bioactive compounds. But appropriate extraction method can be selected aimed at extracting a given compound. For example, to extract polysaccharideulvan from green seaweed (Ulva sp.) used as a feed additive for laying hens, extraction with cellulase and later with hydrogen peroxide was applied (Li et al. 2018). However, the most appropriate method of seaweeds delivery to animals is not possible to predict at this moment. It will require animal feeding trials suitable for the animal production method used in a given country (Abbott et al. 2020).
There are several methods used for the extraction of antioxidants such as Soxhlet, maceration, percolation, microwave-, ultrasounds-, enzymeassisted extraction, subcritical, and supercritical fluid extraction, accelerated extraction, etc. Liu and Sun 2020;Monteiro et al. 2020;Matos et al. 2021). The simplest extraction methods can be applied for the isolation of antioxidants, such as maceration or shaking of seaweeds. Considering the potential use of algal extracts in animal nutrition, water as a solvent may be recommended. In the literature, for the extraction of phenolic compounds from seaweeds, usually, polar solvents are used, mainly aqueous mixtures of ethanol, methanol, acetone, or ethyl acetate . For example, Hwang and Thi (2014) compared the extraction method and antioxidant compound content in extracts obtained from edible red seaweed -Porphyra tenera. The extraction yield for water as a solvent at 37 C was 25.5%, and 70% ethanol at 37 C À 17.9%. The total phenolic content from water extraction (28.7 ± 0.5 mg GAE/g extract) was comparable to the ethanolic extract (30.2 ± 0.4 mg GAE/g extract). Phlorotannins from brown seaweeds can be extracted with a mixture of acetone and water (Ford et al. 2020a). As the main component in seaweeds, polysaccharides can be readily extracted with water or acetone (Liu and Sun 2020). Alginate oligosaccharides, which have great potential as a novel feed supplement, are produced via depolymerization of alginic acid polysaccharides from brown seaweeds using alginate lyases (Wan et al. 2016;Wan et al. 2017;Wan et al. 2018).
One seaweed preparation with antioxidant properties is TascoV R , produced by Acadian AgriTech TM (Dartmouth, Nova Scotia, Canada). This product is available in two forms: Tasco-Forage and Tasco-EX. The first one is used as an extract applied to foliage, which is grazed by livestock, and the second is used for direct feeding. Both forms are responsible for antioxidant responses measured in livestock Saker et al. 2001;Saker et al. 2004).
The key issue in the use of seaweeds as animal feed/feed additive is their composition (especially the content of toxic elements that easily accumulate in the biomass, but also bacterial load, pathogens, mycotoxins, pesticides, dioxins, polychlorinated biphenyls) and palatability for the animals (seaweed supplement is usually given to animals in order to verify the feed acceptance) (Dierick et al. 2009;Michiels et al. 2012;Rey-Crespo et al. 2014). In addition, pelleting is recommended to avoid the rejection of seaweeds added to the feed by animals (Rjiba et al. 2010).     Leonard et al. 2011aLeonard et al. , 2011b) and increase the average daily body weight gain of animals (Wan et al. 2016;Wan et al. 2017;Ruiz et al. 2018;Ellamie et al. 2020;Nhlane et al. 2020). Brown seaweeds' polysaccharides like alginate, laminarin, fucoidan, being soluble dietary fiber, increase feed intake ). This effect was not confirmed in green seaweeds (Ulva lactuca) supplemented to the diet of lambs reared under heat stress conditions. This inclusion did not show any beneficial effect on body weight gain or feed conversion efficiency (Abdoun et al. 2014). The species of algae thus plays a key role in its impact on animal health and performance.

