Sirtuin-1 SIRT1 is another important regulator of thermogenesis and its primary role is to deacetylate PPARγ [ 9 ]. Deacetylation of PPARγ is required to recruit PRDM16 which further leads to the induction of BAT genes and repression of WAT genes [ 7 ].

Association between these important transcription factors leads to the development and regulation of BAT function. Not surprisingly, considerable cross-talk in the regulation between BAT and WAT exists where WAT-specific genes downregulate BAT activity.

PRDM16 is required for beiging in WAT and the repression of genes that promote WAT development [ 7 ]. Mice that are deficient in adipose tissue-specific PGC-1α have dulled expression of thermogenic and mitochondrial genes in WAT [ 10 ].

Developmental origins of white , brown and beige adipocytes. Thermogenesis is the process of converting chemical energy into heat.

While shivering thermogenesis makes use of rapid muscular twitches to produce heat, BAT is specialized to generate heat in a process called non-shivering or adaptive thermogenesis [ 13 ]. BAT plays a pivotal role in protecting animals from hypothermia and is used during the periods of hibernation.

It has long been known that BAT is present in newborns, but a number of recent studies conducted through the combined utilization of FDG PET and CT show that human adults do have brown fat [ 14 , 15 ] paving way to a new area in research relating to metabolic and obesity therapies [ 16 ].

The functional properties of BAT that makes it different from WAT mainly come from the lack of a large, unilocular lipid droplet and the presence of numerous mitochondria which allows for the production of energy.

Mitochondria in brown adipocytes have low levels of ATP synthase and so cannot utilize the proton gradient of mitochondria to produce ATP. Instead, they employ UCP1 which uncouples cellular respiration and ATP synthesis, and thus results in the production of heat [ 17 ].

In vivo studies have shown that mice that lack the Ucp1 gene preferentially express an obese phenotype [ 18 ]. These studies show the importance of BAT thermogenesis and its role in preventing obesity.

The sympathetic nervous system plays a significant role in the regulation of BAT thermogenesis. The release of catecholamines such as norepinephrine as a result of sympathetic stimulation from cold induction through the transient receptor potential TRP cation channels members A1, M8, and V1 leads to the activation of the mitochondria in BAT which further leads to heat generation.

The subsequent binding of norepinephrine to β-3 adrenergic receptors causes the secretion of free fatty acids from BAT which is the main energy source for UCP1 driven thermogenesis [ 19 ]. Thyroid hormone is an additional critical driver of the thermogenic response and brown adipose tissue activation.

The conventional signaling cascade for thyroid hormone starts from the release of thyroxin T 4 from thyroid gland upon stimulation by the pituitary. Once released, T 4 travels through the bloodstream to target tissues that express the necessary deiodinase specifically DIO2 for the creation of triiodothyronine T3 [ 20 ].

Relative to other tissues, brown fat expresses a relatively large amount of deiodinase [ 21 ] and thus is reactive to changes in circulating T 4 concentrations, in addition to the sympathetic activation that upregulates deiodinase expression [ 22 ].

The UCP1 promoter contains a transcriptional regulatory region for the thyroid hormone receptor β [ 23 ]. Thus, thyroid hormone can directly upregulate the expression of UCP1 and serves as a necessary regulator for both brown adipogenesis and thermogenesis. Further, the α-subtype of the thyroid hormone receptor also regulates the expression of the β-adrenergic receptors [ 24 ], thereby sensitizing brown fat to sympathetic activation.

Secondarily, active T3 can be released from tissues and interact with additional cell types not believed previously to be regulated by thyroid hormone. Of most interest, T3 has demonstrated the ability to activate the ventral medial hypothalamus which serves as a central mediator of the sympathetic nervous system [ 25 ].

Through this mechanism, T3 appears to further regulate sympathetic activity and drive the activation of BAT in addition to direct transcriptional control of UCP1. It should be noted that the levels of T3 in BAT is influenced by DIO2 activity, which in turn is inhibited by T4 and activated by adrenergic stimulation.

Natural, plant-derived compounds have made up the backbone of many of the synthetic drugs which are used today. The use of natural products for medical purposes dates back thousands of years; however their use in the discovery and development of modern drugs has only occurred since the early 19th century.

The safety of these synthetic compounds however is hotly debated. Recent drug recalls and fatalities have led to resurgence in research on natural products because of their ease of use and efficacy.

In particular, certain anti-obesity medications are removed from market owing to their adverse side effects [ 28 ]. In this context, natural products have been studied for their role in the regulation of adipocyte life cycle [ 29 ].

Phytochemicals can target different stages in the adipocyte life cycle by decreasing adipogenesis, inducing lipolysis, inducing adipocyte-apoptosis and by inducing transdifferentiation of white to brown-like adipocytes [ 30 ].

While the terms nutraceuticals, phytochemicals and bioactives are often used synonymously, it should be noted that phytochemicals are non-nutrient bioactive compounds found in fruits, vegetables and other parts of plants.

Nutraceuticals on the other hand are broadly defined as food supplements that are used to improve health. This review focuses primarily on the effects of purified bioactive compounds rather than the plant extracts.

In the coming sections, we discuss some of the phytochemicals that have shown promise as activators of BAT or have potential to act as thermogenic agents for future applications in the prevention and treatment of obesity and metabolic syndrome. Resveratrol is a polyphenol found in a number of plants including the skin of grapes and several other types of berries.

Numerous studies have indicated the anti-oxidant properties of this compound and the research around resveratrol continues to grow into other therapeutic uses such as cancer suppression and improving insulin sensitivity [ 31 ].

Furthermore, SIRT1 in WAT is activated by resveratrol to promote the mobilization of fat from adipocytes [ 31 , 33 ]. Unsurprisingly, resveratrol has shown the possibility to also regulate BAT activity.

Alberdi et al. found elevated levels of UCP1 expression in the BAT and skeletal muscle of mice that were fed a diet supplemented with resveratrol [ 32 ]. Further, oral administration of resveratrol in mice also showed an increase in SIRT1 expression in WAT [ 34 ].

Authors proposed that the increased UCP1 expression seen in mice is due to stimulation of SIRT1 contributing to the improved energy efficiency and decreased fat mass. On the other hand, Um et al. reported that resveratrol fails to upregulate thermogenic proteins like PGC1α in adenosine monophosphate activated kinase AMPK null mice and AMPK null mice are resistant to the thermogenic effects induced by resveratrol [ 35 ].

