Potential Application of Lonicera japonica Extracts in Animal Production: From the Perspective of Intestinal Health

Lonicera japonica (L. japonica) extract is rich in active substances, such as phenolic acids, essential oils, flavones, saponins, and iridoids, which have a broad spectrum of antioxidant, anti-inflammatory, and anti-microbial effect. Previous studies have demonstrated that L. japonica has a good regulatory effect on animal intestinal health, which can be used as a potential antibiotic substitute product. However, previous studies about intestinal health regulation mainly focus on experimental animals or cells, like mice, rats, HMC-1 Cells, and RAW 264.7 cells. In this review, the intestinal health benefits including antioxidant, anti-inflammatory, and antimicrobial activity, and its potential application in animal production were summarized. Through this review, we can see that the effects and mechanism of L. japonica extract on intestinal health regulation of farm and aquatic animals are still rare and unclear. Further studies could focus on the regulatory mechanism of L. japonica extract on intestinal health especially the protective effects of L. japonica extract on oxidative injury, inflammation, and regulation of intestinal flora in farm animals and aquatic animals, thereby providing references for the rational utilization and application of L. japonica and its extracts in animal production.


INTRODUCTION
The animal intestinal tract is the direct place for the communication between the internal environment and the external environment, and is an important defense line for animals to maintain the homeostasis of the internal environment (Tang et al., 2016). A healthy gut is essential for the growth and development of animals. However, the intestinal epithelium homeostasis of animals is affected by numerous factors, such as bacterial infection, endotoxin challenge, weaning stress, and oxidative stress, leading to intestinal damage and intestinal barrier function dysfunction (Campbell et al., 2013;Yin et al., 2014;. Traditionally, antibiotics are generally used as growth and health promoters, which have achieved certain achievements and promoted the development of animal husbandry (Barton, 2014). However, the abuse of antibiotics in livestock and poultry feeds will destroy the intestinal microecological balance, and lead to the resistance of bacteria (Hashemi and Davoodi, 2011;Looft et al., 2014), which would bring serious negative effects on human health and environmental safety. Therefore, the use of antibiotics as intestinal microecological regulator is no longer popular. Exploring new antibiotic substitutes to regulate intestinal microflora and to maintain the intestinal health of animals is an urgent task in the field of animal nutrition in the post-antibiotic era.
Plant extract is a complex mixture of compounds. It has been reported to possess multiple bioactivities such as antioxidant , anti-inflammatory , antimicrobial (Kavoosi et al., 2013), and immune regulation (Boskabady et al., 2013). Plant extracts have been used for centuries in traditional medicine and as food preservatives, and more recently have been studied as possible feed additives used in animal nutrition due to their multiple biological functions Yejun et al., 2019). Lonicera japonica (L. japonica) extract is extracted from L. japonica Thunberg, a medicine food homologous herb rich in organic acids, volatile oils, flavonoids, iridoids, and saponins (Shang et al., 2011;Fan et al., 2019;Li R. et al., 2020), which have high value of health benefits. Lonicera japonica extract is widely used in pharmacological preparations, cosmetics, food, and animal husbandry because of its diverse pharmacological effects such as antioxidant, anti-microbial, antiviral, antitoxic, antiseptic, and anti-inflammatory properties Park et al., 2012;Yejun et al., 2019). The application of L. japonica extract in animal production mainly focuses on pigs (Liu W. et al., 2016), beef cattle (Yejun et al., 2019), dairy cows (Ma et al., 2020b;Zhao et al., 2020), broiler (Müştak et al., 2015), laying hens (Long et al., 2018), Penaeus monodon (Chen et al., 2013), grass carp (Meng et al., 2019), and olive flounder (Dharaneedharan et al., 2016). From the results of these studies, L. japonica extract can function as a potential alternative antibiotic in animal feeds. However, the studies of the impacts of L. japonica extract on the intestinal health of animals are scattered in different pieces of literature, and little research could aggregate these findings into a single review. Therefore, the objective of this study was to review the effects of L. japonica extract on intestinal health and summarize its application in animal production.

