The mechanism of action and hazards of antibiotics in animal feed

　　Since Moore et al. discovered in 1946 that antibiotics promoted growth in broiler chickens, antibiotics have been widely used as feed additives and research into their growth-promoting mechanisms has deepened. Although the growth-promoting effects of antibiotics are consistently confirmed, the mechanisms by which they enhance animal growth remain unclear.

　　Main Content:

　　I. Mechanisms of Action of Antibiotics in Feed Since Moore et al. discovered in 1946 that antibiotics promoted growth in broiler chickens, antibiotics have been widely used as feed additives and research into their growth-promoting mechanisms has deepened. Although the growth-promoting effects of antibiotics are consistently confirmed, the mechanisms by which they enhance animal growth remain unclear.

　　1. Nutritional Physiological Mechanisms Antibiotics can promote animal growth by inhibiting the subclinical symptoms of anti-growth factors in the environment. Some antibiotics can improve protein metabolism. Tong Jianming (2001) found that adding chlortetracycline to broiler diets can reduce blood ammonia and uric acid levels and increase nitrogen retention. Antibiotics also reduce intestinal wall thickness, improve intestinal mucosal structure, and reduce intestinal maintenance requirements, thus promoting nutrient absorption.

　　2. Microbiological Mechanisms Feed antibiotics can reduce the competition between intestinal microorganisms and the host for nutrients. It has been speculated that antibiotics inhibit the growth and activity of microorganisms in the small intestine, reducing the absorption and utilization of energy and nutrients by microorganisms, thereby increasing the available nutrients for the host. Feed antibiotics can also reduce the concentration of ammonia in animal tissues, blood, and the environment. Therefore, the reduction of toxic metabolites produced by bacteria may be a mechanism of the growth-promoting effect of antibiotics. Another important mechanism of antibiotics is the inhibition of the biotransformation of bile acids by intestinal microorganisms. Lower bile acid concentrations correspond to increased average daily weight gain and feed efficiency.

　　3. Immunological Mechanisms It has been shown that antibiotics not only inhibit the development of the body's immune system but also inhibit the body's immune response. Gordon (1995) found that in conventionally raised chickens fed antibiotics, the number of lymphoid follicles and free plasma cells in the small intestinal mucosa was significantly reduced, approaching that of germ-free chickens. Naqi (1984) and Cook (1984) found that antibiotic treatment reduced the production and distribution density of immunoglobulin-producing cells in chicken digestive tract lymphoid tissues (including the bursa of Fabricius, cecal tonsils, and intestinal lamina propria), significantly reducing serum IgM concentration. Rijkers et al. (1980, 1981) found that feeding oxytetracycline caused immunosuppression in carp, reducing serum immunoglobulin levels and reducing the formation rate of plaque-forming cells in the spleen, foregut, and hindgut by 80%. The research of Voiculesu et al. (1983a, 1983b) showed that erythromycin and polymyxin B significantly inhibited humoral and cellular immunity. Tong Jianming (2001) and Zhang Rijun (2000) found in their studies on the effects of chlortetracycline on the immune function of broiler chickens that adding chlortetracycline to the diet not only significantly reduced the developmental index of the thymus, spleen, and bursa of Fabricius in broiler chickens but also reduced the transformation rate and mitotic activity of T and B lymphocytes in broiler chickens, reducing humoral and cellular immune function. They concluded that chlortetracycline has a barrier effect on the immune system and thus promotes the growth of broiler chickens. Klasing et al. (1987, 1988) reviewed the relationship between the body's immune system and animal growth in detail, believing that antibiotics generally promote animal growth by directly (directly affecting the responsiveness of the immune system) or indirectly (by reducing the intensity of microbial invasion) affecting the immune system, preventing immune system activation. To date, although various hypotheses and inferences have been proposed regarding the growth-promoting mechanism of feed antibiotics, and much scientific evidence has been obtained, there are significant discrepancies in some experimental results, and the exact mechanism of antibiotic growth promotion remains unclear.

