Joana Castro1*
Maria Margarida Barros1
Daniela Araújo1
Ana Maria Campos1
Ricardo Oliveira1,2,3
Sónia Silva1,4,5
Carina Almeida1,2,3,4,5*- 1National Institute for Agrarian and Veterinarian Research (INIAV), Vila do Conde, Portugal
- 2LEPABE – Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Porto, Portugal
- 3ALiCE – Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal
- 4Centre of Biological Engineering, Braga, Portugal
- 5LABBELS – Associate Laboratory, Braga/Guimarães, Portugal
Enteric colibacillosis is a common disease in nursing and weanling pigs. It is caused by the colonization of the small intestine by enterotoxigenic strains of Escherichia coli (ETEC) that make use of specific fimbria or pili to adhere to the absorptive epithelial cells of the jejunum and ileum. Once attached, and when both the immunological systems and the gut microbiota are poorly developed, ETEC produce one or more enterotoxins that can have local and, further on, systemic effects. These enterotoxins cause fluid and electrolytes to be secreted into the intestinal lumen of animals, which results in diarrhea, dehydration, and acidosis. From the diversity of control strategies, antibiotics and zinc oxide are the ones that have contributed more significantly to mitigating post-weaning diarrhea (PWD) economic losses. However, concerns about antibiotic resistance determined the restriction on the use of critically important antimicrobials in food-producing animals and the prohibition of their use as growth promoters. As such, it is important now to begin the transition from these preventive/control measures to other, more sustainable, approaches. This review provides a quick synopsis of the currently approved and available therapies for PWD treatment while presenting an overview of novel antimicrobial strategies that are being explored for the control and treatment of this infection, including, prebiotics, probiotics, synbiotics, organic acids, bacteriophages, spray-dried plasma, antibodies, phytogenic substances, antisense oligonucleotides, and aptamers.
Introduction
Post-weaning period is a critical phase in the pig's life because the immune system is immature, and the sow milk removal, and consequent interruption of nutritive intake of immunoglobulin present in the milk, increases pigs' susceptibility to microbial infections, especially in the current lines of hyperprolific sows (1). As such, piglets are highly susceptible to Post-Weaning Diarrhea (PWD), a disorder that often affects pigs during the first 2 weeks of weaning and is characterized by sudden death or diarrhea and growth retardation in surviving piglets (2). PWD is one of the most serious threats to the swine industry worldwide, with episodes reaching mortality rates of 20 to 30% (2) and is associated with the proliferation of enterotoxigenic Escherichia coli (ETEC) in the pig intestine (3).
ETEC are gram-negative, flagellated bacilli and most pathogenic strains form smooth to mucoid colonies. Virulence factors include fimbriae, enterotoxins, endotoxins, and capsules. Fimbriae are the small hair-like structures on the bacterial surface that allow attachment to specific receptors on the surface of mucosal enterocytes of the small intestine, being crucial in the colonization process. Pathogenic strains also produce one or more enterotoxins, which are exotoxins elaborated locally in the small intestine that can have either local or systemic effects (1). There are 5 common, antigenically different fimbriae types found in pigs: F4 (K88), F5 (K99), F41, F6 (987P), and F18. The first 4 fimbriae types are responsible for mediating adhesion in neonates, while F18 is not associated with neonatal colibacillosis but is common in postweaning colibacillosis as is F4. It is also important to note that hemolysis is a common trait for pathogenic F4 and F18 isolates. Furthermore, the virulence of ETEC can also be characterized by the production of heat-labile toxins (LT), heat-stable toxin A (StA), heat-stable toxin B (StB), and verotoxin (shiga-like toxin, STX). The first three act locally interfering with electrolytes fluid increasing the fluid secretion to the lumen leading to diarrhea while verotoxin is responsible for the systemic vascular effects of edema disease (4).
As an attempt to promote health and growth performance, different approaches have been used to prevent PWD, including mostly dietary supplementation, such as prebiotics and probiotics; genetic breeding for ETEC-resistant herds; administration of growth promotors; and vaccines (5, 6). It is important to highlight that growth promoters and zinc oxide (7), have been (or are being) banned from animal husbandry. Also, antibiotics use is now more restricted because of antimicrobial resistance observed in ETEC and potential consequences for human health (1). These restrictions are strongly affecting the control of PWD (8). This makes room for innovative, antibiotic-free, intervention/control strategies that can control ETEC infections.