BIOACTIVE COMPOUNDS OF L. JAPONICA EXTRACT
Lonicera japonica, also known as Japanese honeysuckle, Jin YinHua or Ren Dong, belongs to the member of the Caprifoliaceae family, is a perennial deciduous shrub native to East Asia and spread throughout Argentina, Brazil, Mexico, Australia, New Zealand, and American . Traditionally, the flower bud of L. japonica, which has been listed in the Chinese Pharmacopeia as L. japonica Flos, is a traditional Chinese medicine that reportedly has antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, and antidiabetic properties Shi et al., 2016;Wang et al., 2017), which has been widely used for preventing and treating influenza, cold, fever, and infections (Kashiwada et al., 2013;Ge et al., 2018;Fang et al., 2020). Lonicera japonica extract is extracted from L. japonica, has complicated chemical composition. So far, more than 300 chemical compounds have been isolated from and identified from L. japonica, and the major compositions are phenolic acids, essential oils, flavones, saponins, and iridoids (Shang et al., 2011;Li et al., 2017Li R. et al., 2020).

Essential Oils
Essential oils are one of the bioactivity components of L. japonica, which mainly composed of acids, aldehydes, alcohols, ketones, and their esters . They exist in the aerial parts of L. japonica, flower (fresh and dry), leaves, and vines with a different content and composition (Shang et al., 2011). Vukovic et al. (2012) showed that the main constituents in the flowers fraction were (Z,Z)-farnesole (16.2%) and linalool (11.0%), the main constituents in the leaves fraction were hexadecanoic acid (16.0%) and linalool (8.7%), and the main constituents in the stems were hexadecanoic acid (31.4%). Essential oils in L. japonica are also affected by different habitats. Du et al. (2015) identified 35 volatile constituents in L. japonica from Guangxi Zhuang Autonomous Region (China), mainly including methyl linolenate, n-hexadecanoic acid, and -muurolene, and 18 volatile constituents in LJF from Hunan province (China), mainly including n-hexadecanoic acid, linoleic acid, and -curcumene. Essential oils, the most kinds of bioactivity component in L. japonica, have important pharmacological effects, and have been used in cosmetics, spices, and other industries widely . It also suggests that the characterization of the volatile compounds could be used as an indicator of the identity and the quality of L. japonica (Cai et al., 2013).

LONICERA JAPONICA (EXTRACTS) AND INTESTINAL ANTIOXIDANT
In addition to its medicinal uses, L. japonica is also widely used in healthy foods and cosmetics in the world because of its health benefits (Seo et al., 2012;Fang et al., 2020;Zhang T. et al., 2020). Modern pharmacological researches have demonstrated that L. japonica extract has a variety of biological activities, which the antioxidant activity is an important biological property of great interest (Hsu et al., 2016;Zhang T. et al., 2020). Antioxidant activity of L. japonica was mainly related to its abundant polyphenols  and polysaccharides .