Subsequent studies however revealed that SIRT1 plays a key role in potentiating resveratrol-induced activation of AMPK and improving mitochondrial function [ 36 ].

These findings suggest that resveratrol — induced increase in whole-body energy expenditure might be partly mediated by the induction of browning in WAT. Curcumin is a flavonoid found in turmeric, a spice popular in south Asian cuisine. Administration of curcumin has been shown to improve insulin sensitivity and increase weight loss in insulin-resistant obese mice [ 37 ].

Furthermore, curcumin-treated mice have lowered amount of free fatty acids, triglycerides, and improvement of insulin resistance and hyperglycemia suggesting its anti-diabetic potential [ 37 ]. Subsequently, curcumin has been shown to induce browning of 3 T3-L1 cells as indicated through increased expression of brown fat markers including PGC-1α, PPARγ, and UCP1 in dose dependent manner [ 39 ].

Further, T-box transcription factor 1 TBX1 , a beige specific marker, was significantly increased in 3 T3-L1 and primary white adipocytes following treatment with curcumin. Within this study, curcumin treatment resulted in the increased expression of many beige specific markers such as Ucp1 , Pgc1α , Dio2 and Prdm Cold tolerance tests conducted on mice showed that curcumin treated mice had increased body temperature compared to temperatures around 4 °C [ 40 ].

Additionally curcumin treatment stimulated the emergence of beige cells in inguinal and subcutaneous WAT but not epididymal WAT. The authors further postulated that the curcumin-induced browning of WAT is mediated by the upregulation of β3-adrenergic receptor expression and elevation of plasma levels of norepinephrine by curcumin [ 40 ].

Not surprisingly, curcumin appears to act through the transient receptor potential vanilloid receptor 1 TRPV1 receptors located in the intestinal jejunum and thus may have downstream effects on both WAT and BAT through direct modulation of the sympathetic nervous system [ 41 ].

Soy isoflavones are phytoestrogens which have shown promise in lipid metabolism. A recent human clinical trial with isoflavone supplemented soy probiotic for 42 days, showed an improvement in the lipid profile of moderately hypercholesteremic men [ 42 ]. One major photochemical belonging to this group of soy isoflavones is genistein.

Genistein is found primarily in soybeans and broad beans, which are harvested in parts of Western Asia and Europe. Effects of genistein on cancer prevention have been under investigation for a long time and these effects are attributed to the epigenetic effects of genistein.

Genistein was shown to target all the epigenetic mechanisms like altering DNA methylation, and histone modifications that control the accessibility of genes of interest reviewed in [ 43 ]. Not only has genistein been described as a PPARγ agonist [ 44 ], but recent studies provide evidence that genistein has the potential to promote characteristics of beiging in WAT.

High dose treatment of genistein 50— μM on NIH3T3-L1 cells was shown to result in the increased expression of SIRT1 and its downstream partner, UCP1 [ 45 ]. Such an effect was also observed in primary culture whereas genistein increased mitochondrial biogenesis by upregulating PGC-1α [ 46 ].

In 3 T3-L1 and human primary adipocytes, genistein has shown to inhibit adipogenesis at concentrations of 50 μM [ 47 ]. However, Zanella et al. found that using minimal doses plasma concentration of 4 μM in mice models, genistein promoted 3 T3-L1 adipogenesis rather than inhibiting it [ 48 ].

This evidence highlights the importance of dose range in the effect of phytochemicals on the cellular mechanisms of adipocyte differentiation. Genistein and its fellow isoflavone resveratrol have shown their ability to defend against metabolic syndrome by regulating lipid and glucose metabolism.

Lastly, it is important to mention that the use of both resveratrol and genistein has shown to have a greater effect on adipogenesis and apoptosis of adipocytes rather than each of these compounds alone [ 49 ]. Thus, it is likely that the combination treatments of both genistein and resveratrol may lead to an even greater anti-obesity effect and activation of BAT which has not yet been explored.

Guggulsterone GS is the bioactive gum resin derived from the bark of the Commiphora mukul tree predominantly found in India, Bangladesh and Pakistan. Cholesterol lowering effects of GS were first reported in hyperlipidemic rabbits [ 50 ] and since then, numerous animal and clinical studies have been conducted to demonstrate the effects of GS on lipid, cholesterol, and triglyceride levels [ 51 ].

However, there is a lack of reliability in several of the human studies that have attempted to explore and better understand the potential of GS due to flawed techniques [ 52 ].

In contrast, in vitro studies investigating the effects of GS on adiposity have found more success and clearly demonstrate i inhibition of adipogenesis [ 53 ], ii increase glucose uptake in insulin resistant conditions [ 54 ], iii lipolytic effects in combination with other agents such as genistein [ 55 ] xanthohumol [ 56 ], and hormonal metabolite of vitamin D [ 57 ].

To date there is no scientific-based research that investigated the ability of GS to stimulate mitochondrial uncoupling and thus increase metabolic rate. GS is structurally similar to bile acids and has been identified as a selective bile acid receptor modulator [ 58 ].

Additionally, GS was also shown to exhibit thyroid stimulating activity [ 59 ], indicating potential for GS as a browning agent. Apart from interacting with farnesoid X receptor [ 58 ], a bile acid receptor, GS may also act as ligand for Takeda-G-protein-receptor-5 TGR5 , another bile acid receptor [ 59 ].

Bile acids have been implicated in weight control by reversing and preventing diet induced obesity [ 60 ]. TGR5 receptor is expressed in many of the gastrointestinal tract organs, lungs, mammary gland, uterus, skeletal muscle, macrophages and brown adipose tissue and mainly functions to increase intracellular adenosine monophosphate AMP [ 61 ].

Activation of TGR5 drives to increase cyclic AMP-dependent upregulation of DIO2 which is a response to sympathetic activation as well as increasing serum concentrations of thyroxine T4 [ 59 ]. GS has been shown to induce DIO2 expression in mature 3 T3-L1 adipocytes [ 63 ], further strengthening the hypothesis that browning effects of GS may, in part, be mediated via the activation of TGR5 signaling pathway.

Model for the induction of browning by phytochemicals. Guggulsterone binds to TGR5 and increases the expression of DIO2 which in turn enhances T3 levels leading to the induction of beiging. Resveratrol is a sirtuin activator and enhances the levels of cAMP and also activates AMPK.

SIRT1 mediates PGC1α deacetylation and AMPK activates PGC1α. PRDM16 co-activates PGC1α and PPARγ driving the upregulation of thermogenic genes. Likewise, naringenin also activates SIRT1 contributing to the induction of beiging.

