Antibiotics Alternatives: the multiple effects of butyrate

Throughout the human history, utilization of antimicrobials in food production and human health have been greatly favored. Tremendous improvement in farm animal production and historically unprecedented enhancement in human health protection were marked benefits of utilizing antibiotic in agricultural and human medical arenas. However, the misuse and overdose of antibiotics has resulted in accelerating antimicrobial resistance (AMR). Although the human use and overdose of antibiotics is believed to be the biggest contributor to AMR in human pathogens, the intensive utilization by farm animals is considered the an important factor contributing to this worldwide problem. Currently, with the increasing public concerns over the development of AMR pathogens due to using (sub-)therapeutic concentrations of antibiotics delivered in poultry feed, many countries all over the world have restricted antimicrobial use for farm animals either as a veterinary drug or as an antibiotic growth promotor (AGP).

Numerous strategies have been suggested to be as means to reduce antibiotic usage. These strategies could be divided into four categories: biosecurity, farm management, vaccination and feed and feeding programs/ alternatives. Feed alternatives like natural growth promotors (NGP) can play a hygiene effect and can have a positive impact on gut health thereby subsequently improving overall animal health. Thus, a noticeable reduction of veterinary drug usage to heal enteric infections is expected to occur. So, NGPs utilization in general, will play a major role in strengthening the gastrointestinal tract and can be recognized as one active strategy to replace AGPs.

Short chain fatty acids (SCFA) are a group of molecules that originate in the gastrointestinal tract naturally as end products of microbial fermentation of dietary fibers in the large intestine. Among SCFA, butyric acid has received considerable attention. It is a natural substance present in the GIT, in milk as well as in the sweat and faeces of most mammals. Butyric acid is available as the Na, K, Mg or Ca salt or as glyceride derivatives. Butyrate helps improving GIT health and reduces colon cancer incidence in humans. Furthermore, it has been shown to have antibacterial activity on some enteric bacteria as well as to stimulate villi growth. Indeed, some coated butyrate products have shown direct effects on improving villi growth in early age as of 3 days in broilers (Fig. 1).

Antibiotics Alternatives: the multiple effects of butyrate - Image 1

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Butyrate is naturally present in high concentration in the lumen of the large intestine. It is preferentially taken up by the colonic epithelium where it is actively metabolized to produce energy. In all tissues, butyrate is a natural component of cellular metabolism, which may also actasaNGPwhen added to diets at low doses (0,1 – 1,0 g/kg diet). Butyrate alsohasanti-inflammatoryproperties,andhasthe potential to play a major role in triggering several physiological pathways when it is delivered through the whole GIT in a coated form. Such a coating allows butyrate to be gradually released after ingestion (precision delivery coated butyrate; PDCB). Precision delivery coated butyrate salts, when delivered post-gastrically, can also activate certain pathways that are not (or less) activated by dietary AGP supplementation. An example; PDCB can fortify the epithelial lining of the intestinal tract, increase nutrients absorption through larger villi surface area, increase secretion of digestive fluids, and may be used by other organs like the liver as an energy source.

A commonly diagnosed disease in poultry flocks’ Necrotic enteritis (NE) is causing severe economic losses. Clostridium perfringens is a gram-positive,sporeforming bacterium that grows only under anaerobic conditions and mainly affects 2- to 5-wk old chickens. Many predisposing factors are responsible for developing NE, including coccidiosis, high dietary protein content, higher stocking density, stress, and immunosuppression. AGPs alternatives, likeorganicacids,short chain fatty acids (SCFA), essential oils, and probiotics have an increasing importance in the prevention and treatment of NE.

Similarly, precision delivery coated butyrate can be used as interventionofseveralintestinal bacterial infections, like salmonellosis. Published research work demonstrated that PDCB reduced the incidence of NE in broilers. It is hypothesized that butyrate, in the form of undissociated butyric acid, can penetrate a bacterial cell wall and dissociate to H⁺ and anions inside the cell, lowering pH and resulting in energy deficiency and osmotic problems in the organism. More importantly, PDCB, with respect to NE, restores villus morphology in chickens at least partly through tightening the junctions in intestinal mucosal epithelial cells.

In a recent NE model in broiler chickens (Fig. 2), supplementing challenged birds with PDCB resulted in reducing NE lesions scores. The opposite was true for challengedgroupwithoutPDCB that showed higherincidenceoflesion scores. In the model used, these effects continued as birds aged, with the challenged PDCB-supplemented group having a higher percentage of birds with no lesions at all at 28 days of age. These results show that PDCB helps to protect and/or repair intestinal epithelial cell damage, and thus reduce nutrients loss and reduce inflammation. So, in generalPDCB establishes conditions in the lower intestinal tract that are not favorable for Clostridium perfringens.

Antibiotics Alternatives: the multiple effects of butyrate - Image 3

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Necropsied birds at day 21 and 28 examined for gross pathological lesion scoring of the small intestine. The scoring systemcriteriaisthesix-point system of Keyburn et al. (2006) modified by Shojadoost et al.( 2012) as follows:

0 =No gross lesions -

1 =Thin or friable walls, or diffuse superficial but removable fibrin

2 = Focal necrosis or ulceration, or non-removable fibrin deposit 1 to 5 foci

3 = Focal necrosis or ulceration, or non-removable fibrin deposit 6 to 15 foci

4 = Focal necrosis or ulceration, or non-removable fibrin deposit 16 or more foci

5 = Patches of necrosis 2 to 3 cm long variable

6 = Diffuse necrosis typical of field cases variable, but extensive.

Tim: chi-square: score 0-1 en 1-2; ADIMIX®Precision en no ADIMIX®Precision: p < 0,05

Additionally, dietary supplementation of PDCB showed positive affects regarding broiler performance, as it improved performance including BW gain and final body weight. In the same NE model, broilers (challenged ornon- challenged) with Clostridium perfringens, when fed diets supplemented with PDCB, had significantly higher FBW in comparison to those fed diets without PDCB (Fig 3). Furthermore, administering challenged birds with PDCB resulted in better FCR (1.78) which followed a similar trend to that of the control group (1.77.; Fig. 3).

Antibiotics Alternatives: the multiple effects of butyrate - Image 5

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In conclusion, feeding AGPs alternatives, such as precision delivery coated butyrate (PDCB) show a great potential as strong candidates for supporting broiler performance, especially when supplemented at earlier age. Dietary supplementation of PDCB improves the digestion and absorptive processes and consequently birds’ overall performance results and controls gut health disorders caused by bacterial pathogens. Although they do not offer a cure to acute bacterial challenges, they would play a major role in prevention and preparing the gastro-intestinal tract to overcome the negative consequences of some diseases (i.e. NE, salmonellosis, etc.) as birds grow older.