Antioxidant Activity of Polyphenols
The antioxidative property of L. japonica is mainly attributed to the specific chemical structure of polyphenols, a widespread group of secondary metabolites that include various phenolic acids and flavonoids, which have a common character of having at least one aromatic ring substituted with one or more hydroxyl groups (Kong et al., 2017;Fan et al., 2019). Lee et al. (2019) who reported that the antioxidant activities of L. japonica were positively correlated with total phenolic, total flavonoid, CGA, CA, and quercetin contents, and Kong et al. (2017) who reported that antioxidative activity of L. japonica presented a significant positive correlation with the content of CGA, cynaroside, rutin, and hyperoside can demonstrate this conclusion. Figure 1 presented the main phenolic acids (GCA, CA, and NGA) and flavonoids (luteolin 7-galactoside, quercetin, and luteolin) in L. japonica. It showed that all these compounds contain an aromatic nucleus and hydroxyl group, which is related to their strong antioxidant capacity (Choi et al., 2007;Guo et al., 2014;Hsu et al., 2016).
The ability to scavenge free radicals may play an important role in preventing some diseases caused by free radicals (Gheisar and Kim, 2018). Normally, 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity assay, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic) acid (ABTS) scavenging activity assay, superoxide radical scavenging activity assay, ferric-reducing antioxidant power (FRAP) assay, and reducing power (RP) assay are the most frequently used to evaluate the antioxidant activity of plant extracts Kong et al., 2017;Zhang T. et al., 2020). DPPH radical scavenging activity and ABTS radical scavenging activity reflect the ability of hydrogen-donating antioxidants and electron transfer to scavenge DPPH and ABTS + radicals . Superoxide radical scavenging activity denotes the ability to remove free radicals, such as peroxyl, alkoxyl, hydroxyl, and nitric oxide, which formed from superoxide anions through the Fenton reaction, lipid oxidation, or nitric oxidation (Hsu et al., 2016). FRAP and RP assays represent their ability to reduce the of ferric (Fe 3+ ) form to the ferrous (Fe 2+ ) form (Seo et al., 2012;Lee et al., 2019). Chaowuttikul et al. (2017) reported that the ethanolic extract of L. japonica showed DPPH and nitric oxide scavenging activities as well as RP property. Lee et al. (2019) showed that DPPH and ABTS radical scavenging activity of L. japonica were significantly increased during 60 min of heating and were retained for 90 min.

Antioxidant Activity of Polysaccharides
Polysaccharides are a kind of natural polymer linked by aldose or ketose through glycosidic bonds (Zhou et al., 2018a(Zhou et al., , 2021. Previous studies have found that polysaccharides extracted from plants can relieve oxidative stress through exerting their antioxidation potentials (Surin et al., 2018;Zhou et al., 2020). Polysaccharide is one of the main active ingredients of L. japonica, which have been isolated and identified in previous studies (Zhou et al., 2018aLiu et al., 2019;Zhang T. et al., 2020). In vitro study showed that polysaccharide extracts from L. japonica exhibited obvious DPPH-scavenging activity, ABTS +scavenging activity, hydroxyl radical-scavenging activity, superoxide radical-scavenging activity, and excellent inhibitory activity on erythrocyte hemolysis induced by H 2 O 2 (Zhang T. et al., 2020). Polysaccharide extracts from L. japonica could protect cardiomyocytes of mice injured by hydrogen peroxide via increasing the activities of catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD), and decreasing ROS production . In vivo study showed that crude polysaccharides extracted from L. japonica could alleviate the oxidative damage of liver in streptozotocin (STZ)-induced diabetic rats by decreasing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) in serum, and improving levels of CAT, SOD, and GSH in liver . It reveals that the polysaccharides play an important role in the antioxidant function of L. japonica.

Potential Intestinal Antioxidant Effects of L. japonica (Extract)
Reactive oxygen species (ROS) are generated along with the process of cell respiration and normal metabolism continuously, and mitochondrion is the primary source of the majority of ROS in organisms Yan Z. et al., 2020). ROS includes free radical ROS and non-radical ROS. Free radical ROS mainly include superoxide anion free radicals (O 2 − ), hydroxyl radical (·OH − ), peroxyl radical (ROO), and alkoxyl radical (RO), and non-radical ROS mainly consist of hydrogen peroxide (H 2 O 2 ), oxygen (O 2 ), ozone (O 3 ), hypochlorous acid (HOCL), hypobromous acid (HOBr), chloramines (RNHCL), and organic hydroperoxides (ROOH; . Under normal physiological conditions, ROS can act as signaling molecules involved in cell growth and cellular adaptive responses (Lum and Roebuck, 2001). However, in commercial animal production, animals often suffer from bacterial infection , endotoxin challenge (Chen et al., 2021), mycotoxin challenge , and weaning stress (Zhou et al., 2018b), which may induce a large number of ROS. When the body cannot remove these ROS in time, oxidative stress injury occurs (Campbell et al., 2013;Yin et al., 2014;Saracila et al., 2021). Numerous studies have demonstrated that oxidative stress is associated with many pathological conditions, including intestinal barrier dysfunction and various digestive tract diseases (Almenier et al., 2012;Navarro-Yepes et al., 2014;Cao et al., 2018;Tang et al., 2018b;Chen et al., , 2021. Thus, alleviating the negative effects of oxidative stress damage is crucial for the development of the animal husbandry.
The latest research progress of antioxidant activity of L. japonica has been summarized in Table 1. These studies suggested that L. japonica might be potential natural antioxidants and beneficial chemopreventive agent, which can be inferred that the extract of L. japonica may have a protective effect on intestinal oxidative damage of animals. However, the direct evidence of the protective effects L. japonica on intestinal oxidative damage is still lack. Therefore, further studies are needed to confirm whether L. japonica have a regulating effect on the intestinal oxidative damage of animals including farm animals and aquatic animals.