Antibiotics used to treat PWD
Antibiotic therapy is required in many cases of enteric colibacillosis, being the main antimicrobials used for the treatment of enteric colibacillosis listed in Supplementary Table 1. According to Luppi, the choice of antibiotics for the treatment of PWD must consider several aspects (1): (i) the local of infection that must be located mainly in the small intestine; (ii) the empiric treatments based on the knowledge of the individual herd and local data on the resistance pattern; and (iii) the evaluation of the isolated strain's antimicrobial susceptibility. However, as an outbreak of colibacillosis frequently requires quick actions, the use of antibiotics almost always precedes the results of the resistance pattern (1, 9).
Also, it has been established that the antibiotic should be administered to all animals exhibiting signs referable to colibacillosis and sick pigs must be treated parenterally since they eat and drink very little. In practice when mortality occurs, a metaphylactic approach is applied wherein all animals in the pens are treated (1, 9–11). Of note that guidelines for the prudent use of antimicrobials in veterinary medicine (2015/C/ 299/04) published in the official journal of the European Union considered the use of metaphylaxis and stated that antimicrobial metaphylaxis should be prescribed only when there is a real need for treatment and that the veterinarian should justify and document the treatment on the basis of clinical findings on the development of a disease in herd or flock (10).
Current measures used to prevent PWD in piglets
As described above, alternatives to antibiotic therapy are some preventive approaches that have been applied to avoid the development of colibacillosis illness. Those therapies are essentially based on genetic breeding, vaccines, and zinc oxide administration, as illustrated in Figure 1.
Figure 1. Current therapies used to control PWD in piglets.
Genetic breeding for ETEC-resistant swine herds
The advances in molecular approaches sparked the interest of the scientific community in obtaining genetic breeding for ETEC-resistant herds. As mentioned above, the pig population presents specific receptors on the intestinal epithelial cells for the F4 and F18 fimbriae, which are the primary virulence factors carried by E. coli responsible for PWD. However, certain pigs do not have receptors for F4 and F18 adhesins and are thus resistant to infection by these fimbriae. Therefore, an attractive approach to preventing PWD is increasing the presence of both the F18 and F4 resistance loci in the pig population through breeding (12). Despite all the efforts, there are more insights about F18 resistance loci than about F4 resistance loci. In this sense, it was employed a molecular test for the large-scale selection of resistant pigs for breeding, using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. In brief, using this approach, we can detect polymorphisms in the FUT1 gene in a piglet, that encodes an α-(1,2) fucosyltransferase protein. It is important to highlight that FUT1 polymorphisms are responsible for controlling the expression of the receptor for F18 fimbriated E. coli in the intestinal mucosa. Regarding the F4 resistance loci, by using PCR-RFLP approach (13), it is also possible to detect polymorphisms in the MUC4 gene in a piglet, that encodes for a membrane-bound-O-glycoprotein that is extensively expressed on the surface of gastrointestinal epithelial cells in which protects and lubricates the epithelial surfaces (14, 15). As such, using this approach, it was possible to select the piglets that do not present these receptors for the E. coli F18 and F4 adhesion (12, 16, 17).
Vaccines
It is known that newborn pigs can establish immune reactions against mucosal antigens (18, 19). However, the newly weaned pigs need active intestinal mucosal immunization due to the lack of passive lactogenic immunity. Therefore, these vaccines can induce this protective effect by activating the mucosal immune system and antigen-specific immunoglobulins (A and M) responses (20, 21). Thus, 3 main types of vaccines have been used on pigs. Firstly, intramuscular injectable vaccines stimulate systemic immunity by increasing circulating antibodies to keep intestinal bacteria levels low enough to be non-pathogenic (21). Secondly, an oral administration of live attenuated or live wild-type non-enterotoxigenic E. coli strains with fimbrial adhesins can stimulate intestinal colonization by this E. coli by inducing the secretion of intestinal antibodies, and finally blocks the adherence of ETEC (22). For example, a single dose of a commercial vaccine (Coliprotec® F4) showed a significant reduction in the incidence of diarrhea, ileum colonization by F4-ETEC, and fecal shedding of F4-ETEC after the heterologous challenge at 7 and 21 days post-vaccination (23). Lastly, the oral administration of purified fimbria results in a specific mucosal immune response in the intestines and may cause a significant decrease in fecal excretion of the pathogenic E. coli (21, 24). Supplementary Table 2 shows the current vaccines available in the market.
