Nutrition strategies to control post-weaning diarrhea of piglets: From the perspective of feeds

Nutrition strategies to control post-weaning diarrhea of piglets: From the perspective of feeds

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Qingsong Tang^a, Tianyi Lan^a, Chengyu Zhou^a, Jingchun Gao^a, Liuting Wu^a, Haiyang Wei^a, Wenxue Li^a, Zhiru Tang^a, Wenjie Tang^b, Hui Diao^b, Yetong Xu^a, Xie Peng^a, Jiaman Pang^a, Xuan Zhao^a, Zhihong Sun^a^,^c^,^*

Animal Nutrition | 2024, 17(1) : 297 - 311

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Animal Nutrition | 2024, 17(1): 297-311

• Review Article •

Nutrition strategies to control post-weaning diarrhea of piglets: From the perspective of feeds

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Affiliations

^aLaboratory for Bio-Feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China

^bAnimal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China

^cYibin Academy of Southwest University, Yibin 644005, China

doi: 10.1016/j.aninu.2024.03.006

Outline

Abstract

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Post-weaning diarrhea (PWD) is a globally significant threat to the swine industry. Historically, antibiotics as well as high doses of zinc oxide and copper sulfate have been commonly used to control PWD. However, the development of bacterial resistance and environmental pollution have created an interest in alternative strategies. In recent years, the research surrounding these alternative strategies and the mechanisms of piglet diarrhea has been continually updated. Mechanically, diarrhea in piglets is a result of an imbalance in intestinal fluid and electrolyte absorption and secretion. In general, enterotoxigenic Escherichia coli (ETEC) and diarrheal viruses are known to cause an imbalance in the absorption and secretion of intestinal fluids and electrolytes in piglets, resulting in diarrhea when Cl⁻ secretion-driven fluid secretion surpasses absorptive capacity. From a perspective of feedstuffs, factors that contribute to imbalances in fluid absorption and secretion in the intestines of weaned piglets include high levels of crude protein (CP), stimulation by certain antigenic proteins, high acid-binding capacity (ABC), and contamination with deoxynivalenol (DON) in the diet. In response, efforts to reduce CP levels in diets, select feedstuffs with lower ABC values, and process feedstuffs using physical, chemical, and biological approaches are important strategies for alleviating PWD in piglets. Additionally, the diet supplementation with additives such as vitamins and natural products can also play a role in reducing the diarrhea incidence in weaned piglets. Here, we examine the mechanisms of absorption and secretion of intestinal fluids and electrolytes in piglets, summarize nutritional strategies to control PWD in piglets from the perspective of feeds, and provide new insights towards future research directions.

Key words

Post-weaning diarrhea / Fluid secretion / Feed / Nutritional regulation strategies / Piglet

Cite this Article

Qingsong Tang, Tianyi Lan, Chengyu Zhou, Jingchun Gao, Liuting Wu, Haiyang Wei, Wenxue Li, Zhiru Tang, Wenjie Tang, Hui Diao, Yetong Xu, Xie Peng, Jiaman Pang, Xuan Zhao, Zhihong Sun. Nutrition strategies to control post-weaning diarrhea of piglets: From the perspective of feeds[J]. Animal Nutrition, 2024 , 17 (1) : 297 -311 . DOI: 10.1016/j.aninu.2024.03.006

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1.　Introduction

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Post-weaning diarrhea (PWD) is one of the largest sources of economic loss in swine production worldwide. Early weaning of piglets frequently disturbs intestinal morphology and undermines the intestinal barrier function, resulting in diarrhea, dehydration, retarded growth, and increased mortality rates (Cao et al., 2022). Post-weaning diarrhea in piglets is closely associated with changes in the nutrient composition and levels of diets, and is accompanied by environmental, psychological and microbiological changes (Rist et al., 2013). These changes usually disrupt the digestive and intestinal functions of the piglets (Souza et al., 2011). At the same time, early weaning of piglets cannot digest solid feed well due to insufficient secretion of digestive enzymes in the incomplete function of the gastrointestinal tract, which is very likely to lead to the damage of intestinal barrier function, including disruption of tight junction proteins, increase in intestinal permeability, and electrolyte imbalance (Ma et al., 2021a, b; Wang et al., 2016). In addition, weaning stress often causes low immune function in piglets, and makes the intestine susceptible to be attacked by pathogens such as enterotoxigenic Escherichia coli (ETEC) and diarrhea virus, which can easily cause intestinal inflammation and PWD (Lodemann et al., 2017). It is difficult for the piglet to dynamically process large amounts of fluid in the intestinal lumen in an organized manner when it is challenged by multiple stresses. In some large-scale pig farms, the diarrhea incidence of piglets is as high as 50%, and the mortality rate is 15% to 20%. In the past decades, antibiotic growth promoters and high dose of zinc oxide and copper sulfate have been widely used in piglet diets to control the diarrhea incidence during the weaning transition. However, the addition of antibiotics, high doses of zinc oxide and copper sulfate to diets of weaned piglets has been challenged by problems of bacterial resistance and has faced restricted use worldwide (Jensen et al., 2016; Pilote et al., 2019). So far, we still do not have a single "magic bullet" to replace antibiotics and high copper and zinc in the diets of weaned piglets.

Finding alternative ways to reduce PWD in piglets has become a priority for sustainable pig production due to the environmental, health and safety concerns. An important change during the weaning period of piglets is the change in diet, including changes in nutrient composition and levels, and the pathogens, antigenic proteins and mycotoxins are important factors to be considered that can cause or exacerbate PWD in piglets. In the last few years, significant progress has been made in the studies towards the mechanism of PWD in piglets as well as the effects of the composition and nutritional properties of dietary ingredients. The modification of dietary composition is one of the important directions to reduce the risk of PWD. The goal of this review, therefore, is to describe the mechanisms of absorption and secretion of intestinal fluids and electrolytes in diarrheic piglets, as well as the pathogenesis of ETEC and diarrheal viruses. Building on this knowledge, we review the effects and propose mechanisms of CP levels, antigenic proteins, acid-binding capacity (ABC) and deoxynivalenol (DON) in diets on diarrhea in weaned piglets. Finally, we discuss recent strategies for nutritional regulation from perspective of diets, and examine the main challenges in the development of therapeutic treatments for diarrhea in weaned piglets.

2.　Mechanisms of diarrhea in piglets

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2.1.　 Mechanisms of fluid secretion and absorption

The fluid load primarily comes from drinking water, salivary glands, digestive secretions from the stomach, pancreas, and gallbladder, as well as the intestinal secretions used to maintain chyme fluidity. The intestinal epithelium is the primary site of fluid absorption and secretion in animals, and both the small and large intestines have a high capacity for fluid absorption and storage. In the intestine, fluid absorption and secretion are mediated by paracellular and partially transcellular pathways (Nagaraju et al., 2016). Fluid absorption and secretion by the paracellular pathway is linked to intestinal permeability, which is controlled by intercellular tight junction proteins, and the transcellular pathway is controlled by aquaporins (AQPs) in the cell membrane (Hu et al., 2015; Ikarashi et al., 2016; Krug et al., 2014). The major AQPs in the intestine of pig are AQP1, AQP2, AQP3, AQP4, AQP5, AQP8 and AQP9, which are mainly distributed in the basolateral membrane of the villus-tip epithelial cells and the basolateral membrane of crypt cells (Matsuzaki et al., 2004; Ren et al., 2023). Abnormal expression of AQPs leads to disturbed fluid and electrolyte transport in the intestinal lumen, and the altered conformation and distribution of AQPs also contribute to the occurrence of diarrhea (Zhu et al., 2017). In addition, differences in osmotic pressure gradients induced by the absorption and secretion of fluid solutes (glucose, amino acids, and fatty acids) and electrolytes are important drivers of fluid absorption and transport in the intestine (Keely and Barrett, 2022). In the intestine, cells on the surface of the finger villi carry out most of the Na⁺ and fluid uptake processes, the crypt is the main site of Cl⁻ and fluid secretion (Foulke-Abel et al., 2016). Under normal conditions, the processes of intestinal fluid and electrolyte absorption and secretion are tightly regulated, with fluid and Na⁺ absorption predominating, thus permitting the large amount of fluid that passes through the intestine each day to be reabsorbed into the bloodstream (Keely and Barrett, 2022). However, in piglets with secretory diarrhea, there is a dynamic imbalance between intestinal fluid absorption and secretion, which is usually accompanied by excessive fluid secretion and reduced electrolyte absorption (Thiagarajah et al., 2015). Most of the intestinal luminal fluid is absorbed and secreted in a passive transport mode, which is co-regulated by active transport osmosis of ions (mainly Na⁺, Cl⁻, HCO₃⁻ and K⁺) and solutes (Thiagarajah et al., 2015). The diarrhea process is mainly driven by the synergistic activity of AQPs, Na⁺/K⁺-ATPase, Na⁺–K⁺–2Cl⁻ cotransporter 1 (NKCC1), K⁺ channels and Cl⁻ channels. The mechanisms of fluid and electrolyte absorption and secretion in the intestine are shown in Fig. 1.