LONICERA JAPONICA (EXTRACTS) AND INTESTINAL INFLAMMATION
The intestine is different from the other organs of animal because it is not only the main part of animal nutrition digestion and absorption, but also consists of a physical and immunological protective barrier against foreign antigens and pathogens from the external environment into the circulation system (Tang et al., 2016(Tang et al., , 2018bCurciarello et al., 2019). Optimum intestinal health is of prime importance to animal growth as well as animal health. Disruption of the intestinal epithelial homeostasis has been reported to increase intestinal permeability, which can cause numerous gastrointestinal diseases (Miner-Williams and Moughan, 2016;Tang et al., 2019;Peng et al., 2020;Tang and Xiong, 2021). Lonicera japonica extract has a significant effect on the intestinal health regulation of animals due to its various biological activities including antiinflammatory activity Han et al., 2016;Zhou et al., 2021).

Anti-inflammatory Activity of L. japonica (Extracts)
Inflammation is a normal protective response induced by tissue injury or infection. It has been proved that L. japonica presents significant anti-inflammatory effects in vitro and in vivo (Jiang et al., 2014;Li R. et al., 2020;Zhou et al., 2021). As we know, proinflammatory cytokines, such as tumor necrosis factor (TNF-α), interleukin 1β (IL-1β), and IL-6 contribute to inflammatory injury and triggers an inflammatory cascade (Bang et al., 2019;Li R. et al., 2020). Kang et al. (2010) showed that L. japonica extract could suppress inflammatory mediators, such as IL6, IL-8, and TNF-α release by blocking nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs) activation pathways in HMC-1 Cells. Su et al. (2021) showed that ethanol extract of L. japonica caulis significantly inhibit the expression of pro-inflammatory factors such as TNF-α, IL-1β, IL-6, and interferon γ (IFN-γ) in mice. The study Li R. et al. (2020) suggested that the flower buds, leaves, and stems of L. japonica extracts showed a cytoprotective effect on lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages by suppressing proinflammatory cytokines including TNF-α, IL-1β, and IL-6 production. Bang et al. (2019) showed that the anti-inflammatory effects of BST-104 (a water extract of L. japonica) were attributed to reduced levels of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 in gastric mucosal tissues. All of these researches suggest that L. japonica is a good anti-inflammatory agent for treating inflammatory disorders.