The effect of seaweed antioxidants on animal health and production
There are several seaweed-based preparations on the market like OceanFeedV R (Milltown, Ireland) designed for nutrition of swine, equine, and bovine. For example, OceanFeedV R Swine brings many benefits for gestating and lactating sows, post-wean pigs, and growing-finishing pigsimproved feed intake, feed conversion ratio, digestive function, nutrient use, enhanced performance, weight gain, gut health, and reduce diarrhea in pigs ( Finally, seaweed feed additives can biofortify animal products with algal active compounds (Dierick et al. 2009;Moroney et al. 2012;Rey-Crespo et al. 2014;Moroney et al. 2015), improve carcass quality, and prolong the retail shelf life (Braden et al. 2007;Moroney et al. 2015). Dietary supplementation of laminarin and fucoidan extracted from Laminaria digitata resulted in enhanced pork meat due to deposition of marine-derived bioactive antioxidant components in longissimus thoracis et lumborum muscle (Moroney et al. 2015). Moroney et al. (2012) found that the use of seaweed extracts containing fucoidan and laminarin reduced lipid oxidation to the minimum level in liver tissue homogenates. Thus, the use of natural antioxidants in the meat industry is a practical approach to minimize or prevent lipid oxidation (Moroney et al. 2015).

The main seaweed antioxidants examined in animal feeding
As shown in Table 1, mainly brown seaweeds were used in animal feeding as a source of antioxidants. Their main representatives were Ascophyllum nodosum, Sargassum sp. and Laminaria sp. The antioxidant function is played dominantly by polysaccharideslaminarin, fucoidan, and alginate. It is hypothesized that these polysaccharides positively influence the gut environment, immunoglobulins output, and the growth performance of animals (Del Tuffo et al. 2019).

Effect of seaweed antioxidants on animal health and infectious diseases
Seaweeds and their active molecules with antioxidant and immunomodulatory activities can reduce oxidative damage, which might play a crucial role in the prognosis and amelioration of several infectious diseases, thereby safeguarding animal and human health (Shi et al. 2017;Ju arez-Portilla et al. 2019). In addition, the biologically active compounds function as modulators of various cellular signaling mechanisms implicated in a plethora of infectious diseases (Ju arez-Portilla et al. 2019). Furthermore, distinct extracts from different seaweeds can promote growth efficiency and gastrointestinal tract health by changing its anatomy and thus enhancing the intestinal absorption and utilization of nutrients and by modifying intestinal flora and attenuating the immune system and hence strengthening the gut structural integrity (Reilly et al. 2008;McDonnell et al. 2010;Sweeney et al. 2012).
Seaweeds have been found as a beneficial diet supplement as they enhanced pig growth and improved the digestibility of animal feed due to the content of bioactive phytochemicals (Corona et al. 2017). Further, the efficacy of the seaweeds diet was linked with its antioxidant compounds as seaweed can enhance the immune system functioning by reducing oxidative damage. The highest content of phenols and phlorotannins (up to 12-14%) is observed in brown seaweeds -Ascophyllum nodosum, Sargassum spp., and Fucus spp. In green and red seaweeds, this content is below 1% (Holdt and Kraan 2011).
Based on the data collected in Table 1, it can be concluded that seaweeds with antioxidant compounds used in feed improved mainly gut health and enhanced the function of the immune system. Seaweeds' polysaccharides can improve the composition of animal's gastro-intestinal microbiota without disrupting their performance (Reilly et al. 2008). Laminarin and fucoidan extracted from Laminaria sp. may provide a dietary means to improve gut health as these polysaccharides with antioxidant and antimicrobial properties can reduce the intestinal population of Enterobacterium spp. and increase the population of Lactobacilli spp. (Lynch et al. 2010;McDonnell et al. 2010;O'Doherty et al. 2010). Gahan et al. (2009) suggested that the extract obtained from Laminaria spp., rich in laminarin and fucoidan, can be used as a substitute for lactose in piglet diets, being the substrate for microbial fermentation in the large intestine. This approach could reduce the level of lactose in the diet and maintain postweaned piglet performance fed with the diet free from growth promoters. In addition, extracts from Laminaria hyperborea and L. digitata, containing laminarin and fucoidan reduced Enterobacteria, Bifidobacteria, and Lactobacilli in the caecum and colon of the weaned pigs (Reilly et al. 2008).
