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Overall assessment of antibiotic substitutes for pigs: a set of meta-analyses

Overall assessment of antibiotic substitutes for pigs: a set of meta-analyses Background: Antibiotic growth promoters are widely used to improve weight gain. However, the abuse of antibiotics can have many negative effects on people. Developing alternatives to antibiotics is an urgent need in livestock production. We aimed to perform a meta-analysis and network meta-analysis (NMA) to investigate the effects of feed additives as potential antibiotic substitutes (ASs) on bacteriostasis, growth performance, intestinal morphology and immunity. Furthermore, the primary, secondary, and tertiary ASs were defined by comparing their results with the results of antibiotics. Results: Among 16,309 identified studies, 37 were summarized to study the bacteriostasis effects of feed additives, and 89 were included in the meta-analysis and NMA (10,228 pigs). We summarized 268 associations of 57 interventions with 32 bacteria. The order of bacteriostasis effects was as follows: antimicrobial peptides (AMPs) ≈ antibiotics>organic acids>plant extracts>oligosaccharides. We detected associations of 11 feed additives and 11 outcomes. Compared with a basal diet, plant extract, AMPs, probiotics, microelements, organic acids, bacteriophages, lysozyme, zymin, and oligosaccharides significantly improved growth performance (P < 0.05); organic acids, probiotics, microelements, lysozyme, and AMPs remarkably increased the villus height:crypt depth ratio (V/C) (P < 0.05); and plant extracts, zymin, microelements, probiotics, and organic acids notably improved immunity (P < 0.05). The optimal AMP, bacteriophage, lysozyme, microelements, oligosaccharides, organic acids, plants, plant extracts, probiotics, and zymin doses were 0.100%, 0.150%, 0.012%, 0.010%, 0.050%, 0.750%, 0.20%, 0.040%, 0.180%, and 0.100%, respectively. Compared with antibiotics, all investigated feed additives exhibited no significant difference in effects on growth performance, IgG, and diarrhoea index/rate (P > 0.05); AMPs and microelements significantly increased V/C (P < 0.05); and zymin significantly improved lymphocyte levels (P < 0.05). Furthermore, linear weighting sum models were used to comprehensively estimate the overall impact of each feed additive on pig growth and health. Conclusions: Our findings suggest that AMPs and plant extracts can be used as primary ASs for weaned piglets and growing pigs, respectively. Bacteriophages, zymin, plants, probiotics, oligosaccharides, lysozyme, and microelements can be regarded as secondary ASs. Nucleotides and organic acids can be considered as tertiary ASs. Future studies should further assess the alternative effects of combinational feed additives. Keywords: Antibiotic substitutes, Dose-effect relationship, Feed additives, Meta-analysis, Network meta-analysis, Pigs * Correspondence: yzwang321@zju.edu.cn National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Nutrition and Feed of Ministry of Agriculture, Key Laboratory of Animal Nutrition and Feed Science of Zhejiang Province, Institute of Feed Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang Province, People’s Republic of China © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Journal of Animal Science and Biotechnology (2021) 12:3 Page 2 of 15 Background Selection criteria Antibiotics are widely used in commercial pig produc- The inclusion criteria were as follows: 1) studies investi- tion for growth promotion and disease prevention [1]. gating the effects of ASs on bacteriostasis; 2) studies in- Subtherapeutic doses of antibiotics are used as feed ad- vestigating the effects of potential ASs as feed additives ditives to promote growth performance, improving aver- on pig growth performance, the villus height:crypt depth age daily gain (ADG) and gain:feed ratio (G/F) through ratio, blood haematology, or diarrhoea; and 3) studies in alterations in intestinal morphology and digestion and which the breeding background was commercial pigs. the suppression of harmful bacteria [2]. However, feed- The exclusion criteria were as follows: 1) studies on anti- ing pigs subtherapeutic doses of antibiotics in the long bacterial effects that did not report minimum inhibitory term leads to the development of antimicrobial resist- concentrations (MICs) or animal-specific bacteria; 2) ance, which is seriously endangering public health [3]. studies without a basal diet or a positive control group; Considering its harm, in 1999, the European Union 3) studies where pig growth was not assessed in stages; banned the use of subtherapeutic doses of antibiotics in 4) studies in which pigs were challenged with pathogenic livestock [3]. In 2017, the FDA reported that antibiotics bacteria, viruses, or lipopolysaccharide; 5) studies that that are important for human medicine could no longer included multiple factors; and 6) studies in which pigs be used for growth promotion in food animals [4]. Not- exhibited an oxidative stress status or a heat stress state. ably, China will completely ban the use of antibiotics in Three investigators (B. Xu, L. Zhu and J. Fu) reviewed feed in 2020 [5]. Therefore, governments and world or- study titles, abstracts, and full texts to ensure studies sat- ganizations have initiated a series of countermeasures isfied the inclusion criteria, and disagreements were re- and encouraged the research and development of anti- solved by two investigators (M. Jin and Y. Wang). biotic substitutes (ASs). However, some questions about ASs are the following. 1) How should ASs be defined? 2) Information extraction What are the effects of many feed additives on bacterio- The following data were extracted from each selected stasis, growth promotion, improvement of intestinal study: author information (first author, year, country), morphology and immunity? 3) What is the optimal dose interventions, control group, breeding background, for these feed additives? 4) Which additive is the most amount of additive, growth stages (weaned piglets, grow- powerful AS? In this study, we performed a set of meta- ing pigs, finishing pigs), sample size, initial and final analyses to investigate the effects of different feed addi- body weight, experimental duration, and outcome data tives regarded as ASs on growth performance, intestinal and corresponding errors, such as standard deviations or morphology and immunity in pigs. Then, we used net- standard errors. The initial body weight of weaned pig- work meta-analyses (NMAs) to assess and compare the lets was lower than 15 kg, the initial body weight of effects of antibiotics and different ASs that are superior growing pigs was more than 15 kg, and the initial body to the basal diet. Finally, we used a linear weighted weight of finishing pigs was more than 45 kg. Outcomes model to evaluate ASs. To the best of our knowledge, were as follows: MIC; ADG; average daily feed intake this study is the first to comprehensively and systematic- (ADFI); G/F; V/C of duodenum, jejunum, and ileum; im- ally define ASs and investigate their effects. mune globulin (Ig), including IgA, IgM, and IgG; lymphocyte levels, diarrhoea rate, and diarrhoea index. Methods For studies involving multiple interventions, we This meta-analysis is reported according to the Preferred extracted data from all relevant interventions. For stud- Reporting Items for Systematic Reviews and Meta- ies involving multiple concentrations, we extracted all Analyses (PRISMA) Statement [6] and the Approach of the experimental groups with an addition amount less Meta-analysis on Nonruminants [7, 8]. than 1%. When extractions from different plant tissues were used, we chose leaf extractions. Search strategy We performed a series of meta-analyses of studies on Study quality assessment potential ASs indexed on PubMed from January 1, 2000 We conducted a study quality assessment on non- to April 31, 2019, and the language was restricted to ruminants (SQANR) to assess the quality of existing English. The complete search strategy is shown in Table studies [7]. The potential risk of bias was derived from S1. Moreover, studies on antimicrobial peptides (AMPs) missing within-group error, repeated reports, informa- were identified by searches in the Antimicrobial Peptide tion completeness, sample size, and experimental ration- Database (http://aps.unmc.edu/AP/, accessed on April ality. Two investigators (B. Xu and L. Zhu) performed 31, 2019). In addition, a manual search was performed independent study quality assessments. to obtain additional potential studies. Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 3 of 15 Statistical analysis outcomes, the feed additives were rated zero in the cor- We aimed to compare which ASs were most suitable in responding outcomes. For growth performance, the terms of bacteriostasis, growth promotion and disease weights of ADG, ADFI, and G/F were 30%, 10%, and resistance effects. First, we compared the effects of basal 60%, respectively. For intestinal morphology, the weights diet with those of feed additive supplementation on a of V/C of the duodenum, jejunum, and ileum were 30%, range of outcomes. We used a random-effects model to 10%, and 60%, respectively. For immunity, the weights of compute the pooled estimate of standardized mean dif- IgA, IgM, IgG, and lymphocyte levels and diarrhoea ference (SMD) with the 95% confidence interval (CI). If index/rate were 10%, 10%, 10%, 10%, 60%, respectively. the 95% CI contained a zero value, that result indicated The overall score was equal to the sum of the score of that there was no difference. The heterogeneity was bacteriostasis, growth performance, intestinal morph- assessed with the I statistic [9] and Cochran’s Q test ology, and immunity effects multiplied by the corre- [10]; I > 50% and P < 0.1 was regarded as a sponding weight (bacteriostasis = 10%; growth heterogeneity substantial heterogeneity. performance = 50%; intestinal morphology = 10%; im- We used sensitivity analyses to remove individual data munity = 30%). Furthermore, we also conducted the values with large deviations from the overall level. If 10 stage scores based on the growth stage to provide a spe- or more trials were available, we conducted subgroup cial strategy. Feed additives that were superior to antibi- analyses and meta-regression to explore potential otics on the stage scores were regarded as primary ASs. sources of heterogeneity. Publication bias was evaluated Feed additives that were superior to antibiotics on one using Egger’s tests, for which the significance level was outcome were regarded as secondary ASs. Finally, the defined at P < 0.1 [11]. Second, if the data were suffi- remaining feed additives were regarded as tertiary ASs. cient, we used the dose-effect model to find the optimal amount of added feed additives. When the same effect Results size occurred at different concentrations, we chose the We identified 16,309 articles in PubMed, of which 89 lowest concentration to reduce the cost. Third, we per- were included in the meta-analyses [14–102], including formed an NMA to further study feed additives that, 10,228 pigs, and 37 were summarized to investigate the when compared with basal diet, had a significant effect antibacterial effects of feed additives [103–139]. The on growth performance. We aimed to compare the characteristics of the studies are shown in Table S2. The growth performance effects of feed additives with the study quality assessed by SQANR is shown in Table S3. optimal amount of ASs added. NMA enables the incorp- The number of studies rated as “high” and “moderate” oration of indirect comparisons constructed from two were 7 and 61, respectively. The mean initial body trials with the same control group. NMA combined all weights of weaned piglets, growing pigs, and finishing available comparisons among ASs and provided a rank- pigs were 7.7 kg, 28.4 kg, and 57.6 kg, respectively. Feed ing of suitable alternatives to antibiotics [12]. To explore additives included plant extracts, plants, probiotics, mi- evidence of within-network inconsistency, the loop- croelements, organic acids, bacteriophages, lysozyme, specific approach was used [13]. zymin, AMPs, nucleotides, and oligosaccharides. The re- We used Stata 14.0 (Stata Corp., USA) to perform the sults of the meta-regression are shown in Table 1. The meta-analysis. We used R 3.6.1 (The R Foundation Con- different growth stages had a significant influence on ference Committee, USA) to examine the dose-effect re- ADFI and G/F (P < 0.05), while the type of feed additives lationship and perform the NMA. and dose did not have a significant effect on the out- comes of interest (P > 0.05). Therefore, when we per- Assessment of antibiotic substitutes formed meta-analyses for growth performance, the We aimed to use a linear weighting sum model to com- growth stages were divided into weaned piglets, growing prehensively assess the efficacy of feed additives. In pigs, and finishing pigs. terms of bacteriostasis, according to the order of occur- rences, 4 bacteria were chosen from gram-positive/nega- Effects of feed additives on bacteriostasis tive bacteria for analysis. We used the rank score of the We summarized 268 associations of 57 interventions interventions to assess their bacteriostasis effects based with 32 bacteria (Table S4). Due to the number of asso- on MICs. We used the P-score value, which evaluates ciations, Staphylococcus aureus and Bacillus subtilis and ranks the strength of the intervention from the were used to represent gram-positive bacteria, and NMA, to grade available interventions. Each P-score Escherichia coli and Pseudomonas aeruginosa were used value of feed additives was subtracted by that of the cor- to represent gram-negative bacteria. Overall, based on responding basal diet, which was performed to guarantee the rank score, bacteriostasis effects of interventions a consistent background. When feed additives were not were as follows (Table 2): AMPs≈ASs> organic acids> included in the NMA or were not observed in the plant extracts> oligosaccharides, which were in Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 4 of 15 Table 1 Regression analyses of the covariates Outcomes Type of feed additive Growth stage Dose Average daily gain 0.986 0.064 0.954 Average daily feed intake 0.105 0.001 0.466 Gain: feed ratio 0.414 0.009 0.082 Villus height: crypt depth of the duodenum 0.474 0.974 0.949 Villus height: crypt depth of the jejunum 0.168 0.514 0.409 Villus height: crypt depth of the ileum 0.021 0.989 0.397 IgA 0.278 0.196 0.597 IgM 0.552 0.591 0.886 IgG 0.354 0.449 0.976 Lymphocytes 0.156 0.661 0.978 Diarrhoea rate 0.587 NA NA Diarrhoea index 0.535 NA 0.053 accordance with bacteriostasis effects of those interven- oligosaccharides, organic acids, plants, plant extracts, pro- tions on gram-positive or gram-negative bacteria. biotics, and zymin were 0.100%, 0.150%, 0.012%, 0.010%, 0.050%, 0.750%, 0.20%, 0.040%, 0.180%, and 0.100%, respectively. Effect of feed additives on growth performance Figure 3 and Table 3 show the comparison between an- As shown in Fig. 1a-i and Table S5, compared with a tibiotics and feed additives based on NMA. Compared basal diet, plants and probiotics had significant effects with those of antibiotics, feed additives that had a positive on ADG at all stages (P < 0.05), plant extracts and zymin significant effect on growth performance compared with improved weaned and growing pigs’ ADG (P < 0.05), the basal diet had no difference in growth performance. and bacteriophages, lysozyme, and AMPs had significant For weaned piglets’ ADG, the P-score values of bacterio- effects on weaned piglets’ ADG (P < 0.05), while only phages, AMPs, lysozyme, and probiotics were greater than microelements and organic acids had no significant ef- those of antibiotics. For weaned piglets’ ADFI, the P-score fect on growing pigs’ ADG (P > 0.05). With regard to value of AMPs was greater than that of antibiotics. For ADFI, probiotics, microelements, organic acids, bacterio- weaned piglets’ G/F, the P-score values of AMPs, zymin, phages, lysozyme, AMPs, and oligosaccharides had a bacteriophages, and oligosaccharides were greater than notable effect on weaned piglets (P < 0.05), while we de- those of antibiotics. For growing pigs’ ADG, the P-score tected that organic acids improved ADFI in growing pigs values of probiotics, plants, and plant extracts were greater (P < 0.05) and that probiotics had a negative impact on than those of antibiotics. For finishing pigs’ ADG, the P- finishing pigs’ ADFI (P < 0.05). In terms of G/F, plants score value of plants was greater than that of antibiotics. remarkably improved weaned and growing pigs’ G/F However, we did not observe a P-score value of feed addi- (P < 0.05), probiotics had a significant effect on weaned tives greater than that of antibiotics for ADFI and G/F of and finishing pigs’ G/F (P < 0.05), and microelements, growing and finishing pigs. organic acids, bacteriophages, lysozyme, zymin, AMPs, and oligosaccharides had considerable effects on weaned piglets’ G/F (P < 0.05). Effect of feed additives on intestinal morphology Figure 2 show the dose-effect relationship among the As shown in Fig. 1j-l and Table S5, probiotics, organic feed additives and growth performance. The optimal doses acids, microelements, lysozyme, AMPs, plant extracts of AMPs, bacteriophages, lysozyme, microelements, significantly improved the V/C of duodenum and ileum Table 2 The rank of bacteriostasis effects Interventions Staphylococcus aureus Bacillus subtilis Escherichia coli Pseudomonas aeruginosa Antimicrobial peptides 1 2 1 2 Antibiotics 2 1 2 1 Organic acids 3 2 3 3 Plant extracts 4 4 5 4 Oligosaccharides 5 5 4 NA Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 5 of 15 Fig. 1 (See legend on next page.) Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 6 of 15 (See figure on previous page.) Fig. 1 Summary forest plots of the effects of feed additives. a Feed additives and weaned piglets’ average daily gain. b Feed additives and growing pigs’ average daily gain. c Feed additives and finishing pigs’ average daily gain. d Feed additives and weaned piglets’ average daily feed intake. e Feed additives and growing pigs’ average daily feed intake. f Feed additives and finishing pigs’ average daily feed intake. g Feed additives and weaned piglets’ gain:feed ratio. h Feed additives and growing pigs’ gain:feed ratio. i Feed additives and finishing pigs’ gain:feed ratio. j Feed additives and villus height:crypt depth ratio of the duodenum. k Feed additives and villus height:crypt depth ratio of the jejunum. i Feed additives and villus height:crypt depth ratio of the ileum. m Feed additives and IgA level. n Feed additives and IgM level. o Feed additives and IgG level. p Feed additives and lymphocytes. q Feed additives and diarrhoea index/rate Fig. 2 Dose-effect relationship between feed additives and growth performance. a Zymin. b Antimicrobial peptides. c Lysozyme. d Microelement. e Oligosaccharides. f Organic acids. g Plant. h Plant extract. i Probiotics Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 7 of 15 Fig. 3 Forest plots of network meta-analysis. a Feed additives and weaned piglets’ average daily gain. b Feed additives and growing pigs’ average daily gain. c Feed additives and finishing pigs’ average daily gain. d Feed additives and weaned piglets’ average daily feed intake. e Feed additives and weaned piglets’ gain:feed ratio. f Feed additives and villus height:crypt depth ratio of the duodenum. g Feed additives and villus height:crypt depth ratio of the ileum. h Feed additives and lymphocytes. i Feed additives and IgG level. j Feed additives and diarrhoea index/rate Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 8 of 15 Table 3 P-score value table Interventions ADG-w ADG-g ADG-f G/F-w ADFI-w V/C (duodenum) V/C (ileum) Lymphocytes IgG Diarrhoea rate/index Antibiotics 0.552 0.589 0.628 0.493 0.723 0.542 0.037 0.366 0.337 0.664 Antimicrobial peptides 0.852 0.000 0.000 0.796 0.820 0.615 0.841 0.000 0.000 0.000 Bacteriophages 0.898 0.000 0.000 0.980 0.299 0.000 0.000 0.000 0.000 0.000 Basal diet 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Lysozyme 0.790 0.000 0.000 0.454 0.412 0.467 0.000 0.000 0.000 0.000 Microelements 0.331 0.000 0.000 0.319 0.568 0.937 0.686 0.000 0.370 0.327 Oligosaccharides 0.524 0.000 0.000 0.622 0.500 0.000 0.000 0.000 0.000 0.000 Organic acids 0.256 0.000 0.000 0.244 0.311 0.519 0.000 0.000 0.000 0.433 Plants 0.235 0.647 0.914 0.286 0.000 0.000 0.000 0.385 0.000 0.000 Plant extracts 0.515 0.646 0.252 0.000 0.000 0.000 0.399 0.856 0.496 0.735 Probiotics 0.625 0.843 0.531 0.371 0.587 0.139 0.000 0.000 0.000 0.000 Zymin 0.334 0.266 0.000 0.755 0.001 0.000 0.000 0.893 0.740 0.807 w Weaned piglets, g Growing pigs, f Finishing pigs in weaned piglets (P < 0.05), while plant extracts notably bacteriostasis, AMPs were observed to have an antibac- improved the V/C of jejunum and ileum in growing and terial effect similar to that of antibiotics. For growth per- finishing pigs (P < 0.05). formance, AMPs, bacteriophages, zymin, and As shown in Fig. 3f-g and Table 3, in weaned piglets, oligosaccharides could replace antibiotics in weaned pig- microelements were greater than AS on V/C of the duo- lets; probiotics, plants, and plant extracts could replace denum and ileum, plant extracts and AMPs were greater antibiotics in growing pigs; and plants could replace an- than AS on V/C of the ileum, and probiotics, organic tibiotics in finishing pigs. With regard to intestinal acids, lysozyme, and AMPs had no difference with AS morphology, AMPs, plant extracts, and microelements on V/C of the duodenum. Specifically, the P-score value were superior to antibiotics. Zymin and plant extracts of microelements and AMPs was greater than that of AS were better than antibiotics at improving immunity. on V/C of ileum. Discussion Effect of feed additives on immunity We used meta-analysis and NMA to define ASs. We de- As shown in Fig. 1m-q and Table S5, plant extracts, tected the associations of 11 feed additives and 11 out- zymin, and microelements were associated with im- comes. The findings suggest that AMPs and plant proved Ig levels (P < 0.05); plants, plant extracts, and extracts can be used as ASs for weaned piglets and zymin were associated with improved lymphocyte levels growing pigs, respectively and that bacteriophages, (P < 0.05); and probiotics, organic acids, zymin, plant ex- zymin, plants, probiotics, oligosaccharides, lysozyme, tracts, and microelements were associated with reduced and microelements can be regarded as secondary ASs diarrhoea index/rate (P < 0.05). (Fig. 4). Based on current data, the optimal AMPs, bac- Figure 3h-j and Table 3 show that compared with ASs, teriophage, lysozyme, microelements, oligosaccharides, zymin significantly improved lymphocyte levels. In terms organic acids, plants, plant extracts, probiotics, and of P-score value, plant extracts and zymin were better zymin doses were 0.100%, 0.150%, 0.012%, 0.010%, than ASs at reducing and alleviating diarrhoea; plant ex- 0.050%, 0.750%, 0.20%, 0.040%, 0.180%, and 0.100%, tracts, zymin, and plants were better than ASs at in- respectively. creasing lymphocyte levels; and plant extracts, zymin, To determine whether a feed additive is an eligible AS, and microelements were better than ASs at increasing it is necessary to measure its alternative effects on IgG levels. growth promotion, intestinal morphology improvement, bacteriostasis and immunity. Chief among these effects Feed additives assessment is growth promotion dependent on G/F. Feed additives Table 4 shows the assessment score of feed additives. enhance growth performance through improving intes- The findings suggest that AMPs could be regarded as tinal morphology, reducing pernicious bacteria, reducing primary ASs in weaned piglets and that plant extracts anti-nutritional factors, or improving nutrient digestibil- could be considered ASs in growing pigs. Secondary ASs ity. We did not investigate the effects of feed additives included bacteriophages, zymin, plants, probiotics, oligo- on the latter two mechanisms because antibiotics have saccharides, lysozyme, and microelements. In terms of not been reported to have these effects in the primary Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 9 of 15 Table 4 Assessment score of the effects of the interventions on outcomes Interventions Bacteriostasis Growth performance Growth performance Growth performance Intestinal Immunity Sum Sum Sum Sum (weaned piglets) (growing pigs) (finishing pigs) morphology (overall) (weaned (growing (finishing piglets) pigs) pigs) Antibiotics 76.00 53.33 17.66 18.85 18.48 46.89 68.43 50.18 32.34 32.94 AMPs 76.00 81.54 0.00 0.00 68.90 0.00 55.26 55.26 14.49 14.49 Probiotics 0.00 46.85 25.30 15.92 4.18 0.00 44.45 23.84 13.07 8.38 Bacteriophages 0.00 88.74 0.00 0.00 0.00 0.00 44.37 44.37 0.00 0.00 Zymin 0.00 55.33 7.99 0.00 0.00 64.74 51.08 47.09 23.42 19.42 Plants 0.00 24.18 19.42 27.42 0.00 3.85 36.67 13.25 10.86 14.87 Plant extracts 32.00 15.44 19.37 7.55 23.96 57.59 44.05 30.59 32.56 26.65 Microelements 0.00 34.75 0.00 0.00 69.23 23.30 31.29 31.29 13.91 13.91 Oligosaccharides 19.00 58.04 0.00 0.00 0.00 19.39 36.73 36.73 7.72 7.72 Lysozyme 0.00 55.07 0.00 0.00 14.02 0.00 28.94 28.94 1.40 1.40 Organic acids 56.00 25.44 0.00 0.00 15.56 25.96 27.66 27.66 14.94 14.94 Basal diet 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Bold type values for interventions indicates that their effect was superior or equal to that of antibiotics AMPs Antimicrobial peptides Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 10 of 15 Fig. 4 Summary of findings of meta-analyses studies included in this meta-analysis. We measured in- guarantee intestinal integrity and barrier function to testinal morphology through V/C, as V/C is positively protect from bacterial and toxin infections, which may correlated with nutrient absorption capacity, such as that be due to upregulation of the expression of tight junc- of carbohydrates and fatty acids [140]. We measured im- tion proteins [102, 142, 143]. AMPs are critical compo- munity through Ig and lymphocyte levels and the diar- nents of the innate immune system, but evaluations of rhoea index/rate, which are the secondary phenotype immune outcome associations were not conducted due outcomes. Consequently, antimicrobial and anti- to limitation by the lack of data. 2) Plant extracts can inflammatory properties also contribute to promotion of improve immunity (IgA, IgM, IgG, and lymphocyte growth performance. Bacteriostasis is measured by levels) through their antimicrobial and anti- in vitro MIC experiments that are considered to provide inflammatory properties [65]. Changing the microbiota reliable and stable results. Meanwhile, bacteriostasis ef- and regulating intestinal permeability contribute to their fects of interventions are linked to antidiarrhoeal proper- antidiarrhoeal properties. The effects of plant extracts ties to some extent. on growth performance (ADG and G/F) exhibit substan- Our findings, together with mechanisms and possible tial heterogeneity because numerous plant extracts were speculations reported in articles, provide rational inter- included, and there is no feasible subgroup. Growth pro- pretations for growth promotion, immunity enhance- motion associated with improving nutrient digestibility ment, and antidiarrhoeal properties for ASs. and amino acid metabolism also occurred [14]. Our pre- Interpretations of primary ASs are as follows. 1) AMPs analyses identified a subgroup based on whether it is a can promote growth performance (ADG, ADFI, G/F) by plant essential oil, which cannot influence the substantial improving intestinal morphology (V/C of the duodenum heterogeneity. A plant essential oil inhibits the opening and ileum), nutrient digestibility, and antimicrobial ac- of calcium channels and stimulates that of potassium tivity [141]. AMPs can improve the duodenum and channels in smooth muscles, which increases motility of ileum by stimulating intestinal epithelial cell prolifera- the small intestine and produces a significant shortening tion because AMP receptors may be rich in the duode- of the food transit time [64, 144, 145]. However, several num and ileum [142]. AMPs are more likely to studies have suggested that a positive effect of plant Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 11 of 15 essential oils seems to occur in challenged piglets rather on lymphocyte level enhancement. All of the ASs have than healthy piglets [64, 98]. Future meta-analyses potential uses in animal health. However, the high cost should study the effects of plant extracts in pigs with dif- for many ASs, such as AMPs and bacteriophages, may ferent health statuses and the main sources of hetero- be prohibitive for animal use. Future studies should fur- geneity based on a feasible subgroup. ther investigate high-efficiency bacterial engineering, Interpretations of secondary ASs are as follows. 