Lonicera japonica (Extracts) Inhibits Intestinal Inflammation
The intestinal tract is the largest immune organ in the body and acts as the first line of defense against infection and a barrier that prevents commensal bacteria from penetrating the intestinal epithelium (Tang et al., 2016;Clavijo and Flórez, 2018;Qamar et al., 2021). The gut immune system comprises mucosal layer, epithelial cells, antibacterial peptides, immunoglobulins, and cytokines (Yitbarek et al., 2019;Qamar et al., 2021). Previous studies had demonstrated that L. japonica can promote intestinal immune function and has a preventive effect on intestinal inflammation Yang X. et al., 2020). Yang X. et al. (2020) showed that the treatment of the alcohol extract of L. japonica to mice significantly increased intestinal sIgA content. Zhou et al. (2021) showed that with the supplementation of L. japonica polysaccharides, the content of immunoglobulin A (sIgA) secreted from the intestine was significantly higher than that of dextran sulfate sodium (DSS)-induced ulcerative colitis mice. sIgA, an immunoglobulin secreted by plasma cells of the intestinal mucosa, is a major effector of the intestinal mucosal immunity, which acts as the first line of defense in the intestinal mucosa that neutralizes pathogens in the intestinal mucosa and plays an important role in local anti-infection of the body (Salerno-Goncalves et al., 2016;Zhou et al., 2021). These studies indicated that prompting the secretion of sIgA is one of the ways to enhance the immune ability of the intestine by L. japonica Zhou et al., 2021). In addition to promoting the secretion of sIgA, L. japonica can also play the role of intestinal immune function by regulating the secretion of intestinal mucosal cytokines Zhou et al., 2018a). Lee et al. (2011) showed that buthanol (BuOH) extracts of L. japonica inhibited the synthesis of IL-6 in a LPS-stimulated colonic epithelial cell line (HT-29 cell) in vitro and a DSS-induced ulcerative colitis mouse in vivo. Park et al. (2012) showed that L. japonica inhibited the cytokines including TNF-α, IL-1β, IL-6, IFN-γ, IL-12, and IL-17 in DSS-induced ulcerative colitis mice. In an immunosuppressed mice model, the researchers found that polysaccharide extracts from L. japonica could restore the levels of serum cytokines IL-2, TNF-α, and IFN-γ level in cyclophosphamide-induced mice, which indicated that L. japonica can be used as a potential immunomodulatory agent (Zhou et al., 2018a). Through these studies, we can speculate that L. japonica extract may also had regulation on intestinal immune function and intestinal inflammation of farm and aquatic animals, which of course needs further researches to demonstrate it.

LONICERA JAPONICA (EXTRACTS) AND GUT MICROBIOTA Gut Microbiota and Intestinal Health
The gastrointestinal tract, the largest organ in the animal body, provides a broad colonization surface for the flora.  (Tan et al., 2015;. Second, intestinal commensal segmented filamentous bacteria can induce the differentiation of T helper 17 (Th17) in the lamina prima, which in turn stimulates the production of cytokines, IL-1, IL-6, and TNF-α by a variety of cells (Goto et al., 2014;Villena et al., 2014). Metabolites such as short-chain fatty acids (SCFA) produced by the gut bacteria are considered as key molecular intermediates between the microbiota and its host (Beaumont et al., 2020). SCFA can induce the proliferation and differentiation of Treg, thus activating the intestinal immune system and playing the function of immune barrier (Horai et al., 2017). Third, the intestinal floras can influence the intestinal physical barrier by modulating tight junction (TJ) proteins expression and distribution . For example, Hu et al. (2020) reported that piglets receiving protocatechuic acid promoted the expression of ZO-1 and Claudin-1 in the intestinal mucosa by increasing the abundance of the beneficial bacteria Roseburia in the intestinal tract thus maintaining the function of the intestinal barrier. Finally, the intestinal floras can also influence the intestinal chemical barrier by promoting the differentiation of goblet cells, thereby modulating the expression of mucins (MUCs), a family of highly glycosylated protein that are secreted by specialize cells in the gut, which is the main component of intestinal mucus (Sicard et al., 2017). In a word, intestinal flora is closely related to intestinal health.