Recently, brown seaweed-derived laminarin has been shown to possess a considerable level of antioxidant activity (Rajauria et al. 2021), which directly affected gut mucous membranes or gut-associated lymph nodes and lymphoid tissues, improving the integrity of the gut and stimulating the immune function of the digestive tract. Further, it has been reported that dietary laminarin enhanced the expression of several genes encoding mucin production while feeding, specifically MUC2, an important mucin-producing gene in the intestine, resulting in increased mucin production in the digestive tract (Ryan et al. 2010). Laminarin is processed by the GIT's cells and then transferred to certain immunologically important cells such as dendritic cells. Thus, it works on cytokine output to influence the digestive system employing an immunomodulatory effect. In other studies, it has been reported that the diet augmentation with laminarin and other extracts resulted in the downregulation of developing a network of pro-inflammatory chemokines and cytokines in intestinal and hepatic cells Walsh et al. 2013). The ability to lower the levels of pro-inflammatory cytokines can enable the animal to receive more nutrients and thus develop at a greater rate by distributed nutrients apart from strengthening the immune system (Walsh et al. 2013). Because of these immunomodulatory impacts, one might predict that they may regulate hyperinflammatory responses in various autoimmune disorders and viral infections.
The second crucial polysaccharide of brown seaweedsfucoidan, is a critical immunomodulatory compound with many biological functions that have not yet been completely understood. However, it was discovered that the diet supplemented with a consortium of two different macroalgae-derived compounds, including fucoidan, laminarin, and their mixture to pregnant sows, enhanced the antibodies production rate in the breast milk, which, in turn, increased the IgG concentrations in the new-born piglets' serum. The fecal enterobacterial levels in sows shortly before parturition were significantly lower, and an additional observation confirmed the reduced number of coliform bacteria in the suckling pigs, which was correlated with piglets dramatically increasing the length of villi compared to the number of crypts in the upper small intestine, as well as increased growth rate. It is possible that reduced numbers of Escherichia coli and greater pathogen effects in the intestinal tracts of weaned piglets can be driven by the accumulation of mammary laminarin of low-molecular-weight in piglets' gastrointestinal tract. Additionally, algal extract intake induces enhanced TNF and TFF (trefoil factor) production in the gastrointestinal tract, which indicates their beneficial effects in newborn pigs (Leonard et al. 2011b). Moreover, laminarin supplementation to the diet of pregnant sows following by infection of Salmonella Typhimurium resulted in an increase in size, significant increase in the availability of nutrients, and reduced expression of certain interleukins such as IL-22, which is a crucial interleukin or mediator to maintain the gastrointestinal tract integrity and tissue generation (Bouwhuis et al. 2017). Seaweed extract, obtained from Laminaria sp., containing laminarin and fucoidan increased immunoglobulin G (IgG), immunoglobulin A (IgA) in sow's colostrum and serum IgG in piglets (Leonard et al. 2012). Also, extracts from green seaweeds -Ulva armoricana containing sulfated polysaccharide increased IgG in sow's blood and colostrum and the level of total IgA in milk (Bussy et al. 2019). Antioxidant enzymes (CAT and SOD) and immune-related activities (lysozyme, anti-protease, and myeloperoxidase) were higher in Sargassum sp. (2.5% and 5%) groups compared with control in intestinal mucus, several tissues, and serum of goat (Angulo et al. 2020). The use of seaweeds in goat diets is a good strategy to strengthen the antioxidant system and stimulate immunity, which helps to control pathogens (Angulo et al. 2020). Overall, dietary supplementation of seaweeds (Sargassum spp.) and their derivatives enhanced the immune responses and antioxidant capabilities (Telles et al. 2018).
Interesting research was conducted by Vizzari et al. (2021), who evaluated the effect of dietary seaweed extract (containing polysaccharides from Laminaria digitata and Laminaria hyperborea) on male-rabbit semen. It was found that after 90 days of the experiment, a decrease in aspartate aminotransferase (AST) and increase in alanine aminotransferase (ALT) and glutathione peroxidase (GPX) activities, ferric reducing ability of seminal plasma were observed with a dietary mixture of plant polyphenols and seaweed extract. Based on these results, it can be reported that natural polysaccharides extracted from brown seaweeds plus hydroxycinnamic acids, phenolic acid, flavonoids, and tannins from plant extracts mix (0.3 and 0.6%) didn't have any adverse effect on the male rabbit reproductive parameters, but improved the animal antioxidant status, enhanced the antioxidant capability of the seminal plasma and can have a positive impact on growth, health, and development of animals.