1) purification technology, and the design of novel AMPs Zymin can improve growth performance (ADG and G/F), to expedite progress in reducing and alternating antibi- enhance immunity (IgA, IgM, IgG, and lymphocyte levels), otics. Commitment to substantial subsidies might be and reduce and relieve diarrhoea. The reason for the needed to incentivize development of ASs for animal above phenotype is that zymin can increase digestive en- health, in which their use could contribute to a reduc- zyme activities and nutrient digestibility and decrease tion in antibiotic use [146]. Escherichia coli and Salmonella populations [100]. 2) A major strength of the present study is that we inves- Lysozyme can increase growth performance (ADG, ADFI, tigated all feed additives mentioned as ASs, which thus and G/F), improve intestinal morphology (V/C of the duo- comprehensively demonstrated the effects of each feed denum and jejunum), and increase lymphocyte levels. additive on outcomes for which producers and animal Lysozyme increases protein deposition and decreases the nutritionists are interested. A major innovation is that turnover rate of intestinal epithelial cells [25, 85]. 3) Bacte- we used a rational approach, the linear weighting sum riophages promote growth performance (ADG, ADFI, and model, to estimate the overall impact of each feed addi- G/F) through a reduction in coliforms and Clostridium tive and antibiotics on pig health and growth. The limi- [32]. 4) Plants can improve growth performance (ADG tation of the present study is that we failed to further and G/F) and enhance immunity (IgG and lymphocyte investigate the main sources of heterogeneity of every levels). 4) Plants, specifically herbs, have antioxidant activ- AS and effects of combinational feed additives, such as ity and pharmaceutical effects, providing additional bene- combinations of plant essential oils and organic acids fits. Our previous meta-analysis indicated that fermented and those of prebiotics and probiotics. Some ASs were plants promoted growth performance and digestibility at downgraded due to lack of some outcomes data. Future all stages [8]. Additionally, fermented plants significantly studies should investigate effects of feed additives on improved marbling and decreased redness of the meat in various aspects beyond growth performance. finishing pigs but had no effect on lightness, yellowness, drip loss, and flavour [7]. 5) Probiotics can increase Conclusions growth performance (ADG, ADFI, G/F) by improving nu- Here, we recommend supplementing 0.1% AMPs in the trient digestibility and the microbiota structure, enhancing weaned stage, adding 0.04% plant extract in the growing osmotic balance and reducing pernicious bacteria to con- stage and feeding 0.2% plants, especially fermented plants, tribute to the remission of diarrhoea [31]. Immunity pro- in the finishing stage, which may have an approximate ef- motion of probiotics was not observed; hence, the effect of fect compared with antibiotics on all stages. Our research probiotics on immunity is unclear. 6) Oligosaccharides is the first to define and overall assess ASs through meta- can increase growth performance (ADG, ADFI, and G/F) analysis and NMA. Although further research should sup- and have no association with intestinal morphology, plement unobserved data for a more comprehensive as- lymphocyte levels, or the diarrhoea rate. We speculate that sessment, our research clearly and systematically oligosaccharides may increase nutrient digestibility, and investigates AS candidates. However, it is important to the categories of oligosaccharides are related to the diar- note that there is no single alternative to completely sub- rhoea rate. 7) Microelements can increase growth per- stitute antibiotics in feed, and a combination of different formance (ADG, ADFI, and G/F), improve immunity (IgG alternatives to antibiotics may be the most promising levels), and reduce the risk of diarrhoea, which are linked method to reduce or replace antibiotics in animal feeds. to their bacteriostatic properties and improvement of the Future meta-analyses should further study the alternative microbiota structure [74]. effects of combinational feed additives. According to the results of the NMA, the effects of all feed additives investigated showed no significant differ- Supplementary Information ence from those of antibiotics on ADG, ADFI, IgG, and The online version contains supplementary material available at https://doi. diarrhoea rate or index. The effects of bacteriophages org/10.1186/s40104-020-00534-2. are superior to those of antibiotics on weaned piglets’ G/F; the effects of microelements, plant extracts, and Additional file 1: Table S1. Search strategy. Table S2. Characteristics of studies. Table S3. Study quality assessment. Table S4. Minimal AMPs are superior to those of antibiotics on improve- inhibitory concentration table (μg/mL). Table S5. Meta-analyses and sub- ment of intestinal morphology; and the effects of plant group analyses. extracts and zymin are superior to those of antibiotics Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 12 of 15 Abbreviations 11. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 ADFI: Average daily feed intake; ADG: Average daily gain; receptor agonist and basal insulin combination treatment for the AMPs: Antimicrobial peptides; ASs: Antibiotic substitutes; CI: Confidence management of type 2 diabetes: a systematic review and meta-analysis. interval; G/F: Gain: Feed ratio; SD: Standard deviation; SE: Standard error; Lancet. 2014;384:2228–34. SMD: Standard mean difference; SQANR: Study quality assessment on non- 12. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. ruminants; V/C: Villus height:crypt depth ratio Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016;316:313–24. Acknowledgements BX sincerely appreciates his parents for their support through this period. 13. Veroniki AA, Vasiliadis HS, Higgins JP, Salanti G. Evaluation of inconsistency in networks of interventions. Int J Epidemiol. 2013;42:332–45. Authors’ contributions 14. Yin FG, Liu YL, Yin YL, Kong XF, Huang RL, Li TJ, et al. Dietary BX conceived the idea for the study. BX and JF selected the studies for supplementation with Astragalus polysaccharide enhances ileal inclusion. BX, JF, and LZ extracted the data for meta-analysis. BX, LZ and JF digestibilities and serum concentrations of amino acids in early weaned assessed the quality of the included trials. BX and JF performed the statistical piglets. Amino Acids. 2009;37:263–70. analyses. YW and MJ oversaw the development of the study and resolved 15. Chu GM, Jung CK, Kim HY, Ha JH, Kim JH, Jung MS, et al. Effects of bamboo conflicts in the meta-analysis. BX wrote the first draft. YW and MJ critically re- charcoal and bamboo vinegar as antibiotic alternatives on growth vised the paper for important intellectual content. All authors approved the performance, immune responses and fecal microflora population in final draft. YW had final responsibility for the decision to submit the paper fattening pigs. Anim Sci J. 2013;84:113–20. for publication. 16. Chu GM, Lee SJ, Jeong HS, Lee SS. Efficacy of probiotics from anaerobic microflora with prebiotics on growth performance and noxious gas emission in growing pigs. Anim Sci J. 2011;82:282–90. Funding This study was supported by the Key Program of the National Natural 17. Jeong JS, Kim IH. Effect of probiotic bacteria-fermented medicinal plants Science Foundation of China (3163000269), National Special Fund for (Gynura procumbens, Rehmannia glutinosa, Scutellaria baicalensis)as Modern Industrial Technology System (CARS-35), and Major Science and performance enhancers in growing pigs. Anim Sci J. 2015;86:603–9. Technology Special Fund of Zhejiang Province (2015C02022). 18. Kang SN, Chu GM, Song YM, Jin SK, Hwang IH, Kim IS. The effects of replacement of antibiotics with by-products of oriental medicinal plants on growth performance and meat qualities in fattening pigs. Anim Sci J. 2012; Availability of data and materials 83:245–51. All data generated or analysed during this study are included in this 19. Kim J, Kim J, Kim Y, Oh S, Song M, Choe JH, et al. Influences of quorum- published article. quenching probiotic bacteria on the gut microbial community and immune function in weaning pigs. Anim Sci J. 2018;89:412–22. Ethics approval and consent to participate 20. Lan R, Li T, Kim I. Effects of xylanase supplementation on growth Not applicable. performance, nutrient digestibility, blood parameters, fecal microbiota, fecal score and fecal noxious gas emission of weaning pigs fed corn-soybean Consent for publication meal-based diet. Anim Sci J. 2017;88:1398–405. Not applicable. 21. Lei XJ, Lee SI, Kim IH. 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Overall assessment of antibiotic substitutes for pigs: a set of meta-analyses

