Nature-identical compounds (NICs) are new biotechnological feed additives to strengthen and stimulate the fish immune system to prevent and/or control diseases. In this review are presented the most recent studies in which NICs compounds have been used in the fish diet to establish their use and contribute to carrying out more sustainable aquaculture.

Aquaculture sustainable development is necessary since it is categorized as the most important source of aquatic products for human consumption and it is expected to keep growing shortly. In this sense, NICs can be considered a promising alternative to be added to fish diets to promote growth performance, manipulate the gut microbiota, improve the immune and oxidative status of fish, as well as control bacterial infections in this important aquatic industry.

Advantages of using nature-identical compounds instead of plant secondary metabolites

Plant secondary metabolites have enormous economic importance in food, pharmaceutical, chemical, and agricultural industries due to their biological activities and characteristics. However, research about natural product synthesis, started several decades ago and led to the emergence of nature-identical compounds (NICs), which are chemically synthesized compounds but identical to their counterparts present in plant essential oils (EO) and oleoresins (OR) (Rossi et al., 2020).

“NICs present many advantages compared to the use of plant compounds.”

Firstly, NICs are more available than natural compounds since that it is possible to obtain chemicals from plants that are not present in a specific country or region or even outside of the harvesting period. Secondly, NICs are cheaper than natural compounds.

Research on this matter has verified that the production of the desired compounds synthetically is cheaper than obtaining the same substances directly from plants due to the decrease in the number of steps and reagents necessary to obtain the desired compounds, which facilitates and decreases the cost of their production (Figure 1).

Nature-identical compounds as feed additives in aquaculture

Furthermore, the NICs can be used pure and exactly in the required concentration. In addition, to increase the antimicrobial effect and reduce the risk of microbial resistance, which could exist by using NICs at a sub-lethal level, multiple NICs can be used in synergy as well as in combination with antibiotics (Rossi et al., 2020; Giovagnoni et al., 2019).

Considering these advantages, NICs are starting to be widely used as feed additives in animal nutrition instead of plant compounds or extracts as promising non-antibiotics tool since they present the same beneficial effects as those described for plant secondary metabolites.

In this sense, over the last two decades, there have been many studies where the effect of NICs added to animal feed has been analyzed and positive results on growth performance and health status have been obtained on several species, including pigs, broilers, and ruminants.

At present, many commercial formulations including NICs are available such as Xtract® 6930 for broilers, Aviplus® and Enviva® TM EO 101G for broilers and pigs, and Crina® Ruminants for ruminants, among others.

Beneficial effects of NICs when used as feed additives in fish. Comparisons with other animals

Contrary to the information available to some other animal species previously mentioned, very limited information exists about the effect of NICs in fish. The studies carried out till the present using NICs as fish additives are presented and summarized in Table 1.

Nature-identical compounds as feed additives in aquaculture
1.Effects on growth performance

Different results on fish growth performance have been obtained after the incorporation of NICs as feed additives. Seawater Atlantic salmon (Salmo salar) fed NICs alone and European seabass (Dicentrarchus labrax) fed NICs combined with organic acids (AviPlus®) did not show differences in comparison to fish fed control diets.

However, freshwater Prussian carp (Carassius gibelio) fed NICs (Xtract® 6930) and rainbow trout (Oncorhynchus mykiss) fed AviPlus® showed improved growth performance and feed conversion rates compared to control fish. 

Therefore, results obtained can reveal that the specific fish species, the used NICs, and the duration of feed administration play an important role to have better nutrient absorption, optimal feed utilization, and improved animal performance.

The results obtained in fish are similar to those obtained in pigs, broilers, and ruminants.

2.Effects on gut microbiota

Only two research have studied the effects of NICs as fish feed additives on fish gut microbiota and the obtained results were different. European seabass specimens fed AviPlus® showed a proliferation of beneficial lactic acid bacteria as well as an increase in gut microbiota diversity in comparison to the fish-fed control diet; however, no effect was detected on gut microbiota diversity and composition in rainbow trout specimens fed AviPlus® (Busti et al., 2020; Pelusio et al., 2020).

Comparing these results in fish with those in other animals, the positive effects of NICs on the gut microbiota of broilers were described by increasing beneficial bacteria and decreasing harmful bacteria. On the other hand, there are also some studies in which no effect of NICs on pigs or ruminants’ microbiota was observed.

The scarce data make it very difficult to generalize the beneficial or neutral effects of NICs on animal gut microbiota, and more studies in this specific area will be desirable.

3.Effects on the inflammatory status

The inflammatory status of fish can also be modulated by NICs. In this sense, European seabass specimens fed AviPlus® experienced an upregulation in pro- and anti-inflammatory cytokines compared to the fish-fed control diet, while rainbow trout specimens fed AviPlus® did not show any significant difference. However, a stronger immune response by regulation of inflammatory status and activation of w blood cells (WBC) by NICs has been also observed in pigs and broilers.

Regarding literature, the ability to modulate inflammatory activity by phenolic compounds and NICs had already been demonstrated in previous in vivo studies carried out in fish. “

For its part, NICs have also a strong capacity to activate WBCs and modulate the immune response by regulating inflammatory status in pigs and broilers.

It is important to highlight the relationship between inflammation and oxidative stress. In this case, during inflammation, the leucocytes are recruited to the site of damage increasing oxygen consumption and reactive oxygen species (ROS) production while in oxidative stress ROS production leads to the expression of proinflammatory cytokines.

Due to this, the anti-inflammatory and anti-oxidative activities of phenolic compounds and NICs have a huge importance in maintaining the antioxidative and health status of fish (de-Lavor, 2018).