The second most studied macroalga in animal nutrition is Ascophyllum nodosum. This seaweed was used as a feed additive for pigs and participated in pathogen reduction Gardiner et al. 2008). Ford et al. (2020b) tested in vitro the antimicrobial potential of extracts obtained from Ascophyllum nodosum and Fucus serratus containing phlorotannins against foodborne pathogens such as Escherichia coli O157, Salmonella agona, and Streptococcus suis, which often colonize weaning piglets. These extracts were very effective, and for A. nodosum polyphenol extract, the minimum inhibitory concentration was between 1.56 and 0.78 mg/mL for all tested pathogens, whereas for F. serratus was 3.13 mg/mL. In the work of Bach et al. (2008), sundried Ascophyllum nodosum (Tasco-14 TM ) was administered at a dose of 20 g/kg diet of feedlot cattle and was efficient in the reduction in fecal shedding of the pathogen -E. coli O157:H7. In the in vivo conditions, Turner et al. (2002) examined the effect of Ascophyllum nodosum extract on the immune function of young pigs challenged with enteric disease caused by Salmonella Typhimurium. This extract had very little effect on growth performance and a positive effect on the immune function in pigs. Dietary supplementation with seaweeds (Ascophyllum nodosum) at 1.5% or 0.75% for 451 days improved the kidney function of minks infected with Aleutian mink disease virus (AMDV) with no impact on liver function and immunity (Farid and Smith 2020). No differences among groups were observed for antibody titer determined by the counter-immunoelectrophoresis, total serum protein, globulins, albumin, gammaglutamyl transferase and alkaline phosphatase activities, but blood levels of creatine and urea were lower in the 1.5% Ascophyllum nodosum supplemented group than in the unsupplemented group (Farid and Smith 2020).
The high content of antioxidants in A. nodosum is responsible for the improved antioxidant status and immune functions in animals Turner et al. 2002;Saker et al. 2004). In addition, Ascophyllum nodosum has a positive effect on the gut microbiota, translating into increased immunity (Gardiner et al. 2008;Dierick et al. 2009). In animals, modulation of gut microbiota can stimulate immunity and decrease the risk of diarrhea (Gardiner et al. 2008). According to this research, the supplement of A. nodosum can increase nutrient digestibility, improve nutrient availability from the gastrointestinal tract, stimulate the immune system and promote a healthy intestinal flora. When fed with a mixture of laminarin and fucoidan reduce in the growth rate appeared, but feeding purified laminarin emerged to improve health and productivity. Moreover, pigs fed with a laminarin and fucoidan enriched diet also reported increased growth productivity and good health (Gardiner et al. 2008).
When considering poultry research, the addition of A. nodosum extract to the broilers diet had beneficial effects on the gastrointestinal tract's integrity. It reduced the infection rates of newly born chickens colonized with Campylobacter jejuni in the cecum (Sweeney et al. 2016). Dietary addition of marine brown seaweeds (sodium alginate oligosaccharides) significantly reduced the mortality rate and increased body weight gain of chickens diseased with Salmonella Enteritidis (Yan et al. 2011). In layer diets, the use of red seaweeds (Chondrus crispus and Sarcodiotheca gaudichaudii) as prebiotics could enhance the productivity, criteria of eggs, and gut status as well as short-chain fatty acids (acetic acid, propionic acid, n-butyric acid, and butyric acid) in eggs (Kulshreshtha et al. 2014). In broiler chicken rations, Choi et al. (2014) found positive impacts on growth rate and immune response when used byproducts of seaweed fusiforme and brown seaweed.
Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is mainly a disease affecting humans, and its pandemic is ongoing. However, few reports of SARS-CoV-2 infection have been reported from animals such as dogs, cats, lions, tigers, mink (Tiwari et al. 2020;Sharun et al. 2021). Dietary seaweeds contain several nutrients and components such as angiotensin-converting enzyme 2 (ACE2) inhibitory peptides, n-3 fatty acids, soluble dietary fibers (fucoidan and porphyran), fucosterol, fucoxanthin, phlorotannins, and some vitamins (D 3 and cobalamin). In addition, inhibitory action on ACE2 receptor binding of SARS-CoV-2 in the host cells and anti-inflammatory activities of seaweed extracts may also be explored in the treatment of COVID-19, which is marked by a severe hyperinflammatory response that plays a key role in the severity of infection and prognosis of the disease. Both of red algae and brown algae could be potential antiviral therapeutic agents against SARS-CoV-2 and can be used to reduce the deleterious consequences of SARS-CoV-2 infection (Pereira and Critchley 2020;Rauf et al. 2021). Dietary seaweeds and their derivatives can effectively inhibit SARS-CoV-2 entry and may provide protection against COVID-19 through different mechanisms in humans and hypothetically could render protection in animals too, for which purpose further investigation and clinical trials are required to conclude their efficacy Tamama 2021;Kuznetsova et al. 2021;Yim et al. 2021).
Further, several extracts of well-known invasive macroalgae, Codium fragile, have been reported to inhibit the inflammatory cascade in human cell lines and mice models. These studies suggest that C. fragile extracts interrupt the release of several proinflammatory cytokines such as TNF-a, IL-1b, and IL-6 through impairing the mechanisms of a plethora of crucial inflammatory enzymes, including COX-2, iNOS, NF-jB, and MAPK (Lee et al. 2013;Lee et al. 2017). The release of inflammatory mediators, including PGE2, NO, TNF-a, and other inflammatory mediators, such as several interleukins like 1b, and IL-6, is suppressed by seaweed-derived compounds (Hwang et al. 2015, Hwang et al. 2017Lee et al. 2016;Sadeeshkumar et al. 2017). Additionally, fucoidan, a well-known biologically active compound from L. japonica, has been reported to attenuate the inflammatory response through decreased pro-inflammatory cytokines such as TNF-a, IL-6, and IL-1b. The decrease in pro-inflammatory cytokines in rat hepatic ischemia-reperfusion damage was reported to attenuate via the downregulation of several important pathways, including ERK1/2, p38, and JNK MAPK (Li and Ye 2015).
Some emerging or re-emerging viral illnesses have caused significant harm to human health in recent years, owing to the continual occurrence of these diseases. During the previous two decades, the number of antiviral agents that have been approved for clinical use has expanded from five to more than thirty medications. The polysaccharides extracted from the red alga Gelidium robustum (formerly Gelidium cartilagineum) (Rhodophyta) were found to have antiviral activity in embryonic eggs when tested against influenza B or mumps viruses, as reported by Gerber et al. (1958). In large amounts, many species of sea algae contain complex structural sulphated polysaccharides, which have been demonstrated to hinder the replication of enveloped viruses, particularly those belonging to the Nidovirales family. Other compounds, including those derived from red algae (e.g., the lectin griffithsin) and other sulphated polysaccharides derived from green algae (e.g., ulvans) and brown algae (e.g., fucoidans), have been proposed as potential antiviral therapeutic agents against SARS-CoV-2 (Pereira 2018; Barre et al. 2019;Lee 2019;Rosa et al. 2019).

Effect of seaweed antioxidants on animals exposed to stressful conditions
Seaweeds and their compounds are also beneficial to animals exposed to stress. Saker et al. (2004) stated that natural extracts from brown seaweeds might be used to optimize the immunocompetence of stressed animals (e.g., heat-stressed lambs) kept under suboptimal production conditions. Increased antioxidant activity in animals diminishes oxidative stress and enhances tolerance to stress . Antioxidants contained in the biomass of A. nodosum (phlorotannins, vitaminsascorbic acid, tocopherol, and pigmentscarotenoids) can scavenge peroxyl radicals and may prevent or diminish oxidative stress in weaned piglets (Michiels et al. 2012). Seaweeds' minerals with antioxidant propertiesfor example, zinc and selenium also protect animals against oxidant stress (Rey-Crespo et al. 2014). Wan et al. (2017) showed that alginate oligosaccharide extracted from brown seaweeds has the potential to reverse weaning-induced oxidative stress and intestinal digestive disorders in pigs. But in case of dietary inclusion of green seaweeds (Ulva lactuca) to the feed of lambs reared under heat stress conditions, blood constituents and antioxidant capacity were not affected by this supplementation (Abdoun et al. 2014). Seaweed powder obtained from Sargassum latifolium may protect sheep from heat stress , as well as stress caused by bacterial endotoxins  and alleviate their harmful effects. Seaweed's supplementation may improve the antioxidant defense system of animals and regulate their inflammatory and thermo-respiratory responses Ramadan et al. 2020).