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10.1186/s40104-020-00534-2
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Abstract

Background: Antibiotic growth promoters are widely used to improve weight gain. However, the abuse of antibiotics can have many negative effects on people. Developing alternatives to antibiotics is an urgent need in livestock production. We aimed to perform a meta-analysis and network meta-analysis (NMA) to investigate the effects of feed additives as potential antibiotic substitutes (ASs) on bacteriostasis, growth performance, intestinal morphology and immunity. Furthermore, the primary, secondary, and tertiary ASs were defined by comparing their results with the results of antibiotics. Results: Among 16,309 identified studies, 37 were summarized to study the bacteriostasis effects of feed additives, and 89 were included in the meta-analysis and NMA (10,228 pigs). We summarized 268 associations of 57 interventions with 32 bacteria. The order of bacteriostasis effects was as follows: antimicrobial peptides (AMPs) ≈ antibiotics>organic acids>plant extracts>oligosaccharides. We detected associations of 11 feed additives and 11 outcomes. Compared with a basal diet, plant extract, AMPs, probiotics, microelements, organic acids, bacteriophages, lysozyme, zymin, and oligosaccharides significantly improved growth performance (P < 0.05); organic acids, probiotics, microelements, lysozyme, and AMPs remarkably increased the villus height:crypt depth ratio (V/C) (P < 0.05); and plant extracts, zymin, microelements, probiotics, and organic acids notably improved immunity (P < 0.05). The optimal AMP, bacteriophage, lysozyme, microelements, oligosaccharides, organic acids, plants, plant extracts, probiotics, and zymin doses were 0.100%, 0.150%, 0.012%, 0.010%, 0.050%, 0.750%, 0.20%, 0.040%, 0.180%, and 0.100%, respectively. Compared with antibiotics, all investigated feed additives exhibited no significant difference in effects on growth performance, IgG, and diarrhoea index/rate (P > 0.05); AMPs and microelements significantly increased V/C (P < 0.05); and zymin significantly improved lymphocyte levels (P < 0.05). Furthermore, linear weighting sum models were used to comprehensively estimate the overall impact of each feed additive on pig growth and health. Conclusions: Our findings suggest that AMPs and plant extracts can be used as primary ASs for weaned piglets and growing pigs, respectively. Bacteriophages, zymin, plants, probiotics, oligosaccharides, lysozyme, and microelements can be regarded as secondary ASs. Nucleotides and organic acids can be considered as tertiary ASs. Future studies should further assess the alternative effects of combinational feed additives. Keywords: Antibiotic substitutes, Dose-effect relationship, Feed additives, Meta-analysis, Network meta-analysis, Pigs * Correspondence: yzwang321@zju.edu.cn National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Nutrition and Feed of Ministry of Agriculture, Key Laboratory of Animal Nutrition and Feed Science of Zhejiang Province, Institute of Feed Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang Province, People’s Republic of China © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 2 of 15 Background Selection criteria Antibiotics are widely used in commercial pig produc- The inclusion criteria were as follows: 1) studies investi- tion for growth promotion and disease prevention [1]. gating the effects of ASs on bacteriostasis; 2) studies in- Subtherapeutic doses of antibiotics are used as feed ad- vestigating the effects of potential ASs as feed additives ditives to promote growth performance, improving aver- on pig growth performance, the villus height:crypt depth age daily gain (ADG) and gain:feed ratio (G/F) through ratio, blood haematology, or diarrhoea; and 3) studies in alterations in intestinal morphology and digestion and which the breeding background was commercial pigs. the suppression of harmful bacteria [2]. However, feed- The exclusion criteria were as follows: 1) studies on anti- ing pigs subtherapeutic doses of antibiotics in the long bacterial effects that did not report minimum inhibitory term leads to the development of antimicrobial resist- concentrations (MICs) or animal-specific bacteria; 2) ance, which is seriously endangering public health [3]. studies without a basal diet or a positive control group; Considering its harm, in 1999, the European Union 3) studies where pig growth was not assessed in stages; banned the use of subtherapeutic doses of antibiotics in 4) studies in which pigs were challenged with pathogenic livestock [3]. In 2017, the FDA reported that antibiotics bacteria, viruses, or lipopolysaccharide; 5) studies that that are important for human medicine could no longer included multiple factors; and 6) studies in which pigs be used for growth promotion in food animals [4]. Not- exhibited an oxidative stress status or a heat stress state. ably, China will completely ban the use of antibiotics in Three investigators (B. Xu, L. Zhu and J. Fu) reviewed feed in 2020 [5]. Therefore, governments and world or- study titles, abstracts, and full texts to ensure studies sat- ganizations have initiated a series of countermeasures isfied the inclusion criteria, and disagreements were re- and encouraged the research and development of anti- solved by two investigators (M. Jin and Y. Wang). biotic substitutes (ASs). However, some questions about ASs are the following. 1) How should ASs be defined? 2) Information extraction What are the effects of many feed additives on bacterio- The following data were extracted from each selected stasis, growth promotion, improvement of intestinal study: author information (first author, year, country), morphology and immunity? 3) What is the optimal dose interventions, control group, breeding background, for these feed additives? 4) Which additive is the most amount of additive, growth stages (weaned piglets, grow- powerful AS? In this study, we performed a set of meta- ing pigs, finishing pigs), sample size, initial and final analyses to investigate the effects of different feed addi- body weight, experimental duration, and outcome data tives regarded as ASs on growth performance, intestinal and corresponding errors, such as standard deviations or morphology and immunity in pigs. Then, we used net- standard errors. The initial body weight of weaned pig- work meta-analyses (NMAs) to assess and compare the lets was lower than 15 kg, the initial body weight of effects of antibiotics and different ASs that are superior growing pigs was more than 15 kg, and the initial body to the basal diet. Finally, we used a linear weighted weight of finishing pigs was more than 45 kg. Outcomes model to evaluate ASs. To the best of our knowledge, were as follows: MIC; ADG; average daily feed intake this study is the first to comprehensively and systematic- (ADFI); G/F; V/C of duodenum, jejunum, and ileum; im- ally define ASs and investigate their effects. mune globulin (Ig), including IgA, IgM, and IgG; lymphocyte levels, diarrhoea rate, and diarrhoea index. Methods For studies involving multiple interventions, we This meta-analysis is reported according to the Preferred extracted data from all relevant interventions. For stud- Reporting Items for Systematic Reviews and Meta- ies involving multiple concentrations, we extracted all Analyses (PRISMA) Statement [6] and the Approach of the experimental groups with an addition amount less Meta-analysis on Nonruminants [7, 8]. than 1%. When extractions from different plant tissues were used, we chose leaf extractions. Search strategy We performed a series of meta-analyses of studies on Study quality assessment potential ASs indexed on PubMed from January 1, 2000 We conducted a study quality assessment on non- to April 31, 2019, and the language was restricted to ruminants (SQANR) to assess the quality of existing English. The complete search strategy is shown in Table studies [7]. The potential risk of bias was derived from S1. Moreover, studies on antimicrobial peptides (AMPs) missing within-group error, repeated reports, informa- were identified by searches in the Antimicrobial Peptide tion completeness, sample size, and experimental ration- Database (http://aps.unmc.edu/AP/, accessed on April ality. Two investigators (B. Xu and L. Zhu) performed 31, 2019). In addition, a manual search was performed independent study quality assessments. to obtain additional potential studies. Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 3 of 15 Statistical analysis outcomes, the feed additives were rated zero in the cor- We aimed to compare which ASs were most suitable in responding outcomes. For growth performance, the terms of bacteriostasis, growth promotion and disease weights of ADG, ADFI, and G/F were 30%, 10%, and resistance effects. First, we compared the effects of basal 60%, respectively. For intestinal morphology, the weights diet with those of feed additive supplementation on a of V/C of the duodenum, jejunum, and ileum were 30%, range of outcomes. We used a random-effects model to 10%, and 60%, respectively. For immunity, the weights of compute the pooled estimate of standardized mean dif- IgA, IgM, IgG, and lymphocyte levels and diarrhoea ference (SMD) with the 95% confidence interval (CI). If index/rate were 10%, 10%, 10%, 10%, 60%, respectively. the 95% CI contained a zero value, that result indicated The overall score was equal to the sum of the score of that there was no difference. The heterogeneity was bacteriostasis, growth performance, intestinal morph- assessed with the I statistic [9] and Cochran’s Q test ology, and immunity effects multiplied by the corre- [10]; I > 50% and P < 0.1 was regarded as a sponding weight (bacteriostasis = 10%; growth heterogeneity substantial heterogeneity. performance = 50%; intestinal morphology = 10%; im- We used sensitivity analyses to remove individual data munity = 30%). Furthermore, we also conducted the values with large deviations from the overall level. If 10 stage scores based on the growth stage to provide a spe- or more trials were available, we conducted subgroup cial strategy. Feed additives that were superior to antibi- analyses and meta-regression to explore potential otics on the stage scores were regarded as primary ASs. sources of heterogeneity. Publication bias was evaluated Feed additives that were superior to antibiotics on one using Egger’s tests, for which the significance level was outcome were regarded as secondary ASs. Finally, the defined at P < 0.1 [11]. Second, if the data were suffi- remaining feed additives were regarded as tertiary ASs. cient, we used the dose-effect model to find the optimal amount of added feed additives. When the same effect Results size occurred at different concentrations, we chose the We identified 16,309 articles in PubMed, of which 89 lowest concentration to reduce the cost. Third, we per- were included in the meta-analyses [14–102], including formed an NMA to further study feed additives that, 10,228 pigs, and 37 were summarized to investigate the when compared with basal diet, had a significant effect antibacterial effects of feed additives [103–139]. The on growth performance. We aimed to compare the characteristics of the studies are shown in Table S2. The growth performance effects of feed additives with the study quality assessed by SQANR is shown in Table S3. optimal amount of ASs added. NMA enables the incorp- The number of studies rated as “high” and “moderate” oration of indirect comparisons constructed from two were 7 and 61, respectively. The mean initial body trials with the same control group. NMA combined all weights of weaned piglets, growing pigs, and finishing available comparisons among ASs and provided a rank- pigs were 7.7 kg, 28.4 kg, and 57.6 kg, respectively. Feed ing of suitable alternatives to antibiotics [12]. To explore additives included plant extracts, plants, probiotics, mi- evidence of within-network inconsistency, the loop- croelements, organic acids, bacteriophages, lysozyme, specific approach was used [13]. zymin, AMPs, nucleotides, and oligosaccharides. The re- We used Stata 14.0 (Stata Corp., USA) to perform the sults of the meta-regression are shown in Table 1. The meta-analysis. We used R 3.6.1 (The R Foundation Con- different growth stages had a significant influence on ference Committee, USA) to examine the dose-effect re- ADFI and G/F (P < 0.05), while the type of feed additives lationship and perform the NMA. and dose did not have a significant effect on the out- comes of interest (P > 0.05). Therefore, when we per- Assessment of antibiotic substitutes formed meta-analyses for growth performance, the We aimed to use a linear weighting sum model to com- growth stages were divided into weaned piglets, growing prehensively assess the efficacy of feed additives. In pigs, and finishing pigs. terms of bacteriostasis, according to the order of occur- rences, 4 bacteria were chosen from gram-positive/nega- Effects of feed additives on bacteriostasis tive bacteria for analysis. We used the rank score of the We summarized 268 associations of 57 interventions interventions to assess their bacteriostasis effects based with 32 bacteria (Table S4). Due to the number of asso- on MICs. We used the P-score value, which evaluates ciations, Staphylococcus aureus and Bacillus subtilis and ranks the strength of the intervention from the were used to represent gram-positive bacteria, and NMA, to grade available interventions. Each P-score Escherichia coli and Pseudomonas aeruginosa were used value of feed additives was subtracted by that of the cor- to represent gram-negative bacteria. Overall, based on responding basal diet, which was performed to guarantee the rank score, bacteriostasis effects of interventions a consistent background. When feed additives were not were as follows (Table 2): AMPs≈ASs> organic acids> included in the NMA or were not observed in the plant extracts> oligosaccharides, which were in Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 4 of 15 Table 1 Regression analyses of the covariates Outcomes Type of feed additive Growth stage Dose Average daily gain 0.986 0.064 0.954 Average daily feed intake 0.105 0.001 0.466 Gain: feed ratio 0.414 0.009 0.082 Villus height: crypt depth of the duodenum 0.474 0.974 0.949 Villus height: crypt depth of the jejunum 0.168 0.514 0.409 Villus height: crypt depth of the ileum 0.021 0.989 0.397 IgA 0.278 0.196 0.597 IgM 0.552 0.591 0.886 IgG 0.354 0.449 0.976 Lymphocytes 0.156 0.661 0.978 Diarrhoea rate 0.587 NA NA Diarrhoea index 0.535 NA 0.053 accordance with bacteriostasis effects of those interven- oligosaccharides, organic acids, plants, plant extracts, pro- tions on gram-positive or gram-negative bacteria. biotics, and zymin were 0.100%, 0.150%, 0.012%, 0.010%, 0.050%, 0.750%, 0.20%, 0.040%, 0.180%, and 0.100%, respectively. Effect of feed additives on growth performance Figure 3 and Table 3 show the comparison between an- As shown in Fig. 1a-i and Table S5, compared with a tibiotics and feed additives based on NMA. Compared basal diet, plants and probiotics had significant effects with those of antibiotics, feed additives that had a positive on ADG at all stages (P < 0.05), plant extracts and zymin significant effect on growth performance compared with improved weaned and growing pigs’ ADG (P < 0.05), the basal diet had no difference in growth performance. and bacteriophages, lysozyme, and AMPs had significant For weaned piglets’ ADG, the P-score values of bacterio- effects on weaned piglets’ ADG (P < 0.05), while only phages, AMPs, lysozyme, and probiotics were greater than microelements and organic acids had no significant ef- those of antibiotics. For weaned piglets’ ADFI, the P-score fect on growing pigs’ ADG (P > 0.05). With regard to value of AMPs was greater than that of antibiotics. For ADFI, probiotics, microelements, organic acids, bacterio- weaned piglets’ G/F, the P-score values of AMPs, zymin, phages, lysozyme, AMPs, and oligosaccharides had a bacteriophages, and oligosaccharides were greater than notable effect on weaned piglets (P < 0.05), while we de- those of antibiotics. For growing pigs’ ADG, the P-score tected that organic acids improved ADFI in growing pigs values of probiotics, plants, and plant extracts were greater (P < 0.05) and that probiotics had a negative impact on than those of antibiotics. For finishing pigs’ ADG, the P- finishing pigs’ ADFI (P < 0.05). In terms of G/F, plants score value of plants was greater than that of antibiotics. remarkably improved weaned and growing pigs’ G/F However, we did not observe a P-score value of feed addi- (P < 0.05), probiotics had a significant effect on weaned tives greater than that of antibiotics for ADFI and G/F of and finishing pigs’ G/F (P < 0.05), and microelements, growing and finishing pigs. organic acids, bacteriophages, lysozyme, zymin, AMPs, and oligosaccharides had considerable effects on weaned piglets’ G/F (P < 0.05). Effect of feed additives on intestinal morphology Figure 2 show the dose-effect relationship among the As shown in Fig. 1j-l and Table S5, probiotics, organic feed additives and growth performance. The optimal doses acids, microelements, lysozyme, AMPs, plant extracts of AMPs, bacteriophages, lysozyme, microelements, significantly improved the V/C of duodenum and ileum Table 2 The rank of bacteriostasis effects Interventions Staphylococcus aureus Bacillus subtilis Escherichia coli Pseudomonas aeruginosa Antimicrobial peptides 1 2 1 2 Antibiotics 2 1 2 1 Organic acids 3 2 3 3 Plant extracts 4 4 5 4 Oligosaccharides 5 5 4 NA Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 5 of 15 Fig. 1 (See legend on next page.) Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 6 of 15 (See figure on previous page.) Fig. 1 Summary forest plots of the effects of feed additives. a Feed additives and weaned piglets’ average daily gain. b Feed additives and growing pigs’ average daily gain. c Feed additives and finishing pigs’ average daily gain. d Feed additives and weaned piglets’ average daily feed intake. e Feed additives and growing pigs’ average daily feed intake. f Feed additives and finishing pigs’ average daily feed intake. g Feed additives and weaned piglets’ gain:feed ratio. h Feed additives and growing pigs’ gain:feed ratio. i Feed additives and finishing pigs’ gain:feed ratio. j Feed additives and villus height:crypt depth ratio of the duodenum. k Feed additives and villus height:crypt depth ratio of the jejunum. i Feed additives and villus height:crypt depth ratio of the ileum. m Feed additives and IgA level. n Feed additives and IgM level. o Feed additives and IgG level. p Feed additives and lymphocytes. q Feed additives and diarrhoea index/rate Fig. 2 Dose-effect relationship between feed additives and growth performance. a Zymin. b Antimicrobial peptides. c Lysozyme. d Microelement. e Oligosaccharides. f Organic acids. g Plant. h Plant extract. i Probiotics Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 7 of 15 Fig. 3 Forest plots of network meta-analysis. a Feed additives and weaned piglets’ average daily gain. b Feed additives and growing pigs’ average daily gain. c Feed additives and finishing pigs’ average daily gain. d Feed additives and weaned piglets’ average daily feed intake. e Feed additives and weaned piglets’ gain:feed ratio. f Feed additives and villus height:crypt depth ratio of the duodenum. g Feed additives and villus height:crypt depth ratio of the ileum. h Feed additives and lymphocytes. i Feed additives and IgG level. j Feed additives and diarrhoea index/rate Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 8 of 15 Table 3 P-score value table Interventions ADG-w ADG-g ADG-f G/F-w ADFI-w V/C (duodenum) V/C (ileum) Lymphocytes IgG Diarrhoea rate/index Antibiotics 0.552 0.589 0.628 0.493 0.723 0.542 0.037 0.366 0.337 0.664 Antimicrobial peptides 0.852 0.000 0.000 0.796 0.820 0.615 0.841 0.000 0.000 0.000 Bacteriophages 0.898 0.000 0.000 0.980 0.299 0.000 0.000 0.000 0.000 0.000 Basal diet 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Lysozyme 0.790 0.000 0.000 0.454 0.412 0.467 0.000 0.000 0.000 0.000 Microelements 0.331 0.000 0.000 0.319 0.568 0.937 0.686 0.000 0.370 0.327 Oligosaccharides 0.524 0.000 0.000 0.622 0.500 0.000 0.000 0.000 0.000 0.000 Organic acids 0.256 0.000 0.000 0.244 0.311 0.519 0.000 0.000 0.000 0.433 Plants 0.235 0.647 0.914 0.286 0.000 0.000 0.000 0.385 0.000 0.000 Plant extracts 0.515 0.646 0.252 0.000 0.000 0.000 0.399 0.856 0.496 0.735 Probiotics 0.625 0.843 0.531 0.371 0.587 0.139 0.000 0.000 0.000 0.000 Zymin 0.334 0.266 0.000 0.755 0.001 0.000 0.000 0.893 0.740 0.807 w Weaned piglets, g Growing pigs, f Finishing pigs in weaned piglets (P < 0.05), while plant extracts notably bacteriostasis, AMPs were observed to have an antibac- improved the V/C of jejunum and ileum in growing and terial effect similar to that of antibiotics. For growth per- finishing pigs (P < 0.05). formance, AMPs, bacteriophages, zymin, and As shown in Fig. 3f-g and Table 3, in weaned piglets, oligosaccharides could replace antibiotics in weaned pig- microelements were greater than AS on V/C of the duo- lets; probiotics, plants, and plant extracts could replace denum and ileum, plant extracts and AMPs were greater antibiotics in growing pigs; and plants could replace an- than AS on V/C of the ileum, and probiotics, organic tibiotics in finishing pigs. With regard to intestinal acids, lysozyme, and AMPs had no difference with AS morphology, AMPs, plant extracts, and microelements on V/C of the duodenum. Specifically, the P-score value were superior to antibiotics. Zymin and plant extracts of microelements and AMPs was greater than that of AS were better than antibiotics at improving immunity. on V/C of ileum. Discussion Effect of feed additives on immunity We used meta-analysis and NMA to define ASs. We de- As shown in Fig. 1m-q and Table S5, plant extracts, tected the associations of 11 feed additives and 11 out- zymin, and microelements were associated with im- comes. The findings suggest that AMPs and plant proved Ig levels (P < 0.05); plants, plant extracts, and extracts can be used as ASs for weaned piglets and zymin were associated with improved lymphocyte levels growing pigs, respectively and that bacteriophages, (P < 0.05); and probiotics, organic acids, zymin, plant ex- zymin, plants, probiotics, oligosaccharides, lysozyme, tracts, and microelements were associated with reduced and microelements can be regarded as secondary ASs diarrhoea index/rate (P < 0.05). (Fig. 4). Based on current data, the optimal AMPs, bac- Figure 3h-j and Table 3 show that compared with ASs, teriophage, lysozyme, microelements, oligosaccharides, zymin significantly improved lymphocyte levels. In terms organic acids, plants, plant extracts, probiotics, and of P-score value, plant extracts and zymin were better zymin doses were 0.100%, 0.150%, 0.012%, 0.010%, than ASs at reducing and alleviating diarrhoea; plant ex- 0.050%, 0.750%, 0.20%, 0.040%, 0.180%, and 0.100%, tracts, zymin, and plants were better than ASs at in- respectively. creasing lymphocyte levels; and plant extracts, zymin, To determine whether a feed additive is an eligible AS, and microelements were better than ASs at increasing it is necessary to measure its alternative effects on IgG levels. growth promotion, intestinal morphology improvement, bacteriostasis and immunity. Chief among these effects Feed additives assessment is growth promotion dependent on G/F. Feed additives Table 4 shows the assessment score of feed additives. enhance growth performance through improving intes- The findings suggest that AMPs could be regarded as tinal morphology, reducing pernicious bacteria, reducing primary ASs in weaned piglets and that plant extracts anti-nutritional factors, or improving nutrient digestibil- could be considered ASs in growing pigs. Secondary ASs ity. We did not investigate the effects of feed additives included bacteriophages, zymin, plants, probiotics, oligo- on the latter two mechanisms because antibiotics have saccharides, lysozyme, and microelements. In terms of not been reported to have these effects in the primary Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 9 of 15 Table 4 Assessment score of the effects of the interventions on outcomes Interventions Bacteriostasis Growth performance Growth performance Growth performance Intestinal Immunity Sum Sum Sum Sum (weaned piglets) (growing pigs) (finishing pigs) morphology (overall) (weaned (growing (finishing piglets) pigs) pigs) Antibiotics 76.00 53.33 17.66 18.85 18.48 46.89 68.43 50.18 32.34 32.94 AMPs 76.00 81.54 0.00 0.00 68.90 0.00 55.26 55.26 14.49 14.49 Probiotics 0.00 46.85 25.30 15.92 4.18 0.00 44.45 23.84 13.07 8.38 Bacteriophages 0.00 88.74 0.00 0.00 0.00 0.00 44.37 44.37 0.00 0.00 Zymin 0.00 55.33 7.99 0.00 0.00 64.74 51.08 47.09 23.42 19.42 Plants 0.00 24.18 19.42 27.42 0.00 3.85 36.67 13.25 10.86 14.87 Plant extracts 32.00 15.44 19.37 7.55 23.96 57.59 44.05 30.59 32.56 26.65 Microelements 0.00 34.75 0.00 0.00 69.23 23.30 31.29 31.29 13.91 13.91 Oligosaccharides 19.00 58.04 0.00 0.00 0.00 19.39 36.73 36.73 7.72 7.72 Lysozyme 0.00 55.07 0.00 0.00 14.02 0.00 28.94 28.94 1.40 1.40 Organic acids 56.00 25.44 0.00 0.00 15.56 25.96 27.66 27.66 14.94 14.94 Basal diet 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Bold type values for interventions indicates that their effect was superior or equal to that of antibiotics AMPs Antimicrobial peptides Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 10 of 15 Fig. 4 Summary of findings of meta-analyses studies included in this meta-analysis. We measured in- guarantee intestinal integrity and barrier function to testinal morphology through V/C, as V/C is positively protect from bacterial and toxin infections, which may correlated with nutrient absorption capacity, such as that be due to upregulation of the expression of tight junc- of carbohydrates and fatty acids [140]. We measured im- tion proteins [102, 142, 143]. AMPs are critical compo- munity through Ig and lymphocyte levels and the diar- nents of the innate immune system, but evaluations of rhoea index/rate, which are the secondary phenotype immune outcome associations were not conducted due outcomes. Consequently, antimicrobial and anti- to limitation by the lack of data. 2) Plant extracts can inflammatory properties also contribute to promotion of improve immunity (IgA, IgM, IgG, and lymphocyte growth performance. Bacteriostasis is measured by levels) through their antimicrobial and anti- in vitro MIC experiments that are considered to provide inflammatory properties [65]. Changing the microbiota reliable and stable results. Meanwhile, bacteriostasis ef- and regulating intestinal permeability contribute to their fects of interventions are linked to antidiarrhoeal proper- antidiarrhoeal properties. The effects of plant extracts ties to some extent. on growth performance (ADG and G/F) exhibit substan- Our findings, together with mechanisms and possible tial heterogeneity because numerous plant extracts were speculations reported in articles, provide rational inter- included, and there is no feasible subgroup. Growth pro- pretations for growth promotion, immunity enhance- motion associated with improving nutrient digestibility ment, and antidiarrhoeal properties for ASs. and amino acid metabolism also occurred [14]. Our pre- Interpretations of primary ASs are as follows. 1) AMPs analyses identified a subgroup based on whether it is a can promote growth performance (ADG, ADFI, G/F) by plant essential oil, which cannot influence the substantial improving intestinal morphology (V/C of the duodenum heterogeneity. A plant essential oil inhibits the opening and ileum), nutrient digestibility, and antimicrobial ac- of calcium channels and stimulates that of potassium tivity [141]. AMPs can improve the duodenum and channels in smooth muscles, which increases motility of ileum by stimulating intestinal epithelial cell prolifera- the small intestine and produces a significant shortening tion because AMP receptors may be rich in the duode- of the food transit time [64, 144, 145]. However, several num and ileum [142]. AMPs are more likely to studies have suggested that a positive effect of plant Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 11 of 15 essential oils seems to occur in challenged piglets rather on lymphocyte level enhancement. All of the ASs have than healthy piglets [64, 98]. Future meta-analyses potential uses in animal health. However, the high cost should study the effects of plant extracts in pigs with dif- for many ASs, such as AMPs and bacteriophages, may ferent health statuses and the main sources of hetero- be prohibitive for animal use. Future studies should fur- geneity based on a feasible subgroup. ther investigate high-efficiency bacterial engineering, Interpretations of secondary ASs are as follows. 