Intestinal luminal fluid absorption is mainly driven by the basolateral Na⁺/K⁺-ATPase, with Na⁺, Cl⁻ and glucose entering the circulation by active transport to the submucosa along with fluid absorption (Cummings, 1984). In the small intestine, they are mainly transported via Na⁺/H⁺ exchanger 3 (NHE3), sodium glucose cotransporter 1 (solute carrier family 5 member 1 [SLC5A1]), Cl⁻/HCO₃⁻ exchanger (solute carrier family 26 member 3 [SLC26A3] and solute carrier family 26 member 6 [SLC26A6]) to facilitate liquid absorption (Lin et al., 2011; Walker et al., 2009). Electroneutral fluid absorption occurs through the synergistic action of NHE3 and Cl⁻/HCO₃⁻, with SLC26A6 for HCO₃⁻ absorption and SLC26A3 for Cl⁻ absorption in the jejunum and colon (Seidler, 2013; Xia et al., 2014). In addition, short-chain fatty acid transporter in colonic fluid usually also promotes the absorption of electrically neutral fluid (Canessa et al., 1993; Krishnan et al., 1999). Ca²⁺ and cyclic nucleotides including cyclic adenosine 3′–5′-monophosphate (cAMP) and cyclic guanosine 3′–5′-monophosphate (cGMP) in epithelial cells inhibit the absorption of Na⁺, Cl⁻, and fluid in the intestinal cavity by inhibiting the activity of Na⁺ transporters on the cell membrane (Hoque et al., 2010; Namkung et al., 2010a, b).

Fluid secretion is driven by an osmotic gradient established by active transmembrane electrolyte transport, and the Na⁺/K⁺-ATPase provides a large amount of energy to maintain this gradient (Keely and Barrett, 2022). The major transporters involved in secretion are the intestinal epithelial parietal Cl⁻ channel and the basolateral NKCC1 and K⁺ channels (Rao, 2019). The Na⁺/K⁺-ATPase pumps two K⁺ into the cell and expels three Na⁺ to maintain lower intracellular Na⁺ levels. At the same time, K⁺ is pumped through K⁺ channels such as potassium voltage-gated channel subfamily Q member 1 (KCNQ1) and potassium calcium-activated channel subfamily N member 4 (KCNN4) in the basal lamina of the cell, providing the chemical driving force for Cl⁻ to pass through chloride channels (Abbott, 2016; Matos et al., 2007). The cations that NKCC1 cotransports Na⁺ and Cl⁻ into the epithelial cell must subsequently be extruded to maintain the driving force for Cl⁻ efflux across the apical membrane (Keely and Barrett, 2022). Na⁺ is excreted via the Na⁺/K⁺-ATPase pump, whereas K⁺, which enters the cell via either NKCC1 or Na⁺/K⁺-ATPase, is excreted via K⁺ channels in the basolateral membrane. The synergistic action of Na⁺/K⁺-ATPase, NKCC1, and K⁺ channels on the basolateral side of the intestinal epithelial cell leads to intracellular Cl⁻ accumulation, creating an intracellular-extracellular electrochemical gradient. Subsequently, Cl⁻ is released from the cell into the intestinal lumen when Cl⁻ channels including cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated chloride channels (CaCC), and transmembrane protein 16A (TMEM16A) open (Thiagarajah et al., 2015). In the intestinal lumen, Na⁺ from passive transport through the paracellular pathway accumulates with Cl⁻ from the intracellular pathway to form an osmotic gradient that drives fluid secretion and causes diarrhea. The activation of intracellular messengers, including Ca²⁺ signaling and cyclic nucleotide (cAMP and cGMP), increases the conductance of Cl⁻ channels at the enterocyte luminal membrane. This acts primarily on CFTR and CaCC of intestinal epithelial cells (Thiagarajah and Verkman, 2013). Throughout Cl⁻ secretion, the binding of ATP to the nucleotide binding domains and phosphorylation of the R structural domain are required for Cl⁻ channel opening, and cAMP-dependent protein kinase A, cGMP-dependent protein kinase G, protein kinase C, and phosphatases are the major regulators of phosphorylation of proteins such as CFTR (Callebaut et al., 2018; Poroca et al., 2020; Tien et al., 1994). In addition, cAMP-activated anion secretion in intestinal epithelial depends on the KCNQ1-KCNE3 K⁺ channel (and is also dependent on cAMP), with KCNQ1-KCNE3 and TWIK-related acid-sensitive K⁺ channels 2 playing important roles in intestinal anion and fluid secretion (Julio-Kalajzić et al., 2018). Intracellular calcium-sensing receptors (CaSR) in intestinal epithelial cells are thought to regulate intracellular signaling pathways and electrolyte absorption and secretion (Cooke et al., 1983; Geibel et al., 2006). Weaning stress in piglets also usually results in reduced digestion and absorption of nutrients in the piglet intestine, and excess solutes (usually nutrients, not electrolytes) that are retained in the intestinal lumen increase the osmotic pressure of fluids in the lumen and reduce fluid absorption.

2.2.　 Bacterial and viral diarrhea

ETEC infection is one of the most common factors for PWD and mortality in piglets. Most of the ETEC causing diarrhea in weaned piglets carried F4 (K88) or F18 trichomes, and ETEC with both types of trichomes accounted for 92.7% of the induced PWD (Frydendahl, 2002). After entering the animal's gastrointestinal tract, ETEC colonizes the small intestine (F4 tends to colonize the jejunum and ileum) by binding to the epithelial cell receptors via adhesins or by coating the epithelial mucus and rapidly multiplying while secreting large amounts of enterotoxin (Rhouma et al., 2017). ETEC adhere to the intestinal epithelium via colonization factors and secrete heat-stabilizing toxins and/or heat-apoptotic toxins (Smith et al., 2022). The enterotoxins, including stabilizing toxins and heat-apoptotic toxins, increase intracellular cyclic nucleotide levels, thereby activating CFTR and increasing Cl⁻ secretion, leading to dysregulation of cellular ion transport and fluid secretion (Rao et al., 1980). In addition, binding of enterotoxin to enterocyte surface receptors induces activation of Cl⁻ channels and basolateral NKCC1, leading to an increase in Cl⁻ secretion and a decrease in Na⁺ absorption, which accompanies a large amount of fluid entering the intestinal lumen (De Haan and Hirst, 2004; Thiagarajah and Verkman, 2003). Transport of bacterial toxin factors into the intracellular endoplasmic reticulum subsequently induce A subunit-mediated ADP-ribosylation of adenylyl cyclase, irreversibly activating the protein and triggering a dramatic increase in cAMP (Muanprasat and Chatsudthipong, 2013). At the same time, enterotoxin-mediated diarrhea is accompanied by increased secretion of large amounts of pro-inflammatory cytokines and decreased expression of intestinal intercellular tight junction proteins, which induces intestinal inflammation and increases permeability, accelerating fluid loss (Dreyfus et al., 1993; Ngendahayo Mukiza and Dubreuil, 2013). ETEC K88 also reduced the expression levels of AQPs (AQP1, AQP3, AQP7, AQP9, AQP11) and NHE3, as well as cAMP response element binding protein (CREB) and protein kinase A in intestinal porcine epithelial cells (IPEC-J2) (Liu et al., 2022a; Zhu et al., 2017). Pathogenic bacterial infection increases intestinal permeability and decreases the apical abundance of NHE3, SLC5A1, and SLC26A3, leading to dysfunctional absorption of fluid and solutes in the intestine, causing diarrhea (Peritore-Galve et al., 2023). Bacteria can also activate Cl⁻ secretion and inhibit Na⁺ absorption by increasing several neurotransmitters and the activity of certain receptors (Wapnir and Teichberg, 2002).