　　II. The Serious Situation of Antibiotic Abuse For more than half a century, antibiotics have created enormous economic benefits for the animal husbandry industry. Antibiotics have been widely used as feed growth promoters, but their widespread use, especially overuse, in livestock and poultry feed has led to the development of drug resistance in various pathogenic microorganisms and double infections in animals, seriously affecting the health of livestock and poultry. It is also suspected that they may cause drug residues in livestock and poultry products, which not only affect the quality and safety of livestock and poultry products but also lead to drug resistance in pathogenic microorganisms in humans, directly threatening human health. In the past two or three decades, the rate of drug-resistant strains has been increasing, making it increasingly difficult for humans to treat bacterial infectious diseases, and the effective dose of antibiotics required has been rising. People have begun to believe that this is caused by drug residues in animal products, and therefore opposition to feed antibiotics is becoming increasingly strong. China is a major user and producer of antibiotics. Per capita annual consumption is about 138 grams (only 13 grams in the United States). Half of China's antibiotics are used clinically, and half are used in animal husbandry. Experts estimate that of the approximately 210,000 tons of antibiotic raw materials produced in China each year, 97,000 tons are used in animal husbandry, accounting for 46.1% of annual total production. No other country in the world uses antibiotics on such a large scale. Developed countries such as the United States and European countries have very strict and effective regulations on antibiotics, and purchasing antibiotics requires a prescription from a professional doctor. These situations show that China has become one of the countries with the most serious problem of antibiotic abuse in the world. Driven by the pursuit of maximum economic benefits, the entire industry ignores social responsibility and food safety, arbitrarily adding or overdosing antibiotics in feed. It can be said that antibiotic abuse exists throughout the entire production cycle, from the birth of animals to slaughter and marketing. The abuse of antibiotics has caused serious public health problems.

　　1. The prevalence and severity of bacterial resistance are increasing. In animal husbandry, bacterial diseases caused by E. coli, Staphylococcus aureus, Salmonella, etc., which were previously not serious or less frequent, have now become one of the main infectious diseases in poultry. This is directly related to the long-term abuse of antibiotics. From 1990 to 2011, dozens of scholars conducted drug resistance tests on porcine and avian E. coli in China. The results showed that the drug resistance of E. coli is getting stronger, and in recent years, 95% of antibiotics have lost their sensitivity. The average number of drug-resistant genes carried by strains is as high as 17. The more serious the antibiotic use in a region, the stronger the bacterial resistance. It is becoming increasingly difficult to find sensitive drugs in these areas with serious antibiotic pollution. Once an outbreak of drug-resistant bacterial diseases occurs, it will cause serious economic losses. Developing a new antibiotic generally takes about 10 years, while the generation of a new generation of drug-resistant bacteria only takes a short time. Obviously, the research and development speed of antibiotics is far behind the reproduction speed of drug-resistant bacteria, and the beautiful scene of using antibiotics to cure diseases and save people will disappear. Although the transmission frequency of drug resistance factors is only 10-6, due to the large number and rapid reproduction of bacteria, at this frequency, it still causes the spread and spread of drug-resistant strains, and can cause one cell to produce multiple drug resistances. The abuse of antibiotics leads to an increase in drug-resistant strains, and the long-term, large-scale, and unreasonable use of antibiotic feed additives is one of the main reasons. It can be seen that the pollution of antibiotics to the intestinal microorganisms of livestock and poultry and the destruction of the natural environment by humans are equally terrible and require a considerable amount of time to repair. What's even more frightening is that the destruction of nature is easily noticed by people, while the destruction of the intestinal microecological system of livestock and poultry by the abuse of antibiotics has been ignored by people for a long time. Since early August 2010, countries such as India, Pakistan, Canada, Belgium, the United Kingdom, and Japan have reported cases of superbugs (NDM-1) infection. At least 170 people worldwide have been infected, resulting in multiple deaths. On October 26, 2010, the Chinese Center for Disease Control and Prevention reported three cases of infection with super-drug-resistant pathogenic bacteria, one of which resulted in death. In Hangzhou, China in 2011, experts studying superbugs also found the "superbug" MRSA bacteria in patients in the intensive care unit. The emergence of a large number of drug-resistant bacteria has caused great harm to medical care and society, which may lead to the failure of anti-infection treatment, prolonged hospitalization, and even patient death. In the 1960s, the number of people who died from infectious diseases worldwide was about 7 million per year, but this number rose to 20 million at the beginning of this century. The number of deaths from sepsis increased by 89%, and most people died due to the difficulty of using drugs caused by superbugs.