Hop plants or Humulus lupulus are more widely known for their usage in the beer brewing process but far less known are the historic uses of hops in traditional medicine.

Xanthohumol, derived as the prenylated flavonoid of female inflorescences of the hop plant, has some promising anti-obesity effects. In addition to its in vitro effects on inhibiting adipogenesis [ 64 ] and causing apoptosis in mature adipocytes [ 65 ], xanthohumol also extends to in vivo effects where it is found to protect against diet induced obesity [ 66 ].

Xanthohumol increases energy expenditure which has been demonstrated in various cell types including white and brown preadipocytes, hepatocytes and myocytes [ 67 ]. Administration of xanthohumol increases oxygen consumption levels while ATP synthase was inhibited indicating the uncoupling of mitochondria.

Interestingly, xanthohumol, like several other phytochemicals, exhibits hormesis effect, wherein low dose of xanthohumol increased uncoupling and oxygen consumption while high dose inhibited respiration in an ROS-dependent manner.

Nevertheless, xanthohumol may ameliorate metabolic syndrome, at least in part, through mitochondrial uncoupling and stress response induction [ 67 ]. Xanthohumol also has an effect on bile acid generation which may lead to activation of bile acid G-protein coupled receptor TGR5 and downstream activation of T3 and ultimately UCP1 Fig.

The uncoupling ability of xanthohumol can be attributed to its nonpolar nature and the ease of ability to which it can cross the plasma membrane and potentially activate transcription nuclear receptors which regulate metabolic genes [ 67 ].

While xanthohumol has demonstrated anti-obesity potential in rodent studies where dietary xanthohumol-rich hop extract significantly lowered body weight gain, its effects have been more related to WAT and very little attention has been placed on BAT [ 66 ].

Administering mature hop plants to mice was found to induce thermogenesis in brown adipocytes, which is demonstrated by increased expression of PPARγ and UCP1 [ 68 ]. Because xanthohumol has shown the potential to upregulate oxygen consumption rates and chemical uncoupling, it can be suggested that xanthohumol may be inducing such metabolic changes through systemic thyroid hormone signaling.

Small, but significant increases in T4 binding globulin was seen following xanthohumol administration [ 69 ] and additionally, xanthohumol also upregulated iodide uptake by thyrocytes indicating a likely direct role in promoting thyroid hormone biosynthesis [ 70 ].

Naringenin, a flavonoid found in citrus fruits such as grapefruits and oranges, has also been recognized as a bioactive compound with protective properties against adiposity. Significant evidence shows that naringenin prevents metabolic syndrome by inhibiting diet-induced dyslipidemia [ 71 ], lipogenesis [ 72 ] and adipogenesis [ 73 ].

Inflammation of the adipose tissue is one of the hallmarks of obesity. This inflammation is derived from an infiltration of macrophages in the adipose tissue [ 74 ].

The protective effects of naringenin were elucidated in one study where mice fed a high fat diet along with naringenin had decreased levels of macrophage infiltration and thus lower obesity-related adipose tissue inflammation [ 75 ].

Another study shows naringenin administered to rats in conjunction with cholesterol-rich diet reduced total cholesterol and triglyceride levels as well as increased antioxidant activity [ 76 ].

Furthermore, naringenin-fed mice also show an upregulation in gene expression of PPARα, a regulator of lipid catabolism [ 77 ]. In brown fat activators, PPARα is linked to fatty acid oxidation as a direct result of UCP1 induction and thermogenesis [ 78 ].

Further, PPARα-dependent induction of UCP1 is also found in WAT and is suggestive of the beiging potential of naringenin [ 79 ]. Preliminary studies conducted in our lab showed that naringenin at 25 and 50 μM concentration induced a dose-dependent increase in the expression of UCP1 and SIRT1 in primary human omental adipocytes.

These preliminary experiments suggest a possible potential for naringenin as a thermogenic agent with therapeutic applications in obesity and metabolic syndrome. Commonly found in high concentrations in apples, broccoli, berries, onions, leafy vegetables and asparagus, quercetin is a polyphenol that has significant data showing its beneficial effects on cardiovascular system and lipid homeostasis [ 80 ].

Quercetin supplementation in high fat diet-induced obese mice protects against diet-induced obesity by increasing energy expenditure and inflammation [ 81 ].

Other studies demonstrating the protective effects of quercetin supplementation in mice fed high fat diet found lower body weight gain, triglycerides, and plasma cholesterol levels as a result of improved regulation of metabolic genes [ 82 ].

Quercetin also improved metabolic conditions in obese mice, as demonstrated by improved dyslipidemic state [ 83 ].

In vitro studies of quercetin rich extract showed inhibition of adipogenesis, decreased lipid accumulation and apoptosis of mature white adipocytes [ 84 ]. Dietary quercetin has also shown the ability to increase the expression of UCP1 and thus thermogenesis in mice fed with quercetin-enriched diet [ 85 ].

Given the well-established role of SIRT1 and AMPK in energy expenditure [ 86 ] it is likely that quercetin has the potential in induce browning of WAT. Although in vitro and in vivo studies provide significant data in support of quercetin related response to adiposity and obesity, the direct effects of quercetin on white adipocyte transdifferentiation needs to be further researched.

Capsaicinoids are a group of phytochemicals including, but not limited to, capsaicins and capsinoids. The capsaicinoid family consists of capsaicin, dihydrocapsaicin, nordihydrocapsaicin and others. There has been extensive research showing that capsaicin has anti-obesity, anti-diabetic, and anti-inflammatory characteristics.

Recent studies also indicate that capsaicin acts by activating the sympathetic system to induce BAT thermogenesis and reduce fat accumulation [ 87 ]. Administration of capsaicin in mice has shown to induce thermogenesis via the activation of BAT [ 88 ].

This is evidenced by the increase in markers related to mitochondrial biogenesis such as PPARγ, PGC-1α and UCP1 [ 88 ]. Capsaicin also induces the development of beige adipocytes at an early stage of adipogenesis [ 88 ]. Similarly to the aforementioned curcumin, capsaicin binds to the intestinal transient receptor potential vanilloid 1 TRPV1 receptor, also referred to as the capsaicin receptor, thereby launching the sympathetic response observed with treatment [ 89 ].

Surprisingly, capsaicin has also been proven to be harmful to humans and these harmful effects are mediated, in part, by the capsaicin receptor, TRPV1 [ 90 — 92 ]. Capsinoids are capsaicin analogs, similar in function to capsaicins, but are far less pungent thus, less toxic, and physiologically compromising to humans.