Typically, viral infections cause outbreaks of diarrhea in piglets. In particular, porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea syndrome-coronavirus (SADS-CoV) cause necrosis of intestinal epithelial cells in piglets, leading to villous atrophy and malabsorptive diarrhea (Wang et al., 2019a, b). Viral diarrhea is age-dependent and more pathogenic in piglets, leading to intestinal epithelium necrosis, villous atrophy, vomiting, diarrhea, and even death (Yan et al., 2022). Once in the animal intestine, the virus induces necrosis of intestinal epithelial cells and release of inflammatory factors, leading to changes in the structure or activity of water channel proteins and electrolyte transporter proteins, resulting in electrolyte imbalance and increased fluid secretion (Li et al., 2016). Viral infections cause diarrhea by decreasing NHE3 activity and blocking Na⁺ transporters (Song et al., 2021a). Bacterial and viral infections predispose piglets to severe diarrhea at weaning. Since 2010, highly pathogenic PEDV, PDCoV and SADS-CoV have gradually swept through the global pig industry (Li et al., 2020). These viruses can usually infect pigs of different ages and breeds, causing severe watery diarrhea with a mortality rate of up to 30% to 40%, especially in neonatal piglets, which brings huge economic losses to the pig industry (Xu et al., 2018). It is universally acknowledged that ETEC K88 is one of the main causes of diarrhea in weaned pigs, and is strongly associated with retarded growth performance, intestinal barrier dysfunction, and microbiota disorders (Luise et al., 2019). Overall, pathogenic bacteria and viral infections are the main pathogenic factors causing diarrhea in early weaned piglets and have long threatened the healthy development of the pig industry.

3.　Risk factors in feeds leading to diarrhea in piglets

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The extent of intestinal fluid secretion in piglets depends on several factors, including dietary composition, pathogens, hormones, neurotransmitters, immune cell mediators, and intestinal microorganisms. The combined action of these extracellular factors on intracellular regulatory pathways regulates intestinal fluid secretion. For weaned piglets, dietary changes are a major challenge to normal intestinal absorption and secretion, and CP levels, antigenic proteins, ABC, DON and pathogens in the diets are major triggers of PWD in piglets.

3.1.　 Crude protein levels

Piglets require large amounts of protein after weaning to provide a source of amino acids, which are essential for growth and development and immune regulation (Rezaei et al., 2013). However, the incomplete digestive function of the gastrointestinal tract of piglets renders them incapable of secreting sufficient digestive enzymes to digest proteins, causing the excess proteins to enter the hindgut and be fermented by microorganisms. Fermentation of undigested proteins and amino acids by the intestinal microbiota is an important contributor to diarrhea. We summarized the effects of different levels of CP in diets on diarrhea incidence in weaned piglets (Table 1). Protein fermentation in the hindgut produces a number of metabolites, including short-chain fatty acids, sulfur-containing bacterial metabolites (methyl mercaptan, hydrogen sulphide), aromatic compounds (phenols, indole compounds), polyamines and ammonia (Wang et al., 2018). A large amount of ammonia leads to an increase in intestinal pH, creating a micro-ecological environment conducive to the growth and proliferation of pathogenic bacteria, which in turn may lead to bacterial infectious diarrhea in piglets (Bhandari et al., 2010). A research report that 22% and 24% CP diets reduced occludin expression levels, increased the number of pathogenic bacteria such as E. coli and Clostridium difficile in the intestine, and decreased the number of beneficial bacteria such as Lactobacillus, Bifidobacterium, and Roseburia (Ren et al., 2022). The increase in pathogenic bacteria such as E. coli and the damage to intestinal function caused by protein fermentation will further disturb the intestinal electrolyte metabolism, which in turn will cause piglet diarrhea (Argenzio, 1978; Yamamoto et al., 2007). In addition, a series of toxic substances such as cadaverine and putrescine produced by the fermentation of proteins can exacerbate diarrhea in piglets (Fairbrother et al., 2005; Nagy and Fekete, 2005). Ammonia, polyamines, indoles and phenols are also potentially toxic to the host, inducing intestinal inflammation and decreasing the reabsorption of intestinal luminal fluid by damaging the structure of the intestinal villi and increasing the permeability of the intestinal wall (Andriamihaja et al., 2010). Studies have shown that 23% CP diets increased the pH and ammonia-N concentrations in the colonic digesta and significantly increased the concentrations of the microbial metabolites such as putrescine, histamine and spermidine and, as a result, the diarrhea scores were significantly increased (Wen et al., 2018). High CP levels can also lead to imbalances in the expression of AQPs, resulting in imbalances in fluid absorption and secretion. It has been shown that feeding diets with high CP (30%) levels reduced the expression of AQP1, AQP3, AQP8, AQP10 and increased the diarrhea incidence of weaned piglets (Gao et al., 2020). A recent study showed that 22% and 24% CP diets resulted in abnormal expression of AQPs in the small intestine and colon, whereas 20% CP diets favored the normal expression of AQP4 in the small intestine and AQP2, AQP4, and AQP9 in the colon of weaned piglets, thus maintaining the balance of intestinal fluid absorption and secretion in piglets (Ren et al., 2023). Furthermore, in a study of 21-day-old weaned piglets, there was a gradual increase in Cl⁻ concentration and CFTR expression levels in the colonic contents, as well as a gradual increase in diarrhea incidence (24.6% to 56.2%), with increasing dietary CP levels (17%, 19%, 23%) (Wu et al., 2015). Therefore, it can be concluded that high dietary CP levels lead to increased protein fermentation in the hindgut, which is detrimental to intestinal barrier function and electrolyte homeostasis.

3.2.　 Acid-binding capacity

The acidic environment of the nursing piglet stomach mainly depends on the fermentation of lactose in milk to produce lactic acid. The termination of the source of lactose after weaning leads to a decrease in lactic acid content and an increase in gastric pH (Zhao et al., 2021a, b). In addition, gastrointestinal pH is further reduced due to the decrease in gastric acid secretion capacity caused by weaning of piglets (Heo et al., 2013). Maintaining a low gastric fluid pH is critical to the intestinal health of weaned piglets as it positively affects nutrition, digestion, and suppression of pathogenic bacteria. Therefore, not only the nutritional composition (e.g., CP, energy, and amino acids) of the diet, but also the effect of the diets on the pH of the animal's gastrointestinal tract should be considered. Acid-binding capacity refers to the resistance of the diets to a low pH in the pig's stomach, is highly related to feedstuffs used in the diets. It can be calculated the milliequivalent (mEq) H⁺ of 0.1 mol/L HCl or 0.1 mol/L NaOH required to reduce the pH of a sample (1 kg) to pH 4 (ABC-4) and pH 3 (ABC-3) by measuring 0.5 g of the sample (Lawlor et al., 1994). The ABC of feedstuffs or complete diets have a strong influence on pig gastrointestinal pH, nutrient digestibility and intestinal microbiology. Excessive ABC results in reduced digestibility of dietary CP, increased hindgut fermentation of CP, increased release of toxic substances such as ammonia and amines, increased piglet diarrhea and impaired growth performance (He et al., 2022). Furthermore, diets with excessive ABC will tend to raise the pH value of the gastrointestinal tract, leading to increased proliferation of diarrhea-causing bacteria, resulting in bacterial diarrhea. We summarized the initial pH, ABC-4 and ABC-3 in common feedstuffs of piglet, which can provide a reference for formulating diets of weaned piglets (Table 2).