Lonicera japonica (Extracts) Modulates Intestinal Micobiota
Modern pharmacological research has confirmed the strong antimicrobial activity of L. japonica in vivo and in vitro Xiong et al., 2013;Yang et al., 2016;Minami and Makino, 2020;Yan L. et al., 2020). In vitro study showed that L. japonica has antimicrobial effects such as Bacteroides fragilis, Bacteroides ovatus, Clostridium difficile, Clostridium perfringenes, Propionebacterium acnes, Staphylococcus aureus, Shigella, Salmonella, and Escherichia coli (E. coli; Rhee and Lee, 2011;Xiong et al., 2013;Yang et al., 2016Yang et al., , 2018Yan L. et al., 2020). In vivo study showed that L. japonica could significantly promote the colonization of beneficial bacteria and inhibit the reproduction of harmful bacteria (Minami and Makino, 2020;Yang X. et al., 2020). Wang et al. (2014) showed that unfermented or fermented L. japonica both can significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and Bacteroidetes/Firmicutes ratio in obesity rats, which play an essential role in high fat diet or LPS induced enhancement in gut permeability, development of endotoximia, and inflammation. Minami and Makino (2020) showed that L. japonica significantly increased the survival rate and decreased Citrobacter rodentium (C. rodentium) colonization in the large intestine of mice. Citrobacter rodentium is a mucosal pathogen of murine, which has long used as a model to elucidate the molecular and cellular pathogenesis of infection with enteropathogenic E. coli and FIGURE 2 | Relationship between gut microbiota and intestinal health.
Frontiers in Microbiology | www.frontiersin.org 8 August 2021 | Volume 12 | Article 719877 enterohaemorrhagic E. coli, two clinically important human gastrointestinal pathogens (Collins et al., 2014;Bouladoux et al., 2017;Mullineaux-Sanders et al., 2019). Yang X. et al. (2020) showed that the water extract of L. japonica and alcohol extract of L. japonica did not damage the intestinal structure, and both of them could promote the growth of beneficial bacteria Lactobacillus and inhibit the growth of potential pathogenic bacteria E. coli. Lactobacillus is a predominant indigenous bacterial genus found in the human and animal gastrointestinal tract, and species of this genus like Lactobacillus plantarum (L. plantarum; Wang et al., 2018), Lactobacillus casei (Eun et al., 2011), Lactobacillus rhamnosus (Villena et al., 2014), and Lactobacillus reuteri  etc., are commonly used as probiotics, which can affect transepithelial electrical resistance (TER) and epithelial permeability, modulate TJ proteins distribution, and enhance the immune function. Escherichia coli strains are important pathogens that cause diverse diseases in humans and animals, which is a major challenge for intestinal health (Dautzenberg et al., 2016;Stromberg et al., 2017;Desvaux et al., 2020). Therefore, it reveals that L. japonica has a good regulatory effect on animal intestinal microbiota, thus promoting the intestinal health of animals. However, the studies of L. japonica extract on intestinal microbiota of farm and aquatic animals are still lack, which perhaps is a good research direction in the future.