It has been demonstrated that capsinoids decrease fat accumulation in adipocytes both in vitro and in vivo in mice [ 93 ]. Acute administration of capsinoids augments energy expenditure, sympathetic nervous system activation, and thermogenesis with comparable efficacy to capsaicins.

As an inducer of the browning of WAT, a diet supplemented with capsinoids fed to mice kept at 17 °C for 8 weeks, significantly increased energy expenditure, but not at 25 °C. This was confirmed by increased BAT and beige specific gene markers such as Ucp1, Pgc1α, Cidea, Cd, and Tmem26 , in inguinal WAT, respectively.

It has been shown that capsinoids upregulated the expression of the PRDM16 protein in inguinal WAT under ambient and mildly cold temperatures upon β-adrenergic stimulation [ 95 ].

Yoneshiro et al. demonstrated that acute administration of capsinoids increased energy expenditure in BAT-positive subjects, but not in subjects without metabolically active BAT, under cold exposure [ 96 ].

Capsinoids seem to be promising in that they are accompanied with fewer side effects than capsaicins but there are conflicting studies of their potential as browning agents. Therefore, further research needs to establish its role in the browning of WAT and the associated underlying molecular mechanisms.

Cinnamaldehyde is a pungent spice extracted from the plant cassia and is the most abundant phytochemical in cinnamon [ 97 ]. Used since the medieval times for medicinal purposes, cinnamaldehyde has now been identified to have multiple therapeutic uses such as anti-diabetic, anti-arthritic, anti-inflammatory, anti-microbial, and anti-cancer effects [ 98 ].

Cinnamaldehyde activates TRP cation channels, similar to capsaicinoids. More specifically, cinnamaldehyde activates the cold-gated ion channel, transient receptor potential Ankyrin subtype 1, TRPA1 [ 99 ]. It has been shown that the cinnamaldehyde acts as an agonist to TRPA1 and upregulates adrenaline secretion in rats [ ].

This adrenaline secretion stimulation by cinnamaldehyde could explain the induction of thermogenesis and inhibition of heat diffusion in mice [ ]. In a dose-dependent manner, cinnamaldehyde also decreased visceral fat deposition, partly mediated by the activation of interscapular BAT, as evidenced by the upregulation of UCP1 expression levels, in high fat and high sucrose diet-fed mice [ 97 ].

Taken together, this data suggests the potential of cinnamaldehyde to act as a browning agent and exert its anti-obesity effects with future research. Fucoxanthin, extracted from edible brown alga, is a carotenoid known to have anti-carcinogenic, anti-inflammatory, anti-diabetic and apoptotic effects in metastatic cells.

Fucoxanthin has been shown to ameliorate the progression of obesity in vitro and in vivo in mice and human models [ ]. Fucoxanthin reduced lipid accumulation accompanied by a decrease in PPARγ expression in 3T3-L1 adipocytes [ ].

Kang et al. Maeda et al. investigated the potential anti-obesity and anti-diabetic effects of fucoxanthin supplemented diets in rodent models.

Results from these studies suggested that fucoxanthin significantly lowered WAT weight gain in mice with high fat diet-induced obesity, as well as mRNA levels of leptin in WAT.

Further, fucoxanthin stabilized blood glucose and insulin levels and downregulated monocyte chemoattractant protein-1, MCP-1, expression in WAT of diet-induced obese mice.

MCP-1, a protein secreted from adipose tissues, stimulates macrophage accumulation and the production of pro-inflammatory mediators.

Finally, β3-adrenergic receptor, Adrb3, mRNA expression levels were upregulated in WAT of mice maintained on fucoxanthin high fat diets. As discussed earlier, Adrb3, expressed in both BAT and WAT, is suggested to play a role in lipolysis and thermogenesis [ ]. Fucoxanthin-fed obese mice experienced a decrease in WAT weight as well as a significant upregulation in the expression of UCP1 protein and mRNA in WAT, resulting in energy expenditure in the form of heat and fatty acid oxidation in WAT [ ].

This increase in UCP1 expression was nearly diminished in WAT in mice maintained on a control diet. In another study of Maeda and his colleagues, fucoxanthin significantly decreased the body weight of mice on high fat diets [ ].

Overall, these studies suggest that fucoxanthin may have promising anti-diabetic and anti-obesity effects and deserve more research focus, primarily in human subjects.

Natural compounds have clear stimulatory effects on energy metabolism through direct actions on TRP channels and subsequent sympathetic signaling, intracellular regulation of the SIRT1-PRDM16 pathway and through modulation of thyroid hormone Fig.

Through these mechanisms, natural compounds can promote chemical uncoupling and energy dissipation in brown adipose tissue that may be able to counteract the loss of function of brown fat seen in obesity. While safety and efficacy will always be in question with nutraceuticals, the specific compounds described herein have been safely used for hundreds of years without major adverse events that render them unsafe for use.

Future research is needed to more appropriately answer the questions on efficacy, as some compounds which have the potential to stimulate brown adipose tissue have not been thoroughly investigated alone or in combination with other natural products that may act synergistically.

Similarly, few compounds have been used in large, randomized clinical control trials to definitively answer their potential anti-obesity effects. Despite this, the mechanistic data in both cell and rodent models show promise that natural, plant-derived compounds do contain the capacity to promote a beneficial metabolic profile.

Possible TGR5-medaited effects of guggulsterone and xanthohumol. The structural similarity of guggulsterone and xanthohumol to bile acids allows them to bind to bile acid receptor TGR5 which induces cAMP mediated upregulation of DIO2.

DIO2 converts T4 to biologically active T3, which in turn induces UCP1 and increases thermogenic activity of mitochondria. Abbreviations: cAMP cyclic adenosine monophosphate , DIO2 type 2 deiodinase , UCP1 uncoupling protein 1.

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Park HJ, Yang JY, Ambati S, Della-Fera MA, Hausman DB, Rayalam S, Baile CA. Combined effects of genistein, quercetin, and resveratrol in human and 3 T3-L1 adipocytes. J Med Food. Satyavati GV, Dwarakanath C, Tripathi SN.

Experimental studies on the hypocholesterolemic effect of Commiphora mukul. Indian J Med Res. Urizar NL, Moore DD. GUGULIPID: a natural cholesterol-lowering agent. Annu Rev Nutr. Ulbricht C, Basch E, Szapary P, Hammerness P, Axentsev S, Boon H, Kroll D, Garraway L, Vora M, Woods J. Guggul for hyperlipidemia: a review by the Natural Standard Research Collaboration.