3.3.　 Antigenic proteins

Soybean glycinin and β-conglycinin are the most abundant antigenic proteins in soybeans and are two major antinutritional factors that contributing to PWD in piglets. Soybean glycinin makes up 40% of total soybean protein and consists of six subunits (A1A2, A2B1a, AB, A5A4B3, A3B4, and A1bB2). Beta-conglycinin makes up 30% of total soybean protein and consists of three subunits, α′ (57 to 72 kDa), α (57 to 68 kDa), and β (45 to 52 kDa), which are all allergens (Krishnan et al., 2009). Due to insufficient enzyme secretion and the immature development of the digestive tract of weaned piglets, the digestion and absorption of antigenic proteins are very limited. Consequently, after entering the intestine, these proteins stimulate an immune response in the intestinal tissues, causing an allergic reaction (Wang et al., 2014, 2023). Undigested soybean glycinin and β-conglycinin may enter the intestinal tract which keeps the cells proliferating, destroys the cytoskeleton, causes apoptosis of small intestinal cells and trigger allergic reactions (Chen et al., 2014). Symptoms of allergic reactions in piglets mainly present as diarrhea, indigestion, growth retardation (Zheng et al., 2014). Additionally, soybean glycinin and β-conglycinin may induce intestinal injury and inflammation in piglets through the p38 mitogen-activated protein kinase (MAPK)/Jun N-terminal kinase/nuclear factor-κB (NF-κB) pathway, which leads to intestinal villus damage and increased intestinal mucosal permeability (Peng et al., 2018; Sun et al., 2008). Soy protein activates CaSR and intracellular Ca²⁺ signaling, which may lead to an imbalance in electrolyte homeostasis, thereby inducing PWD in piglets (Wang et al., 2021d).

3.4.　 Deoxynivalenol

Deoxynivalenol, also known as vomitoxin, is one of the most common mycotoxins. It is a type B trichothecene and is a secondary metabolite of common field pathogens such as Fusarium graminearum and Fusarium culmorum (Mishra et al., 2020). Deoxynivalenol is one of the most prevalent mycotoxins in livestock feeds, contaminating many agricultural commodities, and is commonly detected in cereals, including maize, soybean, barley, wheat, oats, and their by-products (Sun et al., 2022; Wu et al., 2011). BIOMIN America, Inc. conducted an investigation in 2018, analyszing a total of 13,629 samples from 77 countries worldwide. The findings revealed that DON is one of the widespread toxins, with contamination rates (by continent) found as follows: 80% in Asia, 75% in Africa, 67% in North America, 67% in Central and South America, 65% in the Middle East, and 63% in Europe. In China, a study showed that DON was detected in up to 97% of feedstuffs and complete diets in pig farms in the Beijing area of China (Li et al., 2014). A recent study showed that 3507 feedstuffs samples from various provinces in China during 2018 to 2020 showed a DON detection rate of 96.4%, with average concentrations ranging from 458.0 to 1925.4 μg/kg, which is 0.1% and 0% to 8.9 % higher than the latest Chinese safety standard (GB 13078-2017) for feedstuffs and complete diets, respectively (Zhao et al., 2021a,b). Global warming and associated climatic changes are progressively increasing the susceptibility of crops to mycotoxin infection, further contributing to increased DON contamination in cereals.

DON is rapidly absorbed into circulation via the small intestinal epithelium and is absorbed at a much higher rate in pigs (82%) than in cattle (1%), sheep (5.9% to 9.9%) and chickens (19%) (Hou et al., 2023). Deoxynivalenol is rapidly and efficiently absorbed in the upper part of the small intestine, which is the main target organ for DON damage (Waché et al., 2009). Weaned piglets consuming diets contaminated with low doses of DON for long periods may develop a variety of symptoms, including reduced feed intake and impaired intestinal function. High dose exposure to DON may result in more severe symptoms such as severe diarrhea, vomiting, gastroenteritis and gastrointestinal bleeding (Hooft and Bureau, 2021; Yao and Long, 2020). Deoxynivalenol binds to the eukaryotic 60S ribosomal subunit, blocking peptidyltransferase and inhibiting translation and at the same time inducing intestinal inflammation via MAPK through the ribotoxic stress response (Hooft and Bureau, 2021). Mitochondria are the primary organelles that control the distribution and concentration of Ca²⁺ in the cell. Deoxynivalenol exposure increased intracellular ROS levels, induced mitochondrial damage and increased Ca²⁺ flux, leading to oxidative stress and apoptosis in intestinal epithelial cells (Wang et al., 2021c; Zhou et al., 2017). In recent years, several studies have confirmed that the toxic effects of DON are closely linked to the damage of the intestinal structure, epithelial barrier and mucosal immunity in animals (Liu et al., 2020a; Wang et al., 2021b). These impairments can be a huge challenge for weaned piglets with immature immune systems. Studies have shown that feeding DON to weaned piglets reduced the number of intestinal goblet cells, and decreased the expression of zonula occludens-1 (ZO-1), claudin-1 and mucin-2, and inhibited the toll-like receptor 4 (TLR4)/nod-like receptor 3 (NLRP3) signaling pathway (Liu et al., 2022b). In addition, feeding DON-contaminated diets damages intestinal epithelial cells, and increased susceptibility to diarrhea-causing pathogens such as ETEC and diarrhea viruses (Ling et al., 2016; Liu et al., 2022c). Deoxynivalenol has been shown to exacerbate immunosuppression in weaned piglets under PEDV-infected conditions by inhibiting the TLR4/NLRP3 signaling pathway and promoting p38-mediated autophagy (Liu et al., 2020b, Liu et al., 2022c). In vivo and in vitro experiments shown that the combination of PEDV and DON reduced the expression of claudin-1 in the IPEC-J2 or intestine of weaned piglets, and enhanced the inflammatory response through the p38 and stimulator of interferon genes (STING) signaling pathways, and lead to an increase in the diarrhea incidence in piglets (Liu et al., 2020a; Zhang et al., 2020). A recent report showed that DON-supplemented diets resulted in increased expression of ferroptosis gene (divalent metal transporter 1 [DMT1]) and decreased expression of anti-ferroptosis genes such as ferroportin (FPN), ferroptosis suppressor protein 1 (FSP1) and CDGSH iron sulfur domain 1 (CISD1) in weaned piglets, and the induction of ferroptosis by DON was confirmed to be one of the causes of intestinal damage in piglets by using the RNAi technique and ferroptosis inhibitor treatment of IPEC-J2 (Liu et al., 2023). We summarized the cytotoxic effects of DON and the molecular mechanisms that cause diarrhea in piglets based on research in recent years (Fig. 2). These studies suggest that reducing mycotoxin contamination in feeds is an important part of controlling PWD.

4.　Strategies for changing composition in diets to reduce diarrhea

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4.1.　 Reducing CP levels in diets

Many studies have investigated the degree of reducing dietary CP required to effectively reduce PWD. Studies have shown that reducing dietary CP from 18.5% to 16.5% significantly reduces the diarrhea incidence in weaned piglets (Marchetti et al., 2023). Ammonia, amines, and hydrogen sulfide in the intestine linearly decreased when dietary CP levels were reduced (21%, 20%, 19%, 18%, 17%, and 16%), and diarrhea incidence was significantly reduced in weaned piglets (Kim et al., 2023). Under E. coli infection, weaned piglets fed diets containing 25.6% and 17.5% CP had diarrhea incidences of 44.6% and 31.5%, respectively, and in the absence of E. coli infection, the same piglets had diarrhea incidences of 19.6% and 8.3%, respectively (Heo et al., 2009). Feeding 19% CP levels (22% CP in the control group) reduced the diarrhea incidence in weaned piglets under different hygienic conditions (Lee et al., 2022). It is evident that reducing dietary CP levels is an effective strategy for controlling the incidence of diarrhea in weaned piglets, especially in environments with E. coli infection and poor sanitation. It is worth noting that the effect of dietary CP level on the growth performance of weaned piglets has been a matter of debate among researchers, and lowering it too much tends to limit the growth of piglets and reduce the economic efficiency of farming. The study showed that both average daily gain and gain/feed ratio were significantly reduced by diets with 19% and 16% CP levels (control 22% CP) (Limbach et al., 2021). However, it has also been shown that low-protein diets (as low as 16%) improve intestinal barrier function and reduce PWD in weaned piglets, but do not affect growth performance (Kim et al., 2023; Marchetti et al., 2023). One study showed that a strategy of using a low-protein diets of 17.3% CP for d 5, 7, 10, and 14 after weaning, followed by a switch to a 21.5% CP diets, resulted in a reduction in the piglet diarrhea incidence without affecting piglet growth performance (Heo et al., 2008). Similarly, feeding a low-protein diet (16.6% CP) at the 6 to 9 kg stage, followed by a switch to a standard CP level diet (19.1% CP) at 9 to 15 kg stage, also reduced the diarrhea incidence in piglets (Lynegaard et al., 2021). Adequate protein supply is critical because piglets have a high capacity for rapid growth and protein deposition, and protein intake is highly linearly correlated with ADG. Summarizing recent studies on dietary CP levels for weaned piglets, we can conclude that there exists a regression equation depicting the relationship between dietary CP levels and diarrhea incidence, represented as Y = 3.532 × X − 32.24. Notably, for every 2% decrease in dietary CP levels, the diarrhea incidence is observed to decrease by 7.06% (Fig. 3). Therefore, a way to ensure dietary protein supply of weaned piglets, while avoiding excessive protein into the hindgut fermentation is a key issue in the technology of low-protein diets to reduce diarrhea. With the increasing research on technology of low-protein diets, studies have reported that a 3 to 4 percentage point reduction in CP levels accompanied by supplementation with crystalline lysine, threonine, tryptophan, methionine, and valine did not have a negative effect on animal performance and nitrogen deposition (Wang et al., 2018). It can be seen that reducing the CP level in piglet diets is an effective strategy to reduce PWD in piglets.