Effect of seaweed antioxidants on the quality of animal-derived products
Seaweeds are a rich source of important elements and compounds such as iodine, protein, and sulfated polysaccharides, which are responsible for their bioactivity in the body (Tanna and Mishra 2019;Cermeño et al. 2020;Darias-Rosales et al. 2020). Polysaccharides like laminarin and fucoidan can be used as alternatives to commercial antioxidants incorporated into animal feed (Moroney et al. 2012). An additional advantage of seaweeds, used as a source of antioxidants in animal nutrition, is the production of food enriched with these ingredients. Moroney et al. (2012) showed that there is a possibility to incorporate seaweed antioxidants and polysaccharides into animal muscle through the animal's diet. Meat and meat products enriched with antioxidants can be used to produce functional food with health-promoting properties (Holdt and Kraan 2011;Michalak et al. 2011).
Marine macroalgae can improve the lipid profilethe content of polyunsaturated fatty acids (PUFA) (e.g., Gonz alez-Esquerra and Leeson 2001; Carrillo et al. 2008), the color of animal-derived products (Bonos et al. 2017), and also their multielemental composition (Michalak et al. 2011;Al-Harthi and El-Deek 2012). Rey-Crespo at al. (2014) showed that green -Ulva rigida and brown seaweeds -Sargasum muticum and Saccorhiza polyschides could significantly improve the mineral status of animals and the content of microelements in animal products (e.g., milk, meat). Michalak et al. (2011) found that seaweeds enriched with microelements such as Zn(II), Cu(II), Co(II), Cr(III), and Mn(II) via biosorptionincreased the elements content in eggs when compared to the control group. Dierick et al. (2009) demonstrated that dried and intact Ascophyllum nodosum rich in iodine improved not only pig health and performance but also enriched with iodine porcine tissues (M. psoas, M. longissimus dorsi, back fat, liver, kidney, heart) and blood serum.
The supplementation of Ascophyllum nodosum to the diet of early lactation dairy cows significantly increased the concentration of iodine in milk (without effect on animal performance), which reached the level that may be toxic to humans, particularly children (Antaya et al. 2015). High consumption of iodine can cause damages to animal and human health. The use of analyzed seaweeds at 4 g per day did not pose a health risk (Darias-Rosales et al. 2020).
The use of seaweed feed additives can also improve the quality of animal-derived products. Braden et al. (2007) showed that supplementation of Ascophyllum nodosum biomass (2% Tasco) to the diet of crossbred cattle increased the amount of intramuscular fat, the marbling score, and additionally may increase meat shelf life. No effect on sensory attributes and visual color of strip-loin steaks was observed. Moroney et al. (2015) examined the effect of extract from Laminaria digitata containing polysaccharides (laminarin and fucoidan) on quality indices of fresh pork. This extract did not affect the plasma total antioxidant status, pH of muscle Longissimus thoracis et lumborum, color, microbiology, and sensory parameters, enhanced the visual sensory descriptors (pinkness, whiteness, drip, overall acceptability), and reduced saturated fatty acids and decreased lipid oxidation in fresh muscle. The content of cholesterol tended to be lower in rabbit muscle fed with the diet containing Laminaria spp. (0.3 and 0.6%) when compared to the control group. Also, the content of retinol and a-tocopherol was improved in both muscles (Longissimus lumborum and Semimembranosus) of rabbits receiving the algal feed additives. The sensory attributes of texture were improved in both muscles with brown seaweeds compared to control (Rossi et al. 2020). The use of 0.5, 1, and 2% of Ascophyllum nodosum in broiler diets did not affect the total saturated, polyunsaturated, and monounsaturated (MFA) fatty acids in the breast or the thigh muscle (Bonos et al. 2017). While the birds fed with 2% A. nodosum had a higher content of n-6 (gamma-linolenic fatty acid) in the breast muscle and a lower content of n-9 (eicosenoic fatty acid) when compared to the unsupplemented group (Bonos et al. 2017). The positive effect of seaweed polysaccharides on enhancing meat quality can result from the healthpromoting effects of gut-associated immunity (Moroney et al. 2015). Carrillo et al. (2012) stated that seaweeds could protect polyunsaturated fatty acids accumulated in egg yolks and can increase the storage time of these eggs. Green alga -Enteromorpha spp. had a protective impact on the level of docosahexaenoic acid (DHA) in eggs. In addition, the brown algae had a similar impact on the level of eicosapentaenoic acid (EPA). Furthermore, the antioxidant compounds of seaweeds like phenolic compounds, carotenoids, and vitamins (A, C, and E) play an antioxidant role in eggs enriched with n-3 PUFAs (Carrillo et al. 2012).