Complement Ther Med. These observations indicate that feeding low doses of phytochemicals reduces both systemic and local inflammation caused by E. coli infection. To decipher the underlying mechanism behind the benefits of feeding phytochemicals, microarray analysis has been conducted to characterize gene expression in the ileal mucosa of pigs experimentally infected with E.

Microarray results indicate that feeding phytochemicals enhances the integrity of membranes, especially several tight junction proteins. Supplementation of phytochemicals downregulates expression of genes related to antigen processing and presentation and other immune-response-related pathways, indicating that these phytochemicals attenuate the immune responses caused by E.

coli infection [ 42 ]. Another in vivo study on porcine reproductive and respiratory syndrome virus PRRSV [ 43 ] showed that feeding Capsicum oleoresin, garlicon, and turmeric oleoresin to weaning pigs enhances the immune responses to PRRSV challenge and may help alleviate the negative impact of infection, as indicated by reduced viral load and serum concentrations of inflammatory mediators, and shortened duration of fever.

In summary, phytochemicals are strong candidates to replace antibiotics to improve growth performance and health of pigs. The potential benefits of plant extracts may differ due to the large variation in the composition of plant extracts.

This diversity prompts us to select optimal feed additives for evaluating their possible roles as alternatives to antibiotics in swine production. In ruminants, the host and rumen microorganisms establish a symbiotic relationship by which the animal provides nutrients and the proper fermentation conditions, and microbes degrade fiber and synthesize microbial protein as an energy and protein supply for the host, respectively.

Carbohydrates are fermented in the rumen into pyruvate, resulting in the production of metabolic hydrogen. Volatile fatty acids VFAs are natural hydrogen sinks that help maintain the equilibrium of hydrogen and the fermentation process active.

Although methane is effective in retaining hydrogen, the energy retained is lost through eructation and not available to the host. Manipulation of the relative proportions of these VFAs is key to the development of targets to modify rumen microbial fermentation [ 44 ]. Protein degradation is also important for the supply of nitrogen to rumen microbes for their growth, but excess ammonia nitrogen is absorbed through the rumen wall, transformed into urea in the liver, and excreted through the urine.

In most production systems, ammonia nitrogen in the rumen is produced in excess of the ability of rumen microbes to use it, resulting in significant production costs and an increase in the release of nitrogen into the environment [ 45 ]. Therefore, controlling proteolysis, petidelysis and deamination should also be considered targets of interest in the modulation of rumen fermentation [ 44 ].

In fact, in a recent study, Van der Aar et al. AGPs are efficient in shifting rumen fermentation towards more efficient energy and nitrogen utilization pathways [ 47 ], improving productivity in dairy and beef diets [ 48 , 49 ]. Phytonutrients are a group of small organic molecules present in plants that modify the nutritional value of feeds by either modulating the digestion of nutrients in the digestive tract, or other systemic metabolic pathways.

Some phytonutrients have a strong antimicrobial activity [ 50 ]. However, these molecules are not suitable for use in ruminants because the activity of rumen bacteria is essential for the proper function of the rumen. Research on alternatives to antibiotics as feed supplements in cattle should focus on molecules and doses that are able to produce subtle changes in the microbial metabolism and modify their rate of growth [ 51 ].

In the context of the continuous flow in the rumen, a change in growth rates results in changes in the proportion of rumen bacteria populations, resulting in changes in the fermentation profile.

For example, Patra and Yu [ 52 ] were able to prove how different phytonutrients have different capacities in modifying the structure of the microbial population of the rumen. These changes are large in oregano where thymol and carvacrol are the main active components and peppermint where menthol and menthone are the main active components oils, but smaller, and more adequate, in clove bud where eugenol is the major active component and garlic oils.

Ferme et al. in the rumen; a major group of bacteria involved in amino acid deamination. These findings are important to set clear objectives in the search for alternatives to AGPs, which should identify phytonutrients that can modify the VFA proportions and protein degradation in the rumen without affecting nutrient degradation and the normal function of the rumen.

Most phytonutrients of interest in animal feeding are classified into three main groups: saponins, tannins and EOs. Saponins and sarsaponins are the main active components of several phytochemicals, including yucca, quillaja, alfalfa and fenugreek. Saponins exhibit antibacterial [ 54 ] and antiprotozoal [ 54 , 55 ] activity, resulting in a reduction in ammonia nitrogen concentration.

Tannins are phenolic compounds found in almost every plant part, and are divided into two groups, hydrolysable and condensed tannins. Condensed tannins have the ability to bind and precipitate proteins and may be useful in the control of protein utilization by ruminants [ 56 ], but at high levels may interfere with dry matter DM intake and digestibility of nutrients [ 56 ], and may decrease the incidence of bloating [ 55 ].

EOs are secondary plant metabolites present in many plants and may have a wide range of effects. In this section, we review recent research on the use of EOs as feed additives in ruminants. The increased rumen fermentation is indicated by the increase in propionate and decrease in methane, acetate and ammonia nitrogen, without reducing total VFA [ 57 ] in the in vitro fermentation system.

When phytochemicals are tested, a considerable variation in fermentation with different extracts is observed due to the content of active compounds in these extracts [ 58 ]. Therefore, it is necessary to either report the concentration of these active compounds in phytochemicals, or use the active components to define activities, doses and mechanisms of action in an unequivocal form.

For example, garlic oil reduces the proportions of acetate and branched-chain VFAs, and increases the proportions of propionate and butyrate in vitro [ 57 , 59 ], and the fermentation profile is consistent with changes observed when methane inhibitors are supplied to ruminants.

The anti-methanogenic effect of garlic and its active components is the result of direct inhibition of Archea microorganisms in the rumen through the inhibition of hydroxymethylglutaryl coenzyme A HMG-CoA reductase; a specific pathway essential for the membrane stability of Archea [ 57 , 59 ].

This observation was supported by Miller and Wolin [ 60 ], who reported similar effects when using statins, known to inhibit HMG-CoA reductase. However, benefits are often inconsistent, and strong inhibition of VFA production by garlic oil has been reported in some cases [ 59 , 61 , 62 ].

The variable effects of garlic oil on total VFA production is likely due to the short margin of safety in the doses between adequate and toxic levels.