4.2.　 Reducing ABC in diets

Maintaining a well-structured diet that is low in ABC to support good intestinal barrier function and microbial homeostasis during the weaning period of piglets is essential to reduce piglet diarrhea incidence and improve growth performance. Therefore, the ABC of feedstuffs can be used as a nutritional constraint for dietary formulation, and reducing the ABC value of complete diets by selecting feedstuffs with lower ABC values and exogenously adding acids are good strategies for improving the intestinal barrier function and control diarrhea in weaned piglets (Huting et al., 2021). In general, cereals have low ABC values, ranging from 78 to 147 milliequivalent (mEq) H⁺/kg for ABC-4 and 135 to 286 mEq H⁺/kg for ABC-3, whereas protein feedstuffs have slightly higher ABC values, ranging from −13 to 1059 mEq H⁺/kg for ABC-4 and 823 to 2100 mEq H⁺/kg for ABC-3. Soybean meal (SBM) is known to be the most common source of protein in swine diets and is usually added at 15% to 30% in weaned piglets, but SBM has a high ABC-4 value (618 mEq H⁺/kg) (Stein et al., 2008). Therefore, the use of fermented SBM (ABC-4, 207 mEq H⁺/kg) or fermented soy isolate (ABC-4, −13 mEq H⁺/kg) to partially replace the amount of SBM used, as well as the application of low-protein forage techniques are good strategies to reduce the ABC of the diets. The mineral source was one of the key factors for the high ABC values of the feedstuffs, especially the ABC-4 of calcium carbonate, limestone flour, and zinc oxide were higher than 10,000 mEq H⁺/kg. Calcium carbonate and limestone (as a Ca source) have an ABC-4 of 18,384 mEq H⁺/kg and 12,932 mEq H⁺/kg, respectively, and can therefore be partially replaced with monocalcium phosphate (ABC-4, 1587 mEq H⁺/kg), dicalcium phosphate (ABC-4, 1348 mEq H⁺/kg), or calcium propionate (ABC-4, 9240 mEq H⁺/kg) as a Ca source. At the same time, the use of high doses of phytase reduces the amount of calcium carbonate and limestone flour used in the diets. For example, calcium and phosphorus levels should be reduced to 0.60% to 0.65% and 0.35% to 0.40%, respectively, in piglets during the first 2 weeks after weaning (He et al., 2022). High dosage of zinc oxide is widely used to reduce the diarrhea incidence of weaned piglets because of its strong bacteriostatic property. However, high dosage of zinc oxide leads to increase in ABC value of diets and bacterial resistance, and can also cause environmental pollution, so the use of zinc oxide in weaned piglets is also being gradually limited (Bonetti et al., 2021). Therefore, using low ABC feedstuffs to replace high ABC feedstuffs, as well as techniques such as low-protein diets and the addition of high doses of phytase can be some of the strategies to reduce dietary ABC.

Previous studies have reported that the addition of acidifiers can better reduce the ABC value of diets because organic acids have negative ABC values (ABC4 -13, 550 to −217 mEq H⁺/kg) (Scholten et al., 2001). The main acidifiers used in weaned piglet diets are phosphoric acid, citric acid, sorbic acid, fumaric acid, malic acid, lactic acid, benzoic acid, and some fatty acids (formic acid, acetic acid, propionic acid, butyric acid, lauric acid, etc.). Acidifiers not only reduce the ABC in feedstuffs, but also penetrate pathogenic bacteria such as E. coli, Salmonella, and Clostridium, thus reducing pathogen infections in piglet (Grilli et al., 2015). Studies have reported that the addition of 1% citric acid reduced gastric pH from 4.6 to 3.5 and the addition of 0.7% fumaric acid reduced gastric pH from 4.6 to 4.2 (Scipioni et al., 1979). It is important to note that excessive additions of acidifiers can reduce the palatability of diets and organic acids (formic, butyric, citric, and tartaric) have shown better palatability than inorganic acids (hydrochloric and phosphoric). Moreover, organic acids, as mostly biometabolic intermediates, can serve as a source of energy for the porcine intestine and improve the intestinal barrier function (Suiryanrayna and Ramana, 2015). Feeding 3000 mg/kg of complex organic acids (formic acid ≥23.9%, lactic acid ≥14.5% and citric acid ≥4.0%) has been shown to significantly reduce the diarrhea incidence and improve gut health and growth performance in weaned piglets (Li et al., 2023a). Organic acids have been shown to reduce PWD and improve the growth of weaned piglets by regulating redox homeostasis, intestinal barrier function and intestinal flora (Ma et al., 2021a,b; Xiang et al., 2021; Zeng et al., 2022).

4.3.　 Feed processing for reduced antigenic protein

Feedstuffs processing mainly includes physical methods (expansion, heating, mechanical processing), chemical methods (acid and alkali treatment, alcohol solution treatment, salt treatment), and biological methods (biofermentation, enzyme treatment, breeding). Most feedstuffs processing methods, including biofermentation, bulking, enzyme treatment, not only reduce or inactivate antigenic proteins and pathogens, but also physically alter the raw material through agglomeration or hydrolysis, thereby enhancing feed digestion and absorption (Cervantes-Pahm and Stein, 2010; Singh et al., 2007; Yuan et al., 2017). Consequently, the digestion and absorption of nutrients such as proteins and amino acids is improved, and the rate of hindgut fermentation and diarrhea of nutrients is reduced (Navarro et al., 2017). Fermented SBM is made by using SBM as the main ingredient and treating it with probiotics for fermentation pretreatment in order to reduce the presence of antinutritional factors such as soybean globulin, β-accompanied by soybean globulin, trypsin inhibitory factor, and soybean agglutinin. This process serves to improve the digestibility and absorption of small molecule peptides within SBM. Feed fermentation degrades proteins and carbohydrates into low molecular weight, water-soluble molecules, thus promoting of nutrient digestion and mitigating intestinal damage resulting from hindgut nutrient fermentation (Czech et al., 2021; Jiang et al., 2023; Yuan et al., 2017). In addition, the beneficial microorganisms in fermented feeds can inhibit the colonization of pathogenic bacteria such as E. coli, reducing the susceptibility to pathogens, especially in weaned piglets (Kiers et al., 2003; Pluske et al., 2002).