1) purification technology, and the design of novel AMPs Zymin can improve growth performance (ADG and G/F), to expedite progress in reducing and alternating antibi- enhance immunity (IgA, IgM, IgG, and lymphocyte levels), otics. Commitment to substantial subsidies might be and reduce and relieve diarrhoea. The reason for the needed to incentivize development of ASs for animal above phenotype is that zymin can increase digestive en- health, in which their use could contribute to a reduc- zyme activities and nutrient digestibility and decrease tion in antibiotic use [146]. Escherichia coli and Salmonella populations [100]. 2) A major strength of the present study is that we inves- Lysozyme can increase growth performance (ADG, ADFI, tigated all feed additives mentioned as ASs, which thus and G/F), improve intestinal morphology (V/C of the duo- comprehensively demonstrated the effects of each feed denum and jejunum), and increase lymphocyte levels. additive on outcomes for which producers and animal Lysozyme increases protein deposition and decreases the nutritionists are interested. A major innovation is that turnover rate of intestinal epithelial cells [25, 85]. 3) Bacte- we used a rational approach, the linear weighting sum riophages promote growth performance (ADG, ADFI, and model, to estimate the overall impact of each feed addi- G/F) through a reduction in coliforms and Clostridium tive and antibiotics on pig health and growth. The limi- [32]. 4) Plants can improve growth performance (ADG tation of the present study is that we failed to further and G/F) and enhance immunity (IgG and lymphocyte investigate the main sources of heterogeneity of every levels). 4) Plants, specifically herbs, have antioxidant activ- AS and effects of combinational feed additives, such as ity and pharmaceutical effects, providing additional bene- combinations of plant essential oils and organic acids fits. Our previous meta-analysis indicated that fermented and those of prebiotics and probiotics. Some ASs were plants promoted growth performance and digestibility at downgraded due to lack of some outcomes data. Future all stages [8]. Additionally, fermented plants significantly studies should investigate effects of feed additives on improved marbling and decreased redness of the meat in various aspects beyond growth performance. finishing pigs but had no effect on lightness, yellowness, drip loss, and flavour [7]. 5) Probiotics can increase Conclusions growth performance (ADG, ADFI, G/F) by improving nu- Here, we recommend supplementing 0.1% AMPs in the trient digestibility and the microbiota structure, enhancing weaned stage, adding 0.04% plant extract in the growing osmotic balance and reducing pernicious bacteria to con- stage and feeding 0.2% plants, especially fermented plants, tribute to the remission of diarrhoea [31]. Immunity pro- in the finishing stage, which may have an approximate ef- motion of probiotics was not observed; hence, the effect of fect compared with antibiotics on all stages. Our research probiotics on immunity is unclear. 6) Oligosaccharides is the first to define and overall assess ASs through meta- can increase growth performance (ADG, ADFI, and G/F) analysis and NMA. Although further research should sup- and have no association with intestinal morphology, plement unobserved data for a more comprehensive as- lymphocyte levels, or the diarrhoea rate. We speculate that sessment, our research clearly and systematically oligosaccharides may increase nutrient digestibility, and investigates AS candidates. However, it is important to the categories of oligosaccharides are related to the diar- note that there is no single alternative to completely sub- rhoea rate. 7) Microelements can increase growth per- stitute antibiotics in feed, and a combination of different formance (ADG, ADFI, and G/F), improve immunity (IgG alternatives to antibiotics may be the most promising levels), and reduce the risk of diarrhoea, which are linked method to reduce or replace antibiotics in animal feeds. to their bacteriostatic properties and improvement of the Future meta-analyses should further study the alternative microbiota structure [74]. effects of combinational feed additives. According to the results of the NMA, the effects of all feed additives investigated showed no significant differ- Supplementary Information ence from those of antibiotics on ADG, ADFI, IgG, and The online version contains supplementary material available at https://doi. diarrhoea rate or index. The effects of bacteriophages org/10.1186/s40104-020-00534-2. are superior to those of antibiotics on weaned piglets’ G/F; the effects of microelements, plant extracts, and Additional file 1: Table S1. Search strategy. Table S2. Characteristics of studies. Table S3. Study quality assessment. Table S4. Minimal AMPs are superior to those of antibiotics on improve- inhibitory concentration table (μg/mL). Table S5. Meta-analyses and sub- ment of intestinal morphology; and the effects of plant group analyses. extracts and zymin are superior to those of antibiotics Xu et al. Journal of Animal Science and Biotechnology (2021) 12:3 Page 12 of 15 Abbreviations 11. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 ADFI: Average daily feed intake; ADG: Average daily gain; receptor agonist and basal insulin combination treatment for the AMPs: Antimicrobial peptides; ASs: Antibiotic substitutes; CI: Confidence management of type 2 diabetes: a systematic review and meta-analysis. interval; G/F: Gain: Feed ratio; SD: Standard deviation; SE: Standard error; Lancet. 2014;384:2228–34. SMD: Standard mean difference; SQANR: Study quality assessment on non- 12. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. ruminants; V/C: Villus height:crypt depth ratio Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016;316:313–24. Acknowledgements BX sincerely appreciates his parents for their support through this period. 13. Veroniki AA, Vasiliadis HS, Higgins JP, Salanti G. Evaluation of inconsistency in networks of interventions. Int J Epidemiol. 2013;42:332–45. Authors’ contributions 14. Yin FG, Liu YL, Yin YL, Kong XF, Huang RL, Li TJ, et al. Dietary BX conceived the idea for the study. BX and JF selected the studies for supplementation with Astragalus polysaccharide enhances ileal inclusion. BX, JF, and LZ extracted the data for meta-analysis. BX, LZ and JF digestibilities and serum concentrations of amino acids in early weaned assessed the quality of the included trials. BX and JF performed the statistical piglets. Amino Acids. 2009;37:263–70. analyses. YW and MJ oversaw the development of the study and resolved 15. Chu GM, Jung CK, Kim HY, Ha JH, Kim JH, Jung MS, et al. Effects of bamboo conflicts in the meta-analysis. BX wrote the first draft. YW and MJ critically re- charcoal and bamboo vinegar as antibiotic alternatives on growth vised the paper for important intellectual content. All authors approved the performance, immune responses and fecal microflora population in final draft. YW had final responsibility for the decision to submit the paper fattening pigs. Anim Sci J. 2013;84:113–20. for publication. 16. Chu GM, Lee SJ, Jeong HS, Lee SS. Efficacy of probiotics from anaerobic microflora with prebiotics on growth performance and noxious gas emission in growing pigs. Anim Sci J. 2011;82:282–90. Funding This study was supported by the Key Program of the National Natural 17. Jeong JS, Kim IH. Effect of probiotic bacteria-fermented medicinal plants Science Foundation of China (3163000269), National Special Fund for (Gynura procumbens, Rehmannia glutinosa, Scutellaria baicalensis)as Modern Industrial Technology System (CARS-35), and Major Science and performance enhancers in growing pigs. Anim Sci J. 2015;86:603–9. Technology Special Fund of Zhejiang Province (2015C02022). 18. Kang SN, Chu GM, Song YM, Jin SK, Hwang IH, Kim IS. The effects of replacement of antibiotics with by-products of oriental medicinal plants on growth performance and meat qualities in fattening pigs. Anim Sci J. 2012; Availability of data and materials 83:245–51. All data generated or analysed during this study are included in this 19. Kim J, Kim J, Kim Y, Oh S, Song M, Choe JH, et al. Influences of quorum- published article. quenching probiotic bacteria on the gut microbial community and immune function in weaning pigs. Anim Sci J. 2018;89:412–22. Ethics approval and consent to participate 20. Lan R, Li T, Kim I. Effects of xylanase supplementation on growth Not applicable. performance, nutrient digestibility, blood parameters, fecal microbiota, fecal score and fecal noxious gas emission of weaning pigs fed corn-soybean Consent for publication meal-based diet. Anim Sci J. 2017;88:1398–405. Not applicable. 21. Lei XJ, Lee SI, Kim IH. 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Published: Jan 7, 2021

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