Cinnamaldehyde and eugenol also reduce the molar proportion of acetate, and increase the molar proportions of propionate and butyrate [ 59 , 61 ]. These observations are consistent with improved energy retention by those phytochemicals and potentially due to the inhibition of methanogenesis [ 63 ].

Cinnamaldehyde also reduces ammonia nitrogen and increases free amino acids, suggesting that deamination of amino acids is inhibited in the rumen [ 59 , 61 ]. However, Eugenol inhibits the breakdown of large peptides to amino acids and small peptides [ 59 ]. The combination of eugenol and cinnamaldehyde may work in synergy to inhibit peptidolysis and deamination, and then improve the overall supply of amino acids and small peptides to microorganisms and the host.

Therefore, a synergetic advantage could be expected by combining specific phytonutrients that work at different levels in the same metabolic pathway. There are limited data reported about the effects of phytochemicals on performance of ruminants. Feeding cinnamaldehyde alone or in combination with eugenol results in increased in milk production of 1.

An even better response is reported when a combination of cinnamaldehyde, eugenol and capsicum is fed to dairy cattle, with increases in energy-corrected milk production of 5. However, no differences have been observed in most of cases due to the small size of the studies.

Bravo et al. Many phytonutrients have metabolic effects that are not related to their activities in the rumen [ 68 , 69 ]. Preliminary in vitro rumen fermentation studies in dairy cattle have not identified capsicum as a potential modifier for rumen function [ 61 , 70 ].

Capsicum increases DM and water intake in beef cattle from 9. The benefits may be more significant when intake is compromised, such as when the cattle arrive at feedlots or during heat stress. The increase in DM intake patterns is probably also related to a more stable rumen pH [ 75 ].

Capsicum has been reported to modulate immune function [ 42 ]. Oh et al. Feeding rumen-protected capsicum is reported to improve milk production. Stelwagen et al. Another three studies have also reported that supplementation of rumen-protected capsicum improved milk production by 6.

The average increase in milk production in those studies was higher than the effects attributed to the modulation of rumen fermentation.

These results suggest that capsicum modifies glucose metabolism, redirecting glucose away from peripheral tissues and towards the mammary gland to increase milk production.

This is an exciting new application of phytonutrients that presents an opportunity to improve production, not only by reducing the use of antibiotics, but also by providing an alternative to the use of some hormones.

The mammalian gastrointestinal tract harbors a dense and diverse microbial community, which is composed primarily of bacteria but also includes fungi, Archaea and viruses. Collectively, these are referred to as intestinal microbiota.

These microorganisms are environmentally acquired, and their metabolic functions can shape host physiology. Many vertebrates consume a diet rich in complex nutrients that are indigestible by their own intestinal enzymes, relying on the diverse biochemical catabolic activities of the microbiota.

Available evidence strongly suggests that the gut microbiota plays important roles in host energy harvest, storage and expenditure, as well as overall nutritional status [ 81 , 82 , 83 , 84 ]. It must be highlighted that germ-free animals that lack any microbiota weigh less and have less fat than conventional animals [ 85 ], pointing out a key role of the microbiota in weight gain.

Gut microbiota may affect weight gain through regulating nutrient extraction, and modulating the immune system and metabolic signaling pathways [ 82 ]. Many classes of substances with antibiotic activity that are effective for animal growth promotion display multiple modes of action and spectra of activity over the gastrointestinal microbiota.

It has been difficult to predict which microbial changes are responsible for increases in weight gain, feed efficiency or health promotion.

Culture-independent approaches using next-generation DNA sequencing have provided researchers with a revolutionary tool to look into microbiomes that could not be achieved before, and has begun to transform our view of intestine-associated biodiversity of animal production.

Improving the understanding of microbiota and host metabolism would help to develop better strategies and products for animal production and welfare, food safety and public health. The selection of microbes that aid in nutrient extraction, regulating microbial carbohydrate, protein and lipid metabolism, and the prevention of subclinical infections will help to promote productive parameters [ 83 ].

The intestinal microbiota plays a critical role in inflammatory gut diseases of humans and animals [ 86 ]. Recent development and application of next-generation sequencing technologies using 16S rRNA gene have allowed investigation of the significant roles of the microbiota in gastrointestinal tract diseases, and have facilitated investigation of host—pathogen interaction in NE [ 86 ].

The effect of dietary phytochemicals on gut microbiota was studied in three major commercial broiler chickens fed with Capsicum and C. longa oleoresins [ 13 ]. Among the three chicken breeds, Cobb, Hubbard and Ross, oleoresin supplementation was associated with altered intestinal microbiota.

The results suggested that dietary feeding of Capsicum and C. longa oleoresins reduces the negative consequences of NE, in part, through alteration of the gut microbiome. Although these are preliminary characterizations of the effects of dietary phytochemicals on gut microbiota but document the role of dietary Capsicum and C.

longa oleoresins in regulating disease susceptibility to NE via altering the intestinal microbiota in commercial broiler chickens. A recent study [ 13 ] showed that Firmicutes was the dominant phylum and Lactobacillus was the predominant genus identified in the ileum in all broiler breeds and all treatment groups.

These results are consistent with previous studies that showed Lactobacillus as the principal microorganism in the gastrointestinal tract of uninfected conventional broilers [ 87 ].

Because Firmicutes are fat-loving Gram-positive bacteria [ 88 ] this result suggests an inter-relationship of these bacteria and genetic selection for fast-growing characteristics of these broilers by the industry.

In a recent comparative study [ 13 ], changes in the proportion of intestinal lactobacilli, as well as the total number of operational taxonomic units OTU between the three commercial broiler breeds were observed.

Candidatus Arthromitus is a group of non-cultivable, spore-forming, Clostridium -related, commensal segmented filamentous bacteria SFBs that colonizes in the digestive tracts of animal species, and has been identified in three commercial broiler breeds [ 89 ].

As the core OTU, C. Arthromitus has been identified in all three groups of the Cobb and Hubbard broilers [ 13 ]. The most intriguing feature of SFBs is their close interaction with epithelial cells in the terminal ileum and their intimate cross talk with the host immune system.

Arthromitus belongs to gut-indigenous Clostridium that induce immune regulatory T Treg cells. Intestinal Treg cells express T cell receptors that recognize antigen derived from gut microbiota [ 90 ]. SFBs send signals to control the balance between ILproducing T helper Th17 cells that sustain mucosal immunity, and forkhead box p3 in the intestine [ 90 ].