4.4.　 Biological approaches to detoxify DON

In the past, physical and chemical methods have been widely used to reduce mycotoxin levels in feeds. Physical detoxification includes sieving, stripping, grinding, washing, radiation treatment, thermal treatment and adsorption to feedstuff (Li et al., 2023b). Physical degradation has the problems of low degradation efficiency, high work intensity and expensive equipment. Chemical degradation methods typically use sodium selenite, sodium bisulphite and sodium metabisulfite, which primarily destroy the chemical structure of mycotoxins or to neutralize their active groups (He et al., 2022). Studies have shown that sodium metabisulfite at levels of 0.45% to 0.9% can destroy 70% to 100% of DON in processed grains or feeds in vitro at approximately pH 6.5, but not under acidic conditions (Dänicke et al., 2010a,b; Frobose et al., 2015). Chemical detoxification involves the use of oxidants, aldehydes, acids, bases, and several gases to detoxify DON-contaminated grains (Li et al., 2023c). Sulfite reducers, including sodium sulfite (Na₂SO₃), sodium bisulfite (NaHSO₃), and sodium metabisulfite (SMBS), have the ability to cleave disulfide cross-links (He et al., 2022). Several studies have shown that SMBS can destroy 70% to 100% of the DON in processed grains or feedstuffs in vitro (at concentrations ranging from 0.45% to 0.9%) at pH around 6.5 (Dänicke et al., 2009, 2010a,b; Frobose et al., 2015; Schwartz et al., 2013). Ozone degradation of DON (1 to 5 μg/mL) in solution has been shown to be as high as 93.6% to 98.3% (Li et al., 2015, 2019a,b; Ren et al., 2020). Studies have reported maize and wheat showed 63% to 90% ozone degradation rates (Kells et al., 2001; Young, 1986). However, traditional chemical methods for mycotoxin degradation often have limitations such as reduced nutritional value and palatability of feedstuffs, safety concerns, and expensive equipment (Ji et al., 2016).

In recent years, with the continuous development of biodegradation technology, biodegradation of mycotoxins has the advantages of environmental protection, safety and high efficiency, and has become an emerging and promising technology. The process of converting DON into low or non-toxic products using microorganisms and enzymes is the biological detoxification of DON. The main types of biological detoxification are isomerization, acetylation, glycosylation, oxidation, hydroxylation and hydrolysis (Guo et al., 2020). Bacteria, fungi and the enzymes that they produce are commonly used in these transformations, mainly soil bacteria, phytobacteria, animal rumen and intestinal microorganisms, and yeasts (Fig. 4). It has been shown that bacterial consortium LZ-N1 has stable and efficient DON conversion activity, and its two new strains (Pseudomonas sp. Y1 and Lysobacter sp. S1) can sustainably convert DON to 3-epi-DON and reduce DON toxicity (Zhai et al., 2019). Agrobacterium–Rhizobium strain E3-39 from soil oxidizes the 3-OH group of DON to form 3-keto-4-DON (3-keto-DON), resulting in a reduction of toxicity by over tenfold (Shima et al., 1997). Furthermore, soil-derived Bacillus licheniformis YB9, Devosia insulae A16, desulfitobacterium sp. PGC-3-9, and other bacteria had strong DON detoxification capacity, with degradation rates exceeding 82% during 24- to 48-h incubations (He et al., 2020; Wang et al., 2019a,b, 2020). The Lactobacillus rhamnosus can convert DON to 3-epi-DON in vitro and reduce the toxicity of DON in vivo (Qu et al., 2019). The BBSH 797 strain from the rumen can convert DON to deepoxy-deoxynivalenol (Fuchs et al., 2002). Strains of Aspergillus oryzae and Rhizopus oryzae were also found to adsorb and degrade DON. A. oryzae KKB4 and R. oryzae KP1R1 were inoculated into DON-contaminated corn and fermented for 10 days, resulting in DON reduction of 65.91% and 56.82%, respectively (Arifin et al., 2019). The study reported that the soil-derived fungus Aspergillus tubingensis NJA-1 had a significant ability to degrade DON, with a degradation rate of 94.4% (He et al., 2008). In addition, yeast can convert DON to DON-3-glucoside (Guo et al., 2020). In addition to the above microorganisms, proteins or enzymes produced by microorganisms can also convert DON or combine with DON to produce couplers that play an important role in detoxification. Certain enzymes produced by microorganisms can transform or bind mycotoxins. Some specific enzymes such as DePA, 3-acetyl DON oxidase, Fusarium trichothecene 3-O-acetyltransferases, 3-O-acetyltransferase, DdnA, DepB, UDP-glycosyltransferase are known to convert DON to low or non-toxic products (Fig. 4). UDP-glucosyltransferase was shown to glycosylate DON to DON-3-glucoside and reduced DON toxicity (He et al., 2018). In addition, several research have reported that peroxidase, b-xylanases and amylolytic enzymes can degrade DON (Feltrin et al., 2017; Gauterio et al., 2017). Because the enzymatic degradation is highly specific, efficient and environmentally friendly, studies are increasingly focusing on the identification, purification, and characterization of detoxification enzymes, as well as focusing on the underlying catalytic mechanisms. In short, the use of biological approaches is a promising direction for treating and preventing harms caused by DON.

4.5.　 Dietary vitamin supplementation

In general, the vitamin content of the feed is low and does not meet the nutritional needs of the piglets, so additional vitamins must be used to supplement the diet. Deficiency in vitamins such as niacin (vitamin B₃), vitamin B₆, folic acid (vitamin B₉), vitamin A, and vitamin D damage the morphological structure of the small intestine and reduce the expression of functional genes involved in digestion and absorption (Chawla and Kvarnberg, 2014; Matsui et al., 2018). Niacin would improve intestinal morphology, tight junction protein expression and intestinal barrier function in weaned piglets (Feng et al., 2021; Liu et al., 2021; Yi et al., 2021). Dietary supplementation with 20.4 mg/kg niacin was able to increase the expression of intestinal ZO-1, AQP1 and AQP3, and decrease the diarrhea incidence of weaned piglets (Liu et al., 2022a). In an in vitro experiment, niacin attenuated the reduction of AQPs and ZO-1 expression caused by an infection of IPEC-J2 with ETEC K88 (Liu et al., 2022a). Niacin also attenuated the inflammatory response and diarrhea induced by PDCoV infection in weaned piglets by inhibiting the activation of the TLR2/TLR4-NF-κB signaling pathway in the intestine (Chen et al., 2022). Nicotinamide (amide compounds of niacin) activates the extracellular signaling-regulated kinase 1/2 (ERK1/2)/MAPK pathway to down-regulate transcription factor expression to inhibit PEDV and PDCoV replication (Li et al., 2023a). Dietary supplementation with 7 mg/kg vitamin B₆ significantly reduced diarrhea and improved intestinal morphology and immune status in weaned piglets fed a high-protein diets (Li et al., 2019a,b). Vitamin A (18,000 IU/kg) attenuates irinotecan-induced diarrhea in weaned piglets by modulating intestinal glial and immune cell infiltration and inflammatory response (Li et al., 2022). Studies have shown that folic acid supplementation at 9 mg/kg improved intestinal function and reduces the diarrhea incidence in weaned piglets, and supplementation to 18 mg/kg can down-regulate intestinal tumor necrosis factor-α (TNF-α) and reduce intestinal inflammation in weaned piglets (Wang et al., 2021a). Vitamins have important immunomodulatory functions, and adequate vitamin supplementation is an important way to alleviate diarrhea in piglets.

4.6.　 Novel treatment

Traditionally, antinutritional factors have been considered detrimental to pig production, but in recent years, some of them have been found to have good intestinal astringent properties and are particularly effective in alleviating diarrhea in piglet. Tannic acid has excellent intestinal astringent, antioxidant, anti-inflammatory and antimicrobial properties, and improves intestinal function and diarrhea incidence in weaned piglets without negatively affecting growth performance (Caprarulo et al., 2020; Song et al., 2021b; Yu et al., 2020). It has been shown that dietary supplementation with 0.2% and 0.4% tannic acid reduced the number of E. coli in the colon of weaned piglets, increased the expression of intestinal ZO-1, ZO-2 and claudin-2, and reduced the diarrhea incidence (Song et al., 2021a). Dietary supplementation with 0.15% encapsulated tannic acid significantly increased the expression levels of ZO-1, claudin-1 and reduced PWD in piglets (Xu et al., 2022). Additionally, dietary tannic acid-chelated zinc could alleviate PEDV-induced damage and mitigated diarrhea of weaned piglets (Zhang et al., 2022). Mechanistically, tannic acid is an inhibitor of CFTR and CaCC, counteracting the control of CFTR and voltage-gated K⁺ channels by pathogenic bacteria and inhibiting Ca²⁺ activation, thereby reducing diarrhea caused by Cl⁻ hypersecretion (Namkung et al., 2010a,b; Ramu et al., 2014; Thiagarajah et al., 2015). Dietary supplementation with tannic acid decreased intestinal CFTR and NHE3 expression and increased ZO-1 and occludin expression levels and reduced diarrhea incidence in weaned piglets challenged with ETEC K88 environment (Yi et al., 2023). In addition, by lectin conjugation, lectin increased the inhibitory potency of CFTR by up to 100-fold, blocking cholera toxin-induced intestinal fluid secretion (Sonawane et al., 2007). Plumbagin also inhibited the activity of intestinal epithelial CaCC and CFTR in colon of mouse, but had no effect on the activity of Na⁺-K⁺ ATPase or K⁺ channels (Yu et al., 2019).

