Unlike traditional AGPs which reduce diversity of gut microbiota, a gut health solution product having BSHI functionality supports the diversity of gut microbiota. Since the commensal microbiota have evolved additional detoxification mechanisms, such as bile efflux pumps, to defend against bile acid toxicity, they are hardly affected by both bile acids and the BSH inhibition mechanism.
Technical Marketing Manager of Gut Health
CJ BIO
Enteric diseases are the most critical economic and health problems in the livestock industry, causing reduced growth rates, increased mortality and cost of production. Numerous pathogenic bacterial species, such as Clostridium spp., Escherichia coli, Salmonella spp., Lawsonia intracellularis, Brachyspira (B.) hyodysenteriae, and B. Pilosicoli, are major causes of the enteric diseases during the entire phases of pig production (Figure 1).
WHY GUT HEALTH IS IMPORTANT IN PIG PRODUCTION?
Neonatal and post-weaning diarrhea (PWD) are the most frequently observed enteric diseases in commercial production systems. Multiple enteric infections can coincide during the neonatal and the post-weaning phase, leading to complex clinical disease patterns that make control measures difficult. The transition to the weaning stage is especially challenging in swine production, making piglets vulnerable to gastrointestinal health disruptions. The gut health of nursery pigs right after weaning is closely associated with their growth performance and overall economic returns to the producers. That is why post-weaning diarrhea is one of the major concerns related to the gut health of nursery pigs. As post-weaning diarrhea is often caused by the introduction and overgrowth of specific pathogens, it is crucial to improve gut health and strengthen immunity to effectively control pathogen-originated infections.
THE EXPANSION OF REGULATIONS ON PROPHYLACTIC USE OF ANTIBIOTICS AND ZINC OXIDE
Prophylactic use of antibiotics has been the most effective measure to prevent enteric diseases and to promote animal growth in commercial swine production, hence the term “antibiotic growth promoters (AGPs)” has been used. With the increased bacterial resistance to antibiotics and the strict regulations of the AGPs, however, alternatives to antibiotics are needed to maintain the gut health and the production efficiency of piglets. Furthermore, the pig industry has used antimicrobial minerals, such as zinc oxide (ZnO) and copper sulfate (CuSO4), for many years to reduce diarrhea in post-weaned pigs. Unfortunately, the therapeutic use of zinc oxide was banned across the European Union (EU) in the summer of 2022 due to potential environmental risks and in line with regulations set by the EU.
WHAT ARE BILE SALT HYDROLASE INHIBITORS?
As regulations tighten in pursuing a sustainable livestock industry, efforts to discover effective alternatives to AGPs and zinc oxide are still progressing. Among the many categories and mode-of-actions of the alternatives to AGPs, such as probiotics, organic acids, prebiotic oligosaccharides, and bacteriophages, some of the researchers have focused on one of the mode-of-actions commonly found in AGPs and ZnO (Smith K, et al., 2014; Geng and Lin, 2016), which maintain the bactericidal activity of conjugated bile acids by inhibiting bile salt hydrolase (BSH) activity, known as bile salts hydrolase inhibitor (BSHI).
To figure out more details of the mechanism of BSHI, it is important to understand the functions of bile acids besides boosting fat emulsification and absorption. Bile acids act as innate antibacterial agents by disrupting bacterial cell membranes, inducing DNA damage, protein misfolding. In other words, unique and natural antibiotics already exist in the animal’s body. Especially, when bile acids are released into the duodenum, either glycine or taurine combine with the bile acids, forming ‘conjugated bile acids (or bile salts)’. The form of conjugated bile acids has stronger bactericidal activity due to increased solubility in the small intestine than other forms of bile acids. The bactericidal effects of conjugated bile acids on the major pathogens responsible for enteric diseases in pigs and poultry have been confirmed with internal in vitro test. The data shows that the high level of conjugated bile salts can kill the ETEC (Enterotoxigenic Escherichia coli, F18), S. Typhimurium, and C. perfringens (Figure 2).
However, the problem is that bile salts gradually lose their antibacterial activity as they pass through the intestine because of BSH, which is produced by commensal bacteria. As bile salts can also be toxic to the commensal bacteria (or gut microbiota), they have evolved to produce BSH to survive from the bile salt toxicity and protect themselves. Once BSH deactivates conjugated bile acids, these cannot kill the pathogens introduced from the outside environment as the ability to produce BSH is limited in non-commensal microbiota. Thus, inhibition of BSH is an effective way to control the overgrowth of enteric pathogens without affecting the commensal microbiota. Especially, maintaining a high level of conjugated bile acids in the intestine can supress pathogen overgrowth and the diarrhea issues in the commercial production system.