Our previous studies have also reported that chicken ILA transcripts increase in the duodenum and jejunum of E. maxima -infected chickens [ 13 , 91 ] where early inflammatory response plays an important role for development of protection against Eimeria infection.

longa , there is a different shift in the bacterial community in all broiler breeds with NE. Therefore, co-infection with E. maxima and C. perfringens may influence the presence of C. Arthromitus and the host immune system in Ross chickens. It will be important to conduct further studies to investigate the functional immune modulatory effects of dietary phytonutrients on C.

Arthromitus in genetically different broiler breeds. In conclusion, dietary phytonutrients exert beneficial effects on gut health to reduce the negative consequences of NE, and nutratherapeutics mechanism may involve altering gut microbial communities. Further studies on the effects of dietary phytonutrients on gut microbiota in commercial broiler breeds are needed to develop alternative ways to reduce or replace antibiotics in poultry disease control.

Future studies on the role of the avian intestinal microbiome in immune regulation and host—pathogen interactions are expected to shed new light on the host response to NE that will be beneficial for practical poultry husbandry.

Although these differences seem to be important from a functional point of view, in ruminants or monogastrics, gastrointestinal microbiota composition is similarly central to improved animal production in both groups, and the impact of phytochemicals on these microbiota might be responsible for most of the positive effects observed.

Many beneficial properties of plants are derived from their specific bioactive components, which are also synthesized as chemical protectants against microbial infection.

Some compounds among these categories are known to be important for improving animal production, as well as inducing an extensive number of health-promoting effects. Tannins and EOs are fed commercially to several domestic animal species and, as growth promoters, they modify the gut microbiota in different ways.

Tannins are a complex group of polyphenolic compounds found in many plants species, functionally defined by their capacity to complex macromolecules proteins and polysaccharides and metal ions, which are commonly included in ruminant diets such as forage and sorghum.

Tannins are chemically classified as hydrolysable or condensed based on their chemical structure, and are widely used to improve several aspects of animal husbandry. Some tannins are potent antimicrobials, acting, for example, by iron deprivation or interactions with vital proteins such as enzymes [ 95 ] or bacterial cell wall proteins [ 96 ], displaying either bactericidal or bacteriostatic activities [ 97 ].

Gram-positive bacteria are particularly sensitive to tannins [ 98 ]. In ruminants, tannins modify the digestive processes not only by binding dietary protein rumen bypass , but also through modulation of rumen microbiota and improvement of the growth of certain bacterial populations [ 99 ].

The effects of tannins on rumen microbiota may vary depending on the molecular nature of these polyphenols [ 99 , ]. The understanding of in vivo interactions between rumen bacteria and sources of plant tannins are limited. However, this predominance was inverted when a blend of tannins were added to the feed, with a significantly higher percentage of Firmicutes and a reduction in Bacteroidetes.

Diversity of rumen microbiota is one of the key features in ruminant animals, which confers upon cattle the ability to adapt to a wide range of dietary conditions [ ]. Dietary quebracho and chestnut tannins diminish rumen richness but do not significantly affect the complexity of the bacterial communities i.

balance between the relative abundances of bacterial taxa. Similarly, β-diversity analysis of rumen samples of steers fed with chestnut and quebracho showed no significant changes in bacterial diversity compared with the control group [ ]. Low microbial richness in the rumen is closely linked to a higher feed efficiency in dairy cows [ ].

Diversity analysis indicate that bacterial richness is lowered by tannins, but the overall bacterial complexity of the rumen is not significantly affected by chestnut and quebracho tannins supplementation.

Several studies have found an increase of rumen pH, decrease of ammonia concentration, and lower methane emissions after feed supplementation with several tannins including chestnut and quebracho, resulting in a reduction of protein degradation and therefore an improvement in nitrogen utilization in the rumen [ ].

Tannins are considered as alternative agents to antibiotics, they improve animal health and productive performance while suppressing methanogenesis. These observations could be explained by changes in the microbiota in the rumen.

Significant changes in the abundance of certain taxa have been detected in tannin-treated steers. The abundance of Prevotella was lower in tannin-supplemented animals than in the control group.

Among Clostridia, Ruminococcaceae was the most abundant family and showed a significantly higher abundance in tannin-supplemented animals. Within the Ruminococcaceae, most of the sequences obtained in untreated animals belonged to unclassified members and the genus Ruminococcus , and both taxa were enhanced in tannin-treated steers.

Other non-clostridial bacteria within the phylum Firmicutes were significantly altered by tannins, including members of class Erysipelotrichi.

Members of class Bacilli Streptococcus and Lactobacillus showed moderate increases in their abundance in tannin-treated animals. Genus Fibrobacter was significantly affected by tannins, accounting for 0. Other minor fibrolytic bacteria were more abundant in tannin-treated steers, including the genus Blautia and member of the Eubacteriaceae genus Anaerofustis.

Tannins remodel the bacterial ecosystem of the rumen, particularly the niche of fiber and starch degradation, and the methanogenic bacteria [ ]. Treponema is also reduced by tannins. Among Veillonellaceae members, Succiniclasticum , which specializes in fermenting succinate to propionate, doubles its levels in tannin-treated animals.

Lipolytic genus Anaerovibrio is significantly enhanced by tannins. Selenomonas is also increased in tannin-supplemented animals. Among ureolytic bacteria, Butyrivibrio is the most abundant and it is negatively affected by tannin treatment, as well as Treponema and Succinivibrio.

Methanogens belonging to the phylum Euryarchaeota are less abundant in tannin-supplemented steers and their levels are inversely correlated with rumen pH. Methanosphaera is also reduced by tannins.

Current literature indicates that tannins can be supplemented to improve the sustainability of both dairy and beef cattle by reducing methane emissions and nitrogen excretion, and enhancing animal performance.

In monogastrics, that is, broiler chickens, tannins obtained from several sources seem to improve growth performance and reduce the detrimental effects of pathogenic bacterial species such as C.

perfringens [ ]. The establishment of a stable microbiota is a complex process that is influenced by various factors, including genetic lineage, age, diet, use of growth promoter antibiotics, probiotics, litter composition, stress and disease [ 86 , , , ].

Therefore, any alteration in the intestinal microbiota may have functional consequences to the health of the host and, therefore, productivity. The broiler chicken gastrointestinal tract is colonized by a dense community of microorganisms that is intimately connected to the global heath and development of the host.