The use of seaweeds in poultry diet has a positive effect on PUFA and can improve the color of meat and yolk due to the deposition of carotenoids (Herber-McNeill and Van Elswyk 1998;Saeed et al. 2021). These pigments are important and beneficial for animals and humans due to their antioxidant activities (Al-Harthi and El-Deek 2012). Zeaxanthin, fucoxanthin, and lutein are the main carotenoids of algae that improve egg quality by increasing the yolk color (Carrillo et al. 2012). In the same context, Al-Harthi and El-Deek (2012) found that fucoxanthin improved the coloring of yolks (Al-Harthi and El-Deek 2012). On the contrary, in white leghorn laying hens, Strand et al. (1998) stated that fucoxanthin as the major carotenoid in seaweed meal was not transferred to egg yolks but gave rise to fucoxanthinol sulfate, fucoxanthinol, and paracentrone. In general, the carotenoid content in yolks increased about 12-15 times compared to the control (Strand et al. 1998). The use of Sargassum dentifebium (brown algae) in different sources (sun-dried, autoclaved, or boiled) at levels of 3 and 6% increased the content of lutein and zeaxanthin in egg yolks as compared to control (Al-Harthi and El-Deek 2012).

Conclusions and future prospects
The use of natural antioxidants as feed supplements can enhance not only animal's productivity and health but also increase their ability and resistance to many stresses like diseases, stocking density, high ambient temperatures, inadequate housing systems, and others. Seaweeds as a feed/feed additive can be used in the form of intact natural biomass or in the form of extract. The different types of seaweeds play a vital role in improving the antioxidant system in the body due to their contents of biologically active molecules like phenolic compounds, flavonoids, polysaccharides, pigments, vitamins, minerals, micro-, and macroelements. Dietary bioactive compounds in seaweeds demonstrate potential to improve animal health, productivity, and welfare. Seaweeds' polysaccharides can improve the composition of animal's gastro-intestinal microbiota without disrupting their performance. Also, the use of seaweeds in animal diets can boost antioxidant activity, immunity, and the gut environment. Furthermore, seaweeds have antimicrobial properties; they played an essential role in reducing the prevalence of enterohemorrhagic E. coli on hide swabs and in fecal samples, as well as the growth of Salmonella spp. It can be concluded that seaweeds with antioxidant compounds used in feed improve mainly gut health and enhance the function of the immune system. Hence, due to the available evidence of health benefits related to macroalgae and their extracts, researchers are exploring their relevant biological activities in several pathological conditions. Supplementing specific extracts of seaweeds such as laminarin in the animal feed could act as immunomodulators in many clinical conditions, including viral and bacterial infections.
Moreover, in the future, there is an urgent need to explore the biological activities of specific compounds, specifically exhibiting the antioxidant properties present in seaweeds for the enhanced production of livestock via shielding farmed animals from infections and diseases. Additionally, to acquire the efficient biological active molecules from seaweeds, there is a need to develop techniques to extract and purify biomolecules from seaweeds so that the extraction methods can be incorporated to yield macroalgae extracts with higher proportions to be utilized in several in vitro experiments to prevent and treat several infections in animals. However, in vitro screening studies and in vivo animal studies are needed to identify potential prebiotics from seaweeds, alongside untargeted metabolomics, to decipher microbial-derived metabolites from seaweeds. Furthermore, controlled animal intervention studies with health-related endpoints to elucidate prebiotic efficacy are required.