Zinc oxide and end-of-use policies
Pig producers have been successful with weaning at an early age with limited signs of gastrointestinal disease shortly after weaning (25, 26). In fact, it has been described that feed containing between 2,400 and 3,000 ppm of zinc reduces diarrhea and mortality, and improves the growth of piglets. However, in the last decade, several studies have centered attention on heavy metals used in animal farming and possible mechanisms that could promote the spread of antibiotic resistance via co-selection (1). Furthermore, the use of zinc oxide possesses an environmental hazard, as most of the zinc is excreted with the feces and through manuring, it accumulates in soil (27).
Recently, the Committee for Medicinal Products for Veterinary Use (CVMP) of the European Medicines Agency set the referral procedure for veterinary medicinal products containing zinc oxide to be administered orally to food-producing species. The Committee adopted an opinion by consensus determining that the benefits of zinc oxide for the prevention of diarrhea in pigs do not outweigh the risks to the environment. The CVMP emphasized that there is a risk of co-selection for resistance related to the use of zinc oxide, but at the present time, that risk is not quantifiable. Accordingly, medicinal zinc oxide has been prohibited in the European Union effectively coming into force no later than June 2022 (28, 29). Consequently, there is an urgent need for adopting novel strategies for the control of PWD.
Alternative strategies to current therapies for PWD control
The increasing evidence that the current approaches to treat/prevent PWD raise problems associated with antimicrobial resistance or the risks to the environment sparked the interest of the scientific community in exploring new eco-friendly prophylactic or antimicrobial tools. Thus, in recent years, studies of anti-enteric colibacillosis agents started to include prebiotics, probiotics, synbiotics, organic acids, phytogenic substances, bacteriophages, spray-dried plasma, antibodies, antisense oligonucleotides, and aptamers (see Table 1).
Table 1. Benefits and limitations of the major alternative agents for the control of post-weaning diarrhea (PWD) based on studies published since 2010.
Prebiotics, probiotics, synbiotics
Maintaining a healthy gut is crucial for a pig to digest and absorb dietary nutrients efficiently (76). As such, prebiotics, which are non-digestible feed ingredients positively affecting the host by stimulating the growth and/or the activity of a limited number of bacteria in the gastrointestinal microbiota (5), can be used to modulate the gut microbiota. Probiotics are defined as viable microorganisms that when ingested in sufficient amounts reach the intestine in an active state where they can exert positive effects on the host's health status (77, 78). In last, synbiotics are defined as a mixture comprising live microorganisms (probiotics) and substrate(s) (prebiotics) selectively utilized by host microorganisms that confer a health benefit on the host (79). According to Girard and colleagues, this combination improves the survival rate and favors the growth and activity of beneficial microorganisms in the gut of the piglets (51). Among the prebiotics and probiotics evaluated for the control of ETEC colonization in pigs, inulin and Lactobacillus plantarum are the ones that have been more systematically assessed, either individually or in combination (see Table 1). Overall, the results of the different studies indicate that these strategies can reduce ETEC colonization and relieve some symptoms. However, a few studies also have found no significant differences between the tested probiotics and the respective controls (41). This is not surprising as the effect of these approaches is most probably highly dependent on the strains, concentrations applied, animal age, and the strategies used for the delivery in the gut. Further studies are necessary to systematically evaluate the real potential of those approaches for controlling ETEC.
Organic acids
Organic acids (OA) are considered powerful antimicrobials, which are extensively used as feed additives in pig nutrition, in particular the short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) (80). Because of their antimicrobial effects, OA are able to prevent the colonization and proliferation of pathogenic bacteria (52) and their antimicrobial effects are related to their action on cellular metabolism and their ability to deplete cellular energy. Normally, a reduction in pH of the diet can happen because of the dissociation of OA, which is favorable for the growth of lactic acid bacteria (55). In contrast, the non-dissociated OA can act as an antimicrobial agent, since it can penetrate the cell wall of bacteria and interfere with normal physiology (81). In the pigs with a diet containing OA, gastrointestinal health is improved, reducing the incidence to develop diarrhea as described in Table 1.
Phytogenic substances
Plant-derived compounds are also studied as alternative growth promoters in pigs, as is the case of phytogenic feed additives (82–84). These compounds are added to the pigs' diet, due to their positive effects on animal growth and health, since they present antibacterial, anti-inflammatory, and antioxidant properties (59). Examples of substances used as phytogenic feed additives include essential oils, herbs, and spices (see Table 1). Recent studies reported the positive results of these compounds in pig health, such as growth performance and nutrient digestibility (82). Moreover, to improve its performance, the combination of different phytogenic substances has been explored in order to study the synergistic or complementary activity on pig health.
