For producers to raise healthy pigs and to avoid the use of antibiotics, it is critical the piglet has optimal gastrointestinal functionality. However, around weaning there are significant challenges that make this goal difficult to achieve. Optimal gastrointestinal functionality is a situation where the welfare, health and performance of the pig is not constrained by intestinal dysfunction (Celi et al., 2017).  To achieve optimal gastrointestinal functionality, there has to be effective digestion and absorption of the feed which requires a normal and stable microbiota, appropriate structure and function of the mucosa and a balanced immune system.

Supporting the piglet at weaning starts with protecting the gut. The gut provides four important functions: it regulates nutrient and fluid uptake, it manages immune tolerance, it provides a defense against infections and it provides a barrier to the external environment. In nature, the piglet is weaned over many weeks in a gradual, prolonged process which permits full development of these functions. However, in commercial production, the weaning process is an abrupt one-day event which brings many challenges to the four essential functions of the gut, culminating in the most commonly reported problem in weaned pigs globally of post-weaning diarrhea stemming from leaky gut syndrome. 

Leaky gut syndrome

Leaky gut syndrome is characterized by hyper-permeability of the intestinal epithelium.  A failure in tight-junction functionality results in an increase in paracellular transfer of deleterious compounds (such as bacteria and undigested nutrients) from the intestinal lumen. These deleterious compounds activate the NF_kB pro-inflammatory cytokine cascade causing an increased production of reactive oxygen species such as peroxides to fight the microbes but which can also cause collateral damage to cells. Pathogens, such as enterotoxigenic E. coli (ETEC) are then able to adhere to the intestinal cells and produce toxins that induce a loss of water and electrolytes from the cells resulting in diarrhea (Gresse et al., 2017). In addition to diarrhea, the other outcomes of the enteric infection such as reduced feed intake, weight loss, fever, poor feed efficiency and lack of uniformity are easily seen by the producer.  What is not easily seen though is the underlying increased production of pro-inflammatory cytokines and acute phase proteins that the enteric infection triggers.  The production of these compounds significantly modifies qualitatively and quantitatively the requirement for specific nutrients such as amino acids, vitamins, minerals, antioxidants and lipids.

The severity of leaky gut syndrome is impacted by direct and indirect factors. The direct factors include allergens and antigens that activate the pro-inflammatory cytokine cascade that cause gut inflammation.  Allergens can originate from feed and the most prevalent in piglet diets originate from soybean meal. Antigens can also originate from feed and include components such as mycotoxins, but can also originate in the gut lumen from cellular debris (peptidoglycans) originating from cell walls of dead gram-positive bacteria (McCormack et al., 2020).

The indirect factors contributing to the severity of leaky gut syndrome are the facilitators of a gut environment that supports the growth of pathogens both in terms of the substrates they need to grow and the environment in which they live in. 

The dual strategy to reduce leaky gut syndrome are outlined in Figure 1.  