Insoluble fiber (e.g., wheat bran, oat hulls, barley hulls, and lignocellulose) reduced the residence time of digesta in the gastrointestinal tract, which reduced the proliferation of pathogens in the small intestine, thus contributing in particular to a lower risk of PWD disease (Molist et al., 2014; Tanghe et al., 2023). Accumulated evidence suggests that increasing dietary fiber levels and feeding different sources of fiber to early weaned piglets reduce the diarrhea incidence and improve growth performance (Adams et al., 2019; Liang et al., 2023a,b; Uddin et al., 2023). However, dietary fibers with low hydration properties exacerbate diarrhea and impair intestinal health and nutrient digestibility in weaned piglets (Huang et al., 2022). Therefore, intervening in the hydration properties of feedstuffs using specific dietary fiber can ameliorate diarrhea in weaned piglets and enhance intestinal health. Moderate levels of insoluble fiber sources are more beneficial in promoting intestinal health during the first two weeks after weaning of piglets, and the use of soluble fiber in early-weaned piglets in poor health is detrimental in mitigating PWD (Canibe et al., 2022). Thus, it can be seen that dietary fiber is one of the effective strategies for controlling diarrhea in early weaned piglets. Despite numerous studies supporting this conclusion, there is still a need to develop systematic feeding management strategies in the future.

In addition, non-starch polysaccharides are not detrimental to pig health, and increasing non-starch polysaccharides concentrations in diets that do not increase digestive viscosity may be beneficial in preventing post-weaning E. coli infections (Wellock et al., 2008). Recently it has been reported that decreased expression of microRNAs (miRNA) including ssc-miRNA-425-5p and ssc-miRNA-423-3p leads to an over-enrichment of microbial-produced succinic acid in the gut, increased fluid secretion from intestinal epithelial cells due to elevated Cl⁻ secretion, and increased intestinal inflammatory response due to activation of the myeloid differentiation primary response 88 (MyD88)-dependent TLR4 signaling pathway, resulting in diarrhea (Zhou et al., 2022). MiR-let-7e and miR-27b derived from milk small extracellular vesicles inhibited PEDV infection (Liang et al., 2023a,b). However, miRNA-30d and miR-204 exacerbated Clostridium perfringens β2 toxin-induced inflammatory injury in IPEC-J2 cells by targeting proteasome activator subunit 3 or bcl-2 like protein 2 (Wang et al., 2021a; Xie et al., 2022). Thus, natural product and miRNA modulation strategies provide a new perspective on the prevention and treatment of piglet diarrhea at the molecular level.

5.　Conclusion and perspective

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A dynamic imbalance in the absorption and secretion of intestinal fluids is the underlying cause of diarrhea in piglets. The processes of intestinal luminal fluid absorption and secretion are driven by the active transport of electrolytes (Na⁺, Cl⁻, HCO₃⁻, and K⁺) and solutes (glucose, amino acids, fatty acids, etc.) and are closely linked to AQPs and intestinal permeability. Bacterial and viral infections usually cause imbalances in electrolyte absorption and secretion in the intestinal lumen of piglets, and the nutrient level and composition of feeds influence the pathogenicity of bacteria and viruses. Based on the literature report, excessive levels of CP in the diets, stimulation by antigenic proteins, and DON contamination are important factors contributing to the imbalance of intestinal fluid absorption and secretion. Although various dietary strategies (e.g. CP reduction, ABC reduction, processing, vitamin supplementation, vomitoxin detoxification) have been widely recognized as promising strategies to reduce PWD in piglets, an integrated approach should be taken to control PWD, including nutritional and management-related measures. Finally, it is necessary to consider the impact on the growth performance of weaned piglets and economic benefits of these strategies. For example, excessive reduction in CP levels can lead to piglet growth restriction, and excessive reduction in ABC can reduce the palatability of the feeds and increase costs related to feed processing.

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Year 2024 volume 17 Issue 1

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doi: 10.1016/j.aninu.2024.03.006

Receive Date：2023-09-09
Online Date：2026-01-28

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Received：2023-09-09
Revised：2024-01-26
Accepted：2024-03-21

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^aLaboratory for Bio-Feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China

^bAnimal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China

^cYibin Academy of Southwest University, Yibin 644005, China

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Corresponding author. E-mail address: s765210@swu.edu.cn (Z. Sun).

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Table 1 Effect of different CP levels in the diets on diarrhea incidence of piglets.

Weaning age	IBW, kg	Experimental period	CP levels	Diarrhea scores or incidence rates	References
20-d-old	5.53	1 to 14 d of age	16%, 19%, 22%	Diarrhea score (1 to 7 d): 1.25 for 16% CP, 1.50 for 19% CP, 1.67 for 22% CP Diarrhea score (8 to 14 d): 1.21 for 16% CP, 1.42 for 19% CP, 1.67 for 22% CP (scores: 1 = normal feces, 2 = moist feces, 3 = mild diarrhea, 4 = severe diarrhea, 5 = watery diarrhea)	Limbach et al. (2021)
21-d-old	5.90	1 to 14 d of age	17.5%, 25.6%	Not infected with Escherichia coli Diarrhea incidence (1 to 7 d): 9.5% for 17.5% CP Diarrhea incidence (1 to 14 d): 8.3% for 17.5% CP, 19.6% for 25.6% CP Infected with E. coli Diarrhea incidence (1 to 7 d): 21.4% for 17.5% CP Diarrhea incidence (1 to 14 d): 31.5% for 17.5% CP, 44.6% for 25.6% CP	Heo et al. (2009)
21-d-old	5.99	1 to 14 d of age	17%, 19%, 23%	Diarrhea incidence: 24.6% for 17% CP, 43.65% for 19% CP, 54.9% for 23% CP	Wu et al. (2015)
28-d-old	7.98	1 to 14 d of age	17%, 30%	Diarrhea incidence: 13% for 17% CP, 96% for 30% CP	Gao et al. (2020)
NA	8.25	1 to 21 d of age	16%, 17%, 18%, 19%, 20%, 21%	Diarrhea score: 1.4 for 16% CP, 1.58 for 17% CP, 2.12 for 18% CP, 2.48 for 19% CP, 2.62 for 20% CP, 3.23 for 21% CP (scores: 0 = normal feces, 1 = moist feces, 2 = mild diarrhea, 3 = severe and watery diarrhea)	Kim et al. (2023)
NA	10.00	10 to 20 kg of BW	12%, 14%, 16%, 18%, 20%	Diarrhea incidence: 13.36% for 12% CP, 24.63% for 14% CP, 28.31% for 16% CP, 49.55% for 18% CP, 46.39% for 20% CP	Liu et al. (2022a)

NA = not available in the publication; IBW = initial body weigh; CP = crude protein.