Bacteriophages
Bacteriophages are non-hazardous self-replicating agents that increase their numbers as they destroy specific target bacteria (85). It is noteworthy, that groundbreaking work in bacteriophage therapy addressing colibacillosis in swine was performed in the 1980s by Smith and Huggings (86–88). After 2 decades, efforts conducted by Jamalludeen and colleagues showed that the 6 tested bacteriophages exhibited prophylactic activity against diarrhea and shedding of the challenge ETEC following experimental oral infection of pigs (89). More recently, some studies on dietary supplementation of bacteriophages for E. coli have been conducted aiming to improve the performance, feed efficiency, and fecal microbiota in pigs as mentioned in Table 1.
Spray-dried animal plasma
Spray-dried plasma (SDP) is a protein-rich product from the industrial fractionation of blood from healthy animals (90). To obtain SDP, blood is collected with an anticoagulant and centrifuged to separate the blood cells. Plasma is then concentrated and spray-dried under high pressure to achieve a minimum of 80°C throughout its substance. Of note that through this procedure, proteins preserve most of their biological activity (91). Multiple modes of action of SDP have been described, including either directly influencing the immune inflammatory response locally or systemically, and/or through the indirect modification of beneficial microbial populations (90). As such, in the past decades, several studies have been conducted to assess the role of SDP in swine production and calf milk replacers to improve performance, feed efficiency, and swine health (92, 93). Furthermore, some evidence suggests that SDP supplementation can modify the composition of the intestinal microbiota (92). More recently, few researchers have also conducted experiments in this field, as depicted in Table 1.
Specific egg yolk antibodies
Chicken IgY, known as the immunoglobulin Y (IgY), is an antigen-specific antibody produced by B lymphocytes and accumulated in the yolk of chicken eggs (94). Due to its high specificity, this approach has attracted considerable attention for the treatment of gastrointestinal infections. Importantly, Wang and colleagues proved that IgY was able to significantly inhibit the growth of E. coli K88 by blocking the binding of E. coli to small intestinal mucus (73). Nevertheless, the activity of orally administered IgY can reduce rapidly under gastric conditions. Hence several nanotechnology applications, such as chitosan-alginate microcapsules, methacrylic acid copolymers, liposomes, polymeric microspheres multiple emulsification and more recently hydrogel-carbon nanotubes composites, have been used to protect IgY from hydrolysis by gastric enzymes (72), as described in Table 1.
Porcine and bovine forms of lactoferrin
Lactoferrin (LF), an iron-binding glycoprotein, is found in the colostrum, milk, and other secretions of many mammalian species. Lactoferrin is indicated to have several physiologic functions, including regulation of iron absorption, and it has an important role in host defense, including broad-spectrum antibacterial effects (74, 95). Recently, efforts have been conducted to assess if lactoferrin can be used to control PWD, as shown in Table 1.
Antisense oligonucleotides
An alternative antibacterial strategy to treat colibacillosis is the development of antisense oligonucleotides therapy against E. coli (75, 96–98). Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid sequences that are complementary to a target mRNA. They can down-regulate gene expression by binding to their target mRNA and inhibiting its translation through the creation of a steric block to ribosome binding and/or by facilitating RNase H recruitment and RNA cleavage. ASOs have been proposed to enter into cells through high-and low-binding plasma protein receptors on the cell surface, resulting in ASO compartmentalization into lysosomes and endosomes. Through a largely unknown mechanism, ASOs are released from the vesicles into the cytoplasm where they can freely move in and out of the nucleus. Upon entry into the nucleus, ASOs can bind directly to mRNA structures and prevent the formation of the 5'-mRNA cap, modulate alternative splicing, and recruit RNaseH to induce cleavage. ASOs in the cytoplasm can also bind directly to the target mRNA and sterically block the ribosomal subunits from attaching and/or running along the mRNA transcript during translation. ASOs can also be designed to directly bind to microRNA (miRNA) sequences and natural antisense transcripts (NATs), thereby prohibiting miRNAs and NATs from inhibiting their own specific mRNA targets (99). Typically, ASOs are synthesized from nucleotide analogs in order to enhance the affinity for RNA and decrease the susceptibility to cellular nucleases. A key advantage of the antisense approach is that it should be possible to rationally design an antisense oligonucleotide to target any mRNA. If the target mRNA encodes an essential protein, then the ASOs may have antibacterial properties. A number of ASOs, that target a variety of mRNAs E. coli genes (Supplementary Table 3), have been reported to have antibacterial activity in vitro and provide a proof of concept for further exploitation to test in vivo to control colibacillosis.
