Research Progress of Feed Antibiotic Substitutes

Research Progress of Feed Antibiotic Substitutes

Luo Zhang

DadHank (Chengdu) Biotech Corp., Chengdu 611130

Abstract: Antibiotics play an active role in promoting animal growth, improving feed remuneration and reducing disease mortality. However, the over-dependence on antibiotics can lead to many problems, such as drug residues, drug resistance（resistance of pathogenic microorganisms） and influence on immune system in the feeding industry. The prohibition of antibiotics in feed will become an inevitable trend. This paper reviews the research progress of commonly used feed additives, including acidifier, plant extracts, microbioecological preparations, Chinese herbal preparations and minerals as alternatives to antibiotics.

For a long time, antibiotics have played a crucial role in the development of feeding industry, especially in pig industry. The role of antibiotics is mainly reflected in promoting animal growth, improving feed remuneration and reducing disease mortality rates. Table 1 shows several commonly used antibiotic types and their main effects in piglet feeding ^[1]. In addition（At the same time, ）, the over-dependence of pig industry on antibiotics has also exposed many unavoidable problems, and many scholars have raised doubts about the use of antibiotics, such as drug residues in meat products, resistance of pathogenic microorganisms, influences on immune system, etc. At present, many countries have banned or are going to prohibit use of antibiotics as regular growth promoting additives in pig feed. In order to maintain the health and production performance of pigs, a large amount of researches are focusing on the development of antibiotic substitutes. This article mainly reviews the research progress of acidifiers, plant extracts, microecologics, traditional Chinese medicine preparations and minerals as substitutes for antibiotics.

1 Acidifiers

Piglets undergoing early weaning are affected by psychological, environmental and nutritional stress and often manifests as an "Early weaning syndrome" characterized by poor appetite, digestive dysfunction, diarrhea, growth arrest and low feed utilization, which severely affects the growth and development of weaned piglets. There are many factors that cause "Early weaning syndrome" in piglets, among which the diet and the piglets themselves have a lower capacity to secrete acid are the main factors. Acidifier（Acidifiers） can reduce or stabilize the pH value in stomach, increase pepsin activity, improve intestinal microecological environment, promote beneficial microbes and inhibit the growth of harmful microbes, thus increasing nutrient digestibility and growth performance, and reducing diarrhea.

According to their types, acidifiers can be divided into organic acid, inorganic acid or acid salt. The most commonly used organic acids include formic acid, acetic acid, propionic acid, butyric acid, fumaric acid, lactic acid, citric acid, and benzoic acid. Adding organic acids to diet can reduce gastric pH value in the stomach^[2]. The commonly used inorganic acids in diet include hydrochloric acid, sulfuric acid, and phosphoric acid. Research had shown that supplementing with phosphoric acid and hydrochloric acid in diet had a positive effect ^[3], but there were other reports indicating that supplementing with hydrochloric acid had a negative effect ^[4-5], and supplementing with sulfuric acid in diet had a negative impact on growth performance ^[4]. Acid salts were also used as acidifiers for pigs, including calcium formate, potassium diformate, sodium diformate and sodium fumarate. Research had shown that calcium formate had a positive impact on growth performance and diarrhea rate ^[6], but its effect was worse than potassium diformate ^[7]. Supplementing sodium diformate and sodium fumarate in diet had a positive impact on its dry matter and protein digestibility ^[4]. Su Yongteng et al. found that compound acidifiers (adipic acid) can reduce the diarrhea rate of piglets, increase production performance, decrease the pH value of gastrointestinal contents, reduce the proliferation of harmful bacteria and improve intestinal health ^[8]. Yang Feilai et al. ^[9] studied adding different acidifiers to piglet diet and found that the compound acidifier group had higher final weight and daily gain compared to the single acidifier group, and could decrease the pH value of gastrointestinal chyme and increase the activity of pepsin and trypsin.