Unlike traditional AGPs which reduce diversity of gut microbiota, a gut health solution product having BSHI functionality supports the diversity of gut microbiota. Since the commensal microbiota have evolved additional detoxification mechanisms, such as bile efflux pumps, to defend against bile acid toxicity, they are hardly affected by both bile acids and the BSH inhibition mechanism. In relation to the above-mentioned notion, several studies have reported that microbial diversity is reduced in organisms with the disorder of bile acid production and release (ex, cholestasis and bile duct ligation) in humans and mice. It’s been well acknowledged that the secretion of bile acids provides sufficient momentum to support the diversity of microorganisms in the intestine (Collins et al., 2023).
WHAT IS THE BEST OPTION FOR INHIBITION OF BSH ACTIVITY?
After years of research and development, CJ BIO has developed a combination of natural ingredients with BSHI function and the best blends to provide gut health solutions through in vitro, ex-vivo, and in-vivo validation. GutLuk™ is composed of an optimum ratio of four selected epicatechins, vitamin K, and tributyrin. The product blend showed the best functionality of BSH inhibition and the rapid regeneration of damaged gut epithelium (Figure 3).
VERIFICATION OF EFFICACY IN PIGLETS AND POULTRY
To verify the effect of GutLuk™ on piglet performance and intestinal health (diarrhea and mucosa-associated microbiota as indices), an academic research was conducted. The result confirmed that pigs fed a diet containing GutLuk™ significantly improved average daily gain (ADG) compared to the piglets fed a negative control (NC) diet without AGP or ZnO supplementation. GutLuk™ fed piglets also showed a comparable growth performance to the pigs fed diets supplemented with AGP (PC1) and ZnO (PC2). Additionally, GutLuk™ significantly reduced the incidence of diarrhea and improved gut integrity (V/C ratio) to a comparable level of the AGP- or ZnO-supplemented groups. To assess the effect on gut microbiota, AGP, ZnO, NC, and GutLuk™ 0.1% groups were selected for analysis. With the supplementation of GutLuk™, the composition of mucosa-associated microbiota in the jejunum was positively altered compared to the AGP- and ZnO-supplemented groups, as GutLuk™ increased Firmicutes:Bacteroidetes (F:B) ratio and reduced population of Proteobacteria in the phylum level. It is well known that the increased F:B ratio positively affects pigs’ weight gain. In addition, Proteobacteria is the phylum the major pathogens, such as Escherichia, Salmonella, are included. This research confirmed the hypothesis that maintaining the concentration of conjugated bile salts can control the overgrowth of pathogens while supporting the growth of beneficial microbiota (Figure 4).
A product verified in academic research often fails to show the same efficacy in the commercial production system due to the multiple challenges animals are experiencing. Therefore, it is more important to validate the impact of GutLuk™ on the health of piglets in a commercial production system. Efficacies in boosting growth performance and reducing mortality were confirmed in a commercial farm trial with 13,200 piglets in South Korea. The farm has confirmed the presence of ETEC (F4) in feces, wet feeds, and pens. Even though the farm had used ZnO at 2,000 ppm, piglets suffered from a chronic ETEC-associated clinical disease. However, once GutLuk™ is supplemented instead of ZnO in the piglet diet, the ADG and FCR were improved, and the mortality rate was reduced (Figure 5).
Moreover, GutLuk™ also shows the efficacies in boosting growth performance and egg production in broilers and layers. For example, a research farm trial in which broilers were fed a diet supplemented with GutLuk™ 0.03% showed increased average daily gain and production indices and decreased mortality. Furthermore, egg production rate of layers fed a diet supplemented with GutLuk™ 0.03% were remarkably increased to 87% from 83% in a commercial farm trial conducted in Indonesia.
CONCLUSIONS
The livestock industry is struggling with increasing concerns about numerous enteric diseases and elevated regulations for sustainable farming. Therefore, choosing an effective gut health solution product can be a breakthrough in reducing production costs and improving production efficiency. GutLuk™ is a natural AGP alternative, which improves growth performance through inhibition of pathogen overgrowth. Furthermore, it is free from resistance and residue concerns because it is a phytogenic blend that maintains the bactericidal effects of bile salts, an innate antimicrobial agent. Lastly, compared to other phytogenic products, GutLuk™ has superior anti-microbial effects verified in commercial farm studies. The gut health solution of GutLuk™ can be a strategic asset that contributes to successful and sustainable swine and poultry production.
References available upon your request.
About Vicky Hyejin Yoo
Vicky Yoo joined CJ BIO as a Technical Marketing Manager of Animal Health in 2019. She holds a Master’s degree in Veterinary Medicine at Seoul National University. Since joining CJ BIO, she has gained extensive experience in conducting experimental trials on enzymes and gut health products. Vicky Hyejin Yoo provides technical support to end users, helping them maximize animal health and productivity through value-added solutions.