Aptamers
Aptamers are quickly gaining significance as alternative biorecognition molecules to antibodies in targeted therapy (100). They are able to bind (i.e., diagnosis tool) and inhibit the function (i.e., therapeutic tool) of other biomolecules such as virulence factors normally associated with ETEC (i.e., toxins and fimbriae), as well as being used as carriers for other biochemical compounds (i.e., drug-delivery tool) (101). Sometimes referred to as “synthetic antibodies”, aptamers are typically single-stranded DNA or RNA oligonucleotides with defined secondary motifs (e.g., loop, stem, or G-quadruplex) that confer them complex three-dimensional structures and the ability to recognize and bind targets with exceptional binding affinity and specificity to their target (102). The aptamer-target interaction results mainly from the compatibility of physical structures and/or the stacking of chemical groups that are stabilized by hydrogen bonds, electrostatic interactions, hydrophobic effects, π-π stacking, Van der Waals forces, or combinations of these different forces (103). As a diagnostic or drug-delivery tool, aptamers can be chemically linked to other compounds (e.g., fluorophores or drugs) that will have a direct action on the target when the binding complexes are formed. As a therapeutic tool, the physicochemical binding can block receptor-binding domains of the target from interacting with receptors and, thus, neutralize their action by blocking vital proteins on the cell membrane and/or cytoplasmic proteins such as virulence factors normally associated with ETEC (i.e., toxins and fimbriae) (104). Aptamers are isolated by a repetitive interactive selection procedure known as Systematic Evolution of Ligands by EXponential enrichment (SELEX). This methodology follows a standard pattern that comprises a large pool of random sequences subjected to successive steps of (1) binding, (2) partition and (3) amplification to obtain a pool of molecules enriched for those with high affinity to the target (105). Some aptamers have been reported to be specific for E. coli and their virulence factors (Supplementary Table 4) providing a proof of concept for further exploration of specific aptamers for the diagnosis and treatment of colibacillosis. Aptamers for E. coli K88 fimbriae have been reported (106) and are of particular relevance as this is a high prevalent ETEC fimbria-type that allows adhesion to the animal gut cells. However, until now the potential of aptamers to block fimbriae-mediated adhesion in animal models has not been evaluated.
Conclusion and future directions
Swine colibacillosis prevention and control therapies are facing a huge challenge because of the recent policies on the pharmacological dose of zinc oxide and antibiotic use. While these policies are inevitable and necessary to deal with the problem of antimicrobial resistance and environmental sustainability; the need for effective strategies to control infectious disease in pigs' production is a pressing matter. By properly addressing the virulence factors of ETEC, novel strategies will hopefully arise with more eco-friendly approaches to control PWD and more in line with the public health concerns regarding antimicrobial resistance.
Author contributions
JC, MB, DA, AC, RO, and SS prepared the first draft of the manuscript. JC and CA defined the content of the manuscript. All authors critically reviewed and approved the final version of the article.
Funding
Research in swine colibacillosis in CA Laboratory was supported by funding from the Fundação para a Ciência e a Tecnologia (FCT) Strategic Project Unit PTDC/CVT-CVT/4620/2021. It was also partially funded by LA/P/0045/2020 (ALiCE), UIDB/00511/2020 and UIDP/00511/2020 (LEPABE), funded by national funds through FCT/MCTES (PIDDAC), by FCT under the scope of the strategic funding of UIDB/04469/2020 unit (CEB), and by LABBELS-Associate Laboratory in Biotechnology, Bioengineering, and Microelectromechnaical Systems, LA/P/0029/2020.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fvets.2022.981207/full#supplementary-material
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Keywords: enteric colibacillosis, post-weaning diarrhea, gut microbiome, antibiotic therapy, zinc oxide, novel antimicrobial approaches
Citation: Castro J, Barros MM, Araújo D, Campos AM, Oliveira R, Silva S and Almeida C (2022) Swine enteric colibacillosis: Current treatment avenues and future directions. Front. Vet. Sci. 9:981207. doi: 10.3389/fvets.2022.981207
Received: 29 June 2022; Accepted: 10 October 2022;
Published: 28 October 2022.
Edited by:
Mariangela Caroprese, University of Foggia, ItalyReviewed by:
Eric R. Burrough, Iowa State University, United StatesYanhong Liu, University of California, Davis, United States
Copyright © 2022 Castro, Barros, Araújo, Campos, Oliveira, Silva and Almeida. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Joana Castro, joana.castro@iniav.pt; Carina Almeida, carina.almeida@iniav.pt