Table 2 Acid-binding capacity of ingredients commonly used for weaned piglets.¹

Ingredients	Initial pH	ABC-4², mEq H⁺/kg	ABC-3², mEq H⁺/kg
Cereals
Corn	6.57	84	135 to 233
Sorghum	6.47	110	NA
Wheat	6.72	78	230
Barley	6.12	95	286
Whole oats	6.33	122	NA
Oat groats	6.44	107	NA
DDGS	4.85	147	NA
Cereal blend	6.08	107	NA
Vegetable protein
SBM (42% CP)	NA	NA	980 to 1240
SBM (48% CP)	NA	NA	1025 to 1035
Expelled SBM	7.13	567	NA
Full fat soya	6.90	480	823
Soy protein concentrate	7.36	737	NA
Fermented SBM	4.69	207	NA
Fermented soy isolate	3.95	−13	NA
Enzymatically treated SBM	6.29	753	NA
Rapeseed meal	6.30	498	945
HPDDGs	4.87	100	NA
Animal proteins and milk
Fish meal	6.51	1059	1457 to 2100
Spray-dried bovine plasma	6.99	713	NA
Meat and bone meal	7.45	595	920
Poultry meal	6.74	1007	NA
Spray-dried whey powder	6.29	440	NA
Whey permeate	6.16	520	NA
Crystalline lactose	7.09	53	NA
Microbial protein
Yeast	3.40	150	130
Fat	4.90	16	137
Vitamins and minerals
Ferrous sulfate	3.20	−655	93
Calcium carbonate	9.62	18,384	19,680 to 20,000
Limestone flour	9.30	12,932	15,044
Copper sulfate	5.10	92	269
Zinc oxide	8.93	19,092	17,908
Monocalcium phosphate	7.61	1587	NA
Dicalcium phosphate	6.81	1348	5666 to 10,105
Calcium propionate	9.11	9240	NA
Sodium chloride	6.75	49	162
Vitamin premix	6.99	10,767	NA
Trace mineral premix	5.37	7867	NA
Vitamin trace mineral premix	4.94	2542	5123
Manganese	8.22	2347	NA
Sodium metabisulfite	4.00	0	NA
Choline chloride	5.96	70.5	226
Amino acids
L-Lysine	5.89	103	724
DL-Methionine	5.96	165	1219
L-Threonine	5.97	189	1386
L-Tryptophan	5.88	149.5	1272
L-Valine	5.53	193	NA
L-Isoleucine	5.76	200	NA
Fiber source
Beet pulp	5.57	151	NA
Acid
Orthophosphoric acid	1.60	−8858	−7957
Fumaric acid	2.30	−10,862	−4093
Formic acid	2.30	−13,550	−3473
Citric acid	2.20	−5605	−2349
Ascorbic acid	2.80	−217	−2249
Malic acid	2.20	−7214	−2550
Lactic acid	2.40	−5079	−1498
Acetic acid	2.90	−2283	−141
Propionic acid	3.00	−1358	−5
Sorbic acid	3.50	−220	120

ABC-3 = acid-binding capacity to pH 3.0; ABC-4 = acid-binding capacity to pH 4.0; mEq = milliequivalent; NA = not available in the publication; SBM = soybean meal; DDGS = distillers dried grains with solubles; HPDDGs = high protein dried distillers' grains. ¹ Adapted from Batonon-Alavo et al. (2016), Hajati (2018), Lawlor et al. (2005), Mihok et al. (2022) and Stas et al. (2022). ² The ABC-4 and ABC-3 values of feedstuffs are calculated as the milliequivalent H⁺ of 0.1 mol/L HCl or 0.1 mol/L NaOH required to reduce the pH of a 1-kg sample to pH 4 and pH 3 by measuring 0.5 g of the sample. The values of the column are averages.

Fig. 1. Mechanisms of diarrhea in weaned piglets. The electrolyte gradient is a major driver of fluid absorption and secretion, and Na⁺/K⁺-ATPase provides a large amount of energy to maintain the electrolyte gradient. Fluid absorption is driven by the active transport of Na⁺ between epithelial cells and the uptake of Cl⁻, a process that is largely dependent on NHE3, SLC5A1, SLC26A3, SLC26A6, and MCT1. Fluid secretion is driven by Cl⁻ secretion. Na⁺/K⁺-ATPase provides energy for Na⁺ pumping out of the cell, and K⁺ channels (KCNQ1 and KCNN4) and NKCC1 work together to form an electrochemical gradient that drives Cl⁻ into the cell. Cl⁻ enters the intestinal lumen from the Cl⁻ channels (CFTR, TMEM16A, and CaCC) to form an osmotic gradient that drives fluid secretion. SLC5A1 = solute carrier family 5 member 1; AQPs = aquaporins; SLC26A3 = solute carrier family 26 member 3; SLC26A6 = solute carrier family 26 member 6; MCT1 = monocarboxylate transporter 1; NHE3 = Na⁺/H⁺ exchanger 3; TJ = tight junction; SCFAs = short chain fatty acids; cAMP = cyclic adenosine 3′–5′-monophosphate; cGMP = cyclic guanosine 3′–5′-monophosphate; NKCC1 = Na⁺–K⁺–2Cl⁻ cotransporter 1; KCNQ1 = potassium voltage-gated channel subfamily Q member 1; KCNN4 = potassium calcium-activated channel subfamily N member 4; CaCC = calcium-activated chloride channels; CFTR = cystic fibrosis transmembrane conductance regulator; TMEM16A = transmembrane protein 16A; CaSR = calcium-sensing receptors.

Fig. 2. Cytotoxic effects of deoxynivalenol (DON) and mechanisms of diarrhea induction. DON activates p38 signaling and triggers autophagy via LC3B and helps diarrhea virus evade natural immunity in the STING signaling pathway, leading to massive viral production. DON enhances the inflammatory response through the NLRP3 signaling pathway. DON induces production of ROS, leading to mitochondrial damage and activation of Ca²⁺. DON induces ferroptosis through FTL. DON with diarrhea virus stimulates inflammatory cytokine production and induces Cl⁻ secretion via cAMP, cGMP and Ca²⁺ signaling. In addition, DON with pathogen infection decreased TJ protein expression and increased intestinal intercellular permeability. PEDV = porcine epidemic diarrhea virus; TLRs = toll-like receptors; NHE3 = Na⁺/H⁺ exchanger 3; CFTR = cystic fibrosis transmembrane conductance regulator; TMEM16A = transmembrane protein 16A; CaCC = calcium-activated chloride channels; AQPs = aquaporins; p38 = p38 mitogen-activated protein kinase; LC3B = light chain 3 β; STING = stimulator of interferon genes; NLRP3 = nod-like receptor 3; NF-κB = nuclear factor-κB; IFN-I = interferon-I; IL-1β = interleukin-1β; IL-6 = interleukin-6; IL-8 = interleukin-8; TNF-α = necrosis factor-α; IFN-γ = interferon-γ; NKCC1 = Na⁺–K⁺–2Cl⁻ cotransporter 1; ZO-1 = zonula occludens-1; cAMP = cyclic adenosine 3′–5′-monophosphate; cGMP = cyclic guanosine 3′–5′-monophosphate; ROS = reactive oxygen species; FTL = ferritin light chain.

Fig. 3. Linear relationship between the dietary CP levels and diarrhea incidence for weaned piglets. The data of regression analyses were obtained from 4 published research papers evaluating the effect of diets with different levels of CP on diarrhea incidence in weaned piglets (Gao et al., 2020; Heo et al., 2009; Liu et al., 2022a; Wu et al., 2015). The initial weight of the piglets was 5.9 to 10 kg and the initial age was 21 or 28 d and Liu et al. (2022a) did not describe the initial age of piglets. CP = crude protein.

Fig. 4. Biological detoxification of deoxynivalenol (DON). Adapted from Hou et al. (2023), Li et al. (2023a) and Yao and Long (2020). The Agrobacteriume–Rhizobium strain E3-39, D. insulae A16, Sphingomonas S3-4, Nocardia WSN05-2, P. shaoguanensis DDB001, and Devosia sp. 17-2-E-8 were sourced from soil. The Eubacterium DSM11798 and BBSH 797 were sourced from the animal rumen. The Raoultibacter sp. DII-9, Lactobacillus rhamnosus, Bacillus LS100, and Slackia sp. D-G6 were sourced from the animal intestine. The strain KSM1 and P. halotolerans ANSP101 were sourced from water. The Devosia sp. DDS-1 were sourced from the plant. The yeasts, Fusarium graminearum, Lactobacillus rhamnosus, Pseudomonas sp. Y1, Lysobacter sp. S1, and Devosia sp. ANSB714 were sourced from others. DepA is a pyrroloquinoline quinone-dependent enzyme and DepB belongs to the aldehyde–ketone reductase family. Fusarium trichothecene 3-O-acetyltransferases (FfTRI201) are sourced yeast. 16-HDON = 16-hydroxy-DON; DOM-1 = deepoxy-deoxynivalenol; UDP = uridine diphosphate.

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