2 Plant Extracts

Plant extract is a product that uses plants as raw materials, undergoes a series of chemical, physical and biological methods, and obtains one or more structurally unchanged functional ingredients according to their corresponding functions. Common extracts include extracts or essential oils from vegetables, fruits, green tea, cloves, locust leaves, juniperis, malt, marigold, bearberry leaves, thistle, coptis, sage, nutmeg, laurel, origanum, seaweed, mushrooms, and other types of plants ^[10-11]. The main functions of plant extracts include antibacterial and anti-corrosion, promoting the growth and development of weaned piglets, reducing the diarrhea rate of piglets, and improving feed utilization. Xiao Chuanming et al. ^[12] found that adding plant extracts to diet can significantly promote the development of immune organs in weaned piglets and replace the use of antibiotics in pig feed. Fang et al. ^[13] added 1 ‰ of Acanthopanax senticosus extract to diet of piglets, significantly reducing diarrhea caused by weaning stress in piglets, and reducing the diarrhea rate by 55.6% compared to piglet fed as basic diet (P<0.05). Studies by Zhou Xuanwu et al. ^[14] showed that adding 200 mg/kg of plant essential oil to diet can improve the content of effective components in blood, enhance the body's immunity, enhance the health of weaned piglets, and promote growth. Research by He Jintian et al. ^[15] found that compound plant extracts (mainly composed of plant essential oils, spicy substances, colloids, flavonoids, thyme oil, and rosemary oil) can improve the production performance of weaned piglets, reduce blood lipids, and improve the serum antioxidant capacity of early weaned piglets. In addition, Yao Jiming ^[16] and other researchers found that adding pentaacid peptide to diet of weaned piglets can significantly improve the growth performance of piglets, increase the content of intestinal lactic acid bacteria（lactobacilli） and reduce the number of Escherichia coli. Li et al. ^[17] added an appropriate amount of essential oil complex, mainly composed of thymol and cinnamaldehyde, to diet of piglets, and found that compared with the control group, the test group increased lymphocyte transformation rate and phagocytosis rate, while increasing the content of IgA, IgM, C3 and C4 in the blood of piglets, which indicated that plant essential oil can improve the humoral and cellular immune abilities of piglets. Yu Huimin et al. ^[18] found that adding plant extract "Liukangsu" to diet of piglets can promote antibody production and complement synthesis, improve the immune and disease resistance abilities of animal body, and ensure the healthy growth of piglets. However, there are many kinds of plant extracts with different functions, and even different plant extracts may have antagonism, affecting animal health, so it is necessary to conduct more researches on the mechanism of plant extracts.

3 Microecologics

Animal microecologics are a type of drug or feed additive made by using normal microbial members and their promoting substances in animal bodies through special processing techniques based on the theories of microecological balance theory, microecological imbalance theory, microecological nutrition theory and microecological prevention and control theory, which mainly include Bacillus species, Yeast species, Lactobacillus species and compound bacteria etc. ^[19]. Their main functions are to regulate and supplement the nutritional components required by weaned piglets, maintain the balance of gut microbiota, improve protein digestion and absorption rate, prevent the production of harmful substances, and improve the body's immunity. Li Xueli et al. ^[20] found that probiotics can significantly increase (P<0.05) the relative weight of the spleen in weaned piglets, significantly increase the height of duodenal villi in weaned piglets (P<0.05), decrease the villous to cryptic ratio of duodenum, jejunum and ileum (P<0.05), and decreased the pH of cecum and colon in weaned piglets. Jiang Jiu et al. ^[21] found that adding antibiotics and microecologics to diet can increase the content of immunoglobulins in the serum of early weaned piglets, improve the immune performance of the body, and the microecologics exhibited better activity. Xie Quanxi et al. ^[21] found that adding microecologics to diet can improve the growth performance of weaned piglets, reduce diarrhea rate, promote the development of immune organs, lower the pH value of gastric and duodenal contents, and improve the balance of gut microbiota. However, current research is limited to the effectiveness of its use, and there is still limited research on its mechanism of action. Depending on types of bacteria used, differences in live bacterial content, product stability, acid resistance, bile resistance, and the presence or absence of intestinal-lysis, can significantly affect the effectiveness.