　　2. Long-term use of antibiotics reduces the immunity of livestock and poultry. One of the mechanisms of action of feed antibiotics is to inhibit the immune response of animals to achieve the purpose of promoting growth. Naqi (1984) and Cook (1984) found that feed antibiotics can reduce the generation and distribution density of immunoglobulin-producing cells in the lymphoid tissues of the chicken digestive tract (including the bursa of Fabricius, cecal tonsils, and intestinal lamina propria), and significantly reduce serum IgM concentration. Rijkers et al. (1980, 1981) found that feeding oxytetracycline can cause humoral immune suppression in carp, reduce the immunoglobulin content in serum, and reduce the plaque-forming cell formation rate in the spleen, foregut, and hindgut by 80%. The research of Voiculesu et al. (1983a, 1983b) showed that erythromycin and polymyxin can significantly inhibit humoral and cellular immunity. A large amount of antibiotics, after being ingested into the body, will be distributed to various tissues and organs such as lymph nodes, kidneys, and liver through blood circulation, and the immune ability of the animal body will be weakened. Antibiotics can also lead to a decrease in antigen quality, directly affecting the immune process, and thus having an adverse effect on vaccination. The use of sulfonamide drugs in the juvenile period of animals will inhibit the hematopoietic function of the bone marrow, causing granulocytopenia, hemolytic anemia, and aplastic anemia. Chloramphenicol acts on the thymus, causing its cortex and medulla to be abnormal; it acts on the spleen, causing its follicles to disappear and the white pulp structure to become loose; it acts on the cecal tonsils, causing a decrease in lymphoid tissue, and can also damage liver and kidney tissues, destroy bone marrow hematopoietic function, comprehensively destroy immune responses, and cause a serious decline in animal resistance and immunity.

　　3. Long-term use of antibiotics can cause endogenous infections and superinfections in livestock and poultry. Although antibiotics have their own antibacterial spectrum, they affect the growth of beneficial bacteria in the body while acting on pathogenic bacteria, especially with long-term and large-scale use, causing the imbalance of the body's flora and the destruction of the microecological balance. Harmful bacteria lurking in the body take the opportunity to multiply, thus causing endogenous infections. Superinfection is also caused by the use of a large amount of antibiotics to kill a certain type of bacteria, destroying the microecological balance, and another or several endogenous or exogenous bacteria subsequently re-infecting the body (Xue Hengping, 1998).

　　4. Long-term use of antibiotics will cause residues in animal products and the environment. Drug residues are one of the controversies surrounding the addition of antibiotics to feed. The arbitrary addition or excessive addition of feed antibiotics will cause antibiotics to accumulate in meat, eggs, and milk, and enter the human body through the food chain, causing people to indirectly contact antibiotics every day, leading to the disappearance of the effect of antibiotic treatment when people get sick. In addition, all drugs have side effects, and no antimicrobial drug is absolutely safe, only the degree is different. For example, sulfonamide drugs are prone to cause allergies and hypersensitivity in humans; chloramphenicol causes regenerative, obstructive, and hemolytic anemia, thrombocytopenia, and liver damage; tetracyclines have photosensitivity and gastrointestinal reactions; olaquindox is a gene mutagen; furazolidone induces animal carcinogenesis, etc. (Zeng Shuqin, 2004). Although some drugs have been banned, some are still in use. After antibiotics are absorbed into the body, they are distributed throughout the body. Antibiotics are distributed more in the liver and less in muscles and fat. The metabolic pathways of antibiotics are diverse, but most are mainly metabolized by the liver. Some stable antibiotics can still exist stably for a period of time after being excreted into the environment, thus causing drug residues in the environment. These residual drugs slowly accumulate in the human body and other plants through animal products and the environment, and finally converge in the human body through various pathways, leading to the production of a large number of drug-resistant strains in the human body, losing resistance to certain diseases, or producing toxic effects on the body due to large-scale accumulation. In addition, antibiotics also have toxic side effects such as gene mutation, teratogenesis, and cancer induction. According to the Beijing Daily, the number of children under 7 years old in China who have become deaf due to the unreasonable use of antibiotics is as high as 300,000, accounting for 30%-40% of the total number of deaf children, while in some developed countries, it is only 0.9%. Among hospitalized patients with infectious diseases, the mortality rate of drug-resistant bacterial infections is 11.7%, while the mortality rate of ordinary infections is only 5.4%.