Strategies to support optimum gastrointestinal functionality

1. Deactivate glycinin with a targeted protease. A major and common allergen found in many swine feeds are the soybean proteins of glycinin and B-conglycinin.  These two proteins typically account for about 75% of the protein fraction of soybeans or 25-35% of the seed weight (Hammond et al., 2016). These soy allergens increase the permeability of the intestine which induces a local immune response leading to sensitization, resulting in impaired gut homeostasis and functionality. Using a targeted protease to deactivate glycinin has shown to decrease pro-inflammatory cytokines in plasma and reduce the permeability of the jejunal barrier (Park et al., 2020).
2. Deactivate mycotoxins. Mycotoxins, particularly compounds such as deoxynivalenol and fumonisins are also known to disrupt tight junction protein function and further facilitate absorption of other mycotoxins and compounds from the gut. Effective deactivation of mycotoxins has shown to improve weight gain of piglets and prevent intestinal histology damage (Maching, 2015).
3. Apply a muramidase to reduce negative effects of the PGN. Peptidoglycans (PGN) are a major component of bacterial cell walls and are significant in gram-positive bacteria but are also found in gram-negative bacteria. Peptidoglycans are a key component of the mechanism by which the gut recognizes the presence of bacteria and initiates an immunological response (Wolf and Underhill, 2018). When bacteria die, the cell debris including PGN can trigger an immune response by binding to the epithelial cell toll-like receptor-2 (TLR-2). The resulting inflammatory processes can lead to a reduction in nutrient absorption in the small intestine and exacerbate nutrient flow to the hindgut where pathogens can grow. Application of a specific muramidase can cleave PGN creating muramyl dipeptide (MDP) thereby reducing the negative effects of the PGN. Furthermore, MDP is taken up by the epithelial cell and activates another receptor, NOD-2.  When NOD-2 receptors are activated, they initiate an anti-inflammatory effect through their role in barrier protection and surveillance of the cell wall.  The use of a muramidase may therefore assist in balancing the pro- and anti-inflammatory effects that bacterial debris create in the intestine and result in improved piglet average daily gain (Wang et al, 2021; EFSA, 2021).

Strategies to create a less favorable gut environment for pathogens

1. Use enzymes to mitigate E. coli risk and improve nutrient digestibility. In addition to the allergens, soybean meal also contains protease inhibitors which interfere with the activity of trypsin and or chymotrypsin, essential endogenous enzymes for protein digestion. While heat treatment during soybean meal production can mitigate some of the protease inhibitor effects, if destruction of the protease inhibitors is not complete, the undigested protein in the diet can be fermented in the hindgut and lead to the production of toxic nitrogen containing metabolites and diarrhea (Jha and Berrocoso, 2016). The presence of viscous fiber has also been shown to support the growth of gram-negative bacteria which are known to have negative effects on gastrointestinal functionality and overall health of the pig (Hopwood et al., 2004). Use of enzymes targeting the soluble non-starch polysaccharide component of the diet have been shown to reduce the viscosity of the digesta and mitigate the risk of pathogenic E. coli growth and lead to improved nutrient digestibility and animal performance as seen by average daily gain improvements and reductions in watery diarrhea (Kim et al., 2011).
2. Deactivating the antinutrient effect of phytate. Dietary phytic acid is known to bind nutrients and enzymes in the stomach and small intestine which can decrease digestibility and increase nutrient flow to the hindgut (Woyengo and Nyachoti, 2013).  Furthermore, the high negative charge density of phytic acid results in strong complexing of cations such as iron as well as calcium, zinc and magnesium (Humer et al., 2014) and therefore may provide a valuable source of iron for supporting pathogen growth in the hindgut. Use of phytases to hydrolyze phytic acid and therefore reduce the negative effects of phytic acid on nutrient flow to the hindgut and mineral binding has been shown to be an effective strategy (Lee and Stahl, 2001). 
3. Change the pH of the gut to reduce pathogen growth. Changing the pH environment of the gut to favor inhibition rather than proliferation is another effective strategy to reduce pathogen growth. Using an ultra-pure benzoic acid to reduce the pH of intestinal content to pH 5.5 has been shown to effectively reduce the growth of E. coli compared to other acids. Furthermore, when ultra-pure benzoic acid was added to piglet diets, a significant and dose dependent response on pH in the stomach and small intestine was observed (Knarreborg et al., 2002).

Conclusion

Reducing the need for medications post-weaning relies on protecting the piglet against gut dysfunction that causes diarrhea and supporting optimum gastrointestinal functionality. The achievement of this objective requires a multifaceted approach that is not dependent on a single product strategy but most encompass a comprehensive nutrition approach. In contrast, to tackle this challenge, success lies in the use of tailormade solutions that create a gut environment that is not favorable for pathogen growth in terms of the environment and nutrient supply for the pathogens and deactivating the anti-nutrients arising from the feed and the microbiome.