4 Chinese Herbal Medicine Preparations

Chinese herbal extract is a compound product formed by extracting, separating, and purifying one or more active ingredients from plants using physical and chemical methods according to the needs of the final use of the product, without changing the structure of its active ingred ients. It mainly includes polysavone, saccharicter-penin, allicin, astragalus root extract, perilla seed extract, and Eucommia leaf extract ^[23]. It has the functions such as antibacterial, enhancing immunity and providing various special nutrients and bioactive substances. Zhang Shichang et al. ^[24] found that adding Chinese herbal extracts to diet of weaned piglets had a better effect on reducing diarrhea rate compared to adding antibiotics, and can significantly improve growth performance. Zhu Yujing ^[25] and other researchers found that adding PE-A (plant extracts, mainly including compounds of natural plant extracts such as Astragalus, Eucommia, Honeysuckle and Coptis chinensis), PE-B (mainly including compounds of plant extracts such as bitterwood, liquorice, etc.) and PE-C (mainly including compounds of natural plant extracts such as origanum, cinnamon, etc.) to piglet diets can effectively reduce the number of Escherichia coli in the intestinal tract, increase the number of lactobacilli, and improve the intestinal microbial balance. Wan Lingli et al. ^[26] found that adding Chinese herbal extracts (mainly including extracts from Coptis chinensis and Acanthopanax senticosus) to piglet diets can effectively reduce the diarrhea rate of piglets. Chinese herbal extracts have the potential to replace antibiotics, but their components are diverse, research on their application effects mostly remains at the macro level and their mechanism of action is not yet fully understood, which needs further researches.

5 Mineral

Zinc is a component and activator of various metal enzymes, playing a major role in hormone production and secretion. Nursing pigs usually require the addition of 80-100 mg/kg of zinc in feed, and the lack of zinc in diet of weaned piglets can lead to growth retardation and loss of appetite. Inorganic zinc added in the form of zinc oxide can be used to reduce postweaning diarrhea and improve growth performance ^[27]. Under the stimulation of high levels of zinc, food intake can be increased by 14%-17% ^[28]. High levels of zinc supplementation will lead to deeper crypts and thicker duodenum, regeneration of injured intestinal epithelial cells, stability of microbial community and diversity of coliform group（E. coli） ^[29-30].

Copper is an important component of many metalloenzymes, including cytochrome oxidase and lysyl oxidase, and also participates in metabolic reactions, including cell respiration, tissue pigmentation, hemoglobin formation and the development of connective tissue ^[31]. Supplementing copper in diet of weaned piglets can relieve post-weaning stress and improve daily gain and daily feed intake ^[32]. The promotion of copper on growth mainly depends on its bacteriostatic and bactericidal properties, which further affects the growth and community structure of microorganisms in cecum and colon.

In 2018, the Announcement No. 2625 "Safe Use Specification for Feed Additives" issued by Ministry of Agriculture and Rural Affairs, which requires the maximum limit of zinc element in formula feed for piglets less than 25 kg to be 110 mg/kg. It can be seen that the quality and safety requirements of regulatory authorities for the feed industry are becoming increasingly strict.

6 Summary and Prospect

Through research on（of） acidifiers, plant extracts, microecologics, Chinese herbal medicine preparations and minerals, it has been found that they have the effect of replacing antibiotics. However, many application tests are lack of theoretical support, and there are many types of antibiotic substitutes with varying composition and no unified standards, resulting in slow research on antibiotic substitutes. At present, most antibiotic substitutes can only meet the needs of improving production performance and strengthening immunity, and the research results are lack of consistency. Therefore, further systematic and deep researches are still needed to develop substitute products that meet the needs, in order to achieve the goal of non-antibiotic feeding and achieve greater economic benefits.