4.Effects after fish bacterial/stress challenge

Stress and disease outbreaks in fish farms are common problems in aquaculture with negative effects on farmed species. For this reason, in some studies fish were challenged to simulate different situations that sometimes take place in fish farms and then fed NICs.

More concretely, Atlantic salmon specimens were challenged with sea lice (Lepeophtheirus salmonis) while European seabass and rainbow trout specimens were exposed to different stress conditions. Those fish-fed NICs diets showed a strong immune response in comparison to the control fish-fed non-supplemented diet.

“Similarly, as to the particular effect of NICs on fish health after the challenge, Atlantic salmon specimens fed NICs decreased sea lice infection and modified the expression of some stress and signaling transduction regulators related to several proteins present in the epidermal mucus.”

On the other hand, European seabass and rainbow trout fed AviPlus® showed a stronger immune response to stress compared to fish fed a control diet. 

European seabass specimens fed control diets up-regulated pro-inflammatory cytokines gene expression while fish fed AviPlus® diet down-regulated also anti-inflammatory cytokine gene expression and maintained gut microbiota comparable to normal conditions.

For its part, rainbow trout specimens fed control and AviPlus® diets up-regulated pro-inflammatory gene expression, especially fish fed AviPlus®. However, in this case, gut microbiota showed lower diversity in specimens fed both control and AviPlus® diets in comparison to normal conditions.

“Therefore, results obtained in these studies reveal that the obtained effects on fish immune status depend mainly on the fish species and the duration and type of feed administration.”

After the addition of NICs to feed, a decrease in bacterial infection has also been observed in pigs against Salmonella typhimurium or broilers against S. enteritidis S. hadar, S. heidelberg, Clostridium perfringens, and Eimeria acervulina.

5.Effects on aquatic Pacific white shrimp

The effect of AviPlus® has been studied on growth, gut microbiota, innate immune response, and disease resistance against V. parahaemolyticus of aquatic Pacific white shrimp (Litopenaeus vannamei) specimens.

Different diets were tested and the specimens were fed ad libitum three times daily for 8 weeks, and then they were challenged with the pathogenic bacteria V. parahaemolyticus. Before the challenge, specimens fed AviPlus® diets did not show differences in growth performance or survival compared to specimens fed the control diet.

“However, specimens fed AviPlus® diets increased serum total protein, alkaline phosphatase, and phenoloxidase activities in comparison to control specimens as well as antioxidant glutathione peroxidase activity.”

Regarding the effect on gut microbiota, specimens fed AviPlus® diets showed more richness and diversity than control specimens by increasing bacteria of Firmicutes phylum and reducing bacteria of Proteobacteria phylum. As to the effect on gut inflammatory gene expression, specimens fed AviPlus® diets decreased pro-inflammatory cytokines gene expression in comparison to specimens fed the control diet.

After a challenge with V. parahaemolyticus (48 h), specimens fed AviPlus® showed higher disease resistance by increasing survival in comparison to control specimens.

Furthermore, shrimp specimens fed AviPlus® diets increased antioxidant catalase gene expression compared to control specimens, as well as antibacterial lysozyme and penaeidin gene expression, demonstrating the possible positive contribution of these molecules against the studied bacterial infection.

6.Bactericidal effects of NICs against fish pathogenic bacteria

Finally, the emergence and increase of infectious diseases are one of the main problems of aquaculture. Normally, the pathogenic bacteria responsible for causing infections are naturally present in the aquatic environment and even in wild fish populations but they rarely cause disease.

However, the conditions of stress that occur in aquaculture encourage the appearance of bacterial infections due to the decreased activity of the host immune system, which is used by bacteria to increase their virulence.

“This is the case of Vibrio species, which most are opportunistic pathogens that take advantage of host immunosuppression to infect them.”

For this reason, in a global context of increased antibiotic resistance, feed additives with antimicrobial properties are a useful and increasingly needed strategy.

In this sense, NICs have been studied against Gram-negative pathogenic fish bacteria V. harveyi and V. anguillarum. Regarding results, the terpenes thymol, carvacrol, eugenol, geraniol, and the terpenic aldehydes vanillin and cinnamaldehyde inhibited the growth of both V. harveyi and V. anguillarum, while eucalyptol, linalool, menthol, alpha-pinene, and limonene had lower activity against the growth of such bacteria.

These results strengthen the use of NICs as possible fish feed additives and corroborate the antibacterial activity of terpenes, phenolic aldehydes, or flavonoids and NICs against Gram-positive Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, Enterococcus cecorum, and Gram-negative Escherichia coli which allow their use in the prevention and therapy of several diseases and/or infections.

Conclusions

The available results of the studies carried out on fish and aquatic animals by using NICs suggest that they can be considered a promising alternative to be included in the diets of these organisms.

Furthermore, it is important to highlight the combination of used NICs, the specific fish species and the duration of feed administration play a crucial role to have positive results to promote growth performance, improving gut microbiota, and reinforcing the immune and oxidative status of animals, as wells as to control bacterial infections such as vibriosis, contributing to carrying out more sustainable aquaculture.

This is a summarized version developed by the editorial team of Aquaculture Magazine based on the review article titled “NATURE-IDENTICAL COMPOUNDS AS FEED ADDITIVES IN AQUACULTURE” developed by JOSE MARÍA GARCÍA BELTRÁN – University of Murcia; MARÍA ANGELES ESTEBAN – Universidad de Murcia.
The original article was published in FISH AND SHELLFISH IMMUNOLOGY in March 2022.
The full version can be accessed freely online through this link: https://doi.org/10.1016/j.fsi.2022.03.010

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