APPLICATION OF L. JAPONICA IN ANIMAL PRODUCTION
Various herbs and their extracts have been used as feed additives due to their anti-oxidative effect, anti-inflammatory activity, anti-microbial effect, and growth-promoting effect (Windisch et al., 2008;Hanczakowska et al., 2015;Lei et al., 2018;Lin et al., 2020). Among them, L. japonica (extract) was widely investigated in animal husbandry because of its diverse pharmacological effects such as antioxidant, anti-microbial, antiviral, antitoxic, antiseptic, and anti-inflammatory properties Park et al., 2012;Wang et al., 2014;Li R. et al., 2020). Table 2 summarized the application of L. japonica (extract) in animal production in recently years. It showed that these studies mainly focus on pigs (Liu W. et al., 2016), beef cattle (Fu et al., 2016;Yejun et al., 2019), dairy cows (Ma et al., 2020a,b;Zhao et al., 2020), broiler (Müştak et al., 2015), laying hens (Long et al., 2018), Penaeus monodon (Chen et al., 2013), grass carp (Meng et al., 2019), and olive flounder (Dharaneedharan et al., 2016). Studies on beef cattle showed that L. japonica extract can effectively alleviate heat stress, improve antioxidant function, and have a good repair effect on skeletal muscle fiber structure damage of beef cattle Fu et al., 2016). Moreover, in vitro studies showed that L. japonica extract could regulate rumen fermentation and reduce methane production by inhibiting the growth of methanogenic bacteria Yejun et al., 2019). Studies on dairy cows showed that dietary supplementation of L. japonica extract could relieve heat stress of dairy cows by improving immune and antioxidant capacity (Ma et al., 2020a,b;Gao et al., 2021), enhancing antiinflammatory activity . Meanwhile, L. japonica extract can improve rumen microbial diversity and improve rumen fermentation capacity (Tang et al., 2018a). In pig production, herbal extract mixture (HEM) may have a better application effect (Liu W. et al., 2016;. For instance, Liu W. et al. (2016) indicated that dietary supplementation with a mixture of 55% Scutellaria baicalensis extract and 25% L. japonica extract administration could improve growth performance and nutrient digestibility, decrease serum cortisol levels, as well as benefit the meat quality in finishing pigs,  showed that dietary supplementation with 1,000 mg/kg a mixture extract of goldenand-silver honeysuckle (L. japonica Thunb.), huangqi (Astragalus menbranaceus), duzhong leaves (Eucommia folium), and dangshen (Codonopsis pilosula) had beneficial effects on intestinal morphology modulation and the mRNA expression of nutrients transporters of pigs. For broilers, dietary supplementation with L. japonica extract could increase weight gain, blood cells, antioxidant activity, and meat quality of broilers (Park et al., 2014), while did not affect the proximate composition of the breast meat, but could increase the antioxidative potential and overall preference of breast meat during cold storage (Jang et al., 2008). Drinking water containing GCA extracted from L. japonica can effectively increase the body weight of broilers and reduce Mycoplasma gallisepticum infection of broilers (Müştak et al., 2015). Studies on laying hens showed that dietary supplementation with L. japonica extract (Long et al., 2018) or HEM containing L. japonica extract (Liu and Kim, 2017) could improve laying performance, eggshell strength, egg quality, and shelf life in laying hens. For aquatic animals, dietary supplementation with L. japonica could improve the growth performance, health condition and survival rate of Penaeus monodon (Chen et al., 2013), and could effectively improve the lipid metabolism and ameliorate the lipid deposition of grass carp (Meng et al., 2019). Flounder fish fed with 0.025, 0.05, 0.1, 0.2, and 0.4% L. japonica leaf powder for 4 weeks showed significantly increased respiratory burst, lysozyme, phagocytic activity, immune function, and antioxidant activity (Dharaneedharan et al., 2016).

CONCLUSION
Intestinal health determines the health status of animals. To regulate intestinal health is always been an important issue in the post-antibiotic era of animal husbandry. As a kind of natural plant extract, L. japonica extract is rich in phenolic acids, essential oils, flavonoids, iridoids, and saponins, which has a good regulating effect on the intestinal health of animals, and is an ideal product of antibiotics substitution. According to the published literature, although the application of L. japonica extract in animal production has been reported, it mainly focuses on the regulation of animal production performance, meat quality, egg quality, rumen fermentation capacity, and anti-heat stress, etc. In animal production, the effects of L. japonica extract on intestinal health may be related to its antioxidant, anti-inflammatory, and antimicrobial activities. Although previous studies had demonstrated that about L. japonica has a good regulatory effect on animal intestinal health, but mainly focus on experimental animals or cells, like mice, rats, HMC-1 Cells, and RAW 264.7 cells, the studies of L. japonica extract on intestinal health regulation of farm and aquatic animals are still rare and unclear. Therefore, it is necessary to increase the research on the regulatory mechanism of L. japonica extract on intestinal health especially the protective effects of L. japonica extract on oxidative injury, inflammation, and regulation of intestinal flora in farm and aquatic animals in the future, so as to provide a theoretical basis for the application of L. japonica extract in animal production.