The cecum houses the highest microbial cell densities of the chicken gut and performs key process for birds such as the fermentation of cellulose, starch and other resistant polysaccharides [ 86 ]. A principal coordinate analysis PCoA based on unweighted UniFrac distances was conducted to determine any differentiation between sample clusters of tannin-treated versus antibiotic-growth-promoter-treated versus untreated birds.

PCoA plots revealed that the samples corresponding to each dietary treatment shaped distinct series, suggesting that tannins differentially modulate cecal microbiota.

High-throughput sequencing of 16S rRNA gene amplicons has been used to identify functional diversity [ ] or variability [ ] of the microbiome in the gut of broiler chickens. The most abundant Bacteroidetes detected in cecal contents belonged to genus Bacteroides and an unclassified genus of the family Barnesiellaceae.

Among the Firmicutes , order Clostridiales and family Ruminococcaceae were the most abundant taxa. Bacteroides is a Gram-negative genus that utilizes plant glycans as its main energy sources. Bacteroides is one of the main bacteria involved in producing short-chain fatty acids SCFAs [ ], and plays an important role in breaking down complex molecules to simpler compounds that are essential for host growth [ ].

SCFAs are absorbed by the host and used as an energy source but also have a variety of distinct physiological effects.

Although Bacteroides generates acetate and propionate, its ability to produce butyrate has not been reported. Order Clostridiales are generally known as important contributors to short-chain fatty acid SCFA metabolism [ 86 ] because it contains a variety of bacterial families, among which Ruminococcaceae and Lachnospiraceae are capable of fermenting various substrates to butyrate.

Feed tannin supplementation of chickens decreases the abundance of Bacteroides , which could reduce acetate and propionate production. However, it would be compensated by an increase in Clostridiales, particularly Ruminococcaceae, with a possible increase in butyrate production [ 96 ].

Concordantly, Masek et al. Lactic acid bacteria, which are usually associated with enhanced gut health and productivity, are interesting. It was reported that cecal microbiota contained lower proportions of Lactobacillus in AGP-fed chickens, compared with chickens in tannin and control groups [ , , ].

Lactic acid bacteria, especially Lactobacillus strains, have been considered as probiotic microorganisms because of their activities in reducing enteric diseases and maintaining poultry health [ , , ].

The presence of Lactococcus spp. has been correlated with weight gain [ ]. The inclusion of different AGPs in diet influences the diversity of gastrointestinal microbiota. These changes would probably be one of the most important driving forces resulting in efficiency improvement of animal production.

Similarly, the existing information clearly shows a significant alteration in the relative abundance of specific bacterial populations by some phytochemicals in the gut of domestic animals These phytochemicals added to feed are also connected with higher productivity parameters.

Therefore, these natural compounds are able not only to improve animal health and welfare directly, but also to modulate gastrointestinal microbiota and increase the impact on health and production. We are just barely starting to understand the dynamics between the highly complex connection between environment, host and microbiota.

More information is necessary to clarify how we can manipulate gastrointestinal microbiota to increase animal productivity under diverse productive settings. Tannins are present in many feeds such as fodder legumes, browse leaves and fruits.

Although the structure of tannins are chemically diverse, they have one unifying property: tannins bind proteins. During the last 30 years, tannins have been successfully used in animal production to improve health and productivity, and several products based on blends of particular amounts of hydrolysable predominantly chestnut and condensed mostly quebracho tannins were developed to take advantage of the benefits of each tannin in livestock.

These products are being used in many countries to improve quality and production of milk, meat and eggs. In poultry, a blend of tannins can be added to feed at a final concentration of 0. The selected blend of tannins added to the diet stabilizes and increases feed intake according to reduction of taste variation by changes in feed formulation [ ], and reduces feed stress by improving the flavoring characteristics.

The distinctive antispasmodic effects of tannins that modulate gut motility [ , ], with strong antibacterial effects on several pathogenic bacterial species and viruses [ 97 , ], as well as their toxins [ 97 ], are used to prevent and control enteric diseases, including several diarrheal diseases [ ] and NE [ 96 ].

Reduction of enteric diseases, intestinal motility and bacterial load, concurrently with an increase of feed digestibility, produces a reduction of humidity in the litter, affecting directly animal health and welfare. These blend of tannins are also being used efficaciously to reduce the incidence of sub-clinical NE, and a slightly different blend is able to strongly reduce intestinal lesions in chickens on farms with a history of severe NE outbreaks.

In experimental conditions, the tannin blend is able to reduce the most severe lesions as well as the number of animals with lesions.

This result is also observed in commercial farms of different European, American and Asian countries where NE is a problem to different degrees. A comparative analysis of AGPs versus tannin blend use in feed was carried out in a commercial trial in Argentina over a period of 13 months 5 cycles in a poultry farm of ~ animals.

The farm was divided into six barns under regular commercial feed; three were fed with AGPs in feed and three with 0. Greater improvements in intestinal health, microbiological quality and humidity of litters, mortality rate, undigested feed, foot-pad lesions, and weight gain were observed in the animals treated with tannins versus antibiotics.

Analysis of the results showed a positive difference of almost 10 points for the Production Efficiency Factor for the blend of tannins against AGPs in feed, showing the benefits of using these blend of tannins during different weather conditions throughout the year [ ].

Tannins added in feed to improve productivity in combination with other products, including EOs, organic acids, probiotics and AGPs, have been used frequently by different companies in several countries with significant positive results Dr Javier Quintar and Dr Joao Battista Lancini, personal communication.

In cattle, historically low doses of quebracho and chestnut tannins have been used in feed by many producers around the world to improve bypass protein from rumen degradation. Rumen bypass protein is one of the strategies to increase the amount of protein that enters abomasum and hence increases ruminant productivity.

The addition of such tannins to a diet reduces the fermentability of protein nitrogen in the rumen [ ]. Consequently, the flow of dietary amino acids into the duodenum of ruminants could be increased, as well as the total duodenal amino acid flow if ammonia nitrogen requirements for microbes could be met by supplementation of urea or ammonia salts.

In addition, added tannins are also used to prevent acidosis and bloating [ ], modulate rumen microbiome to improve feed utilization [ ], and reduce methane emissions [ ] and nitrogen excretion [ ].

Supplementation of tannin also reduced fecal moisture, resulting in better fecal consistency. According to Rivera-Mendez et al. Similarly, DM intake tended to increase with level of tannin.

Tannin supplementation increased gain efficiency 5. These results have been also observed in commercial feedlot finishing settings.

The analysis of 15 different trials in North America between and using tannins at 0. Similar results have been observed in feedlots in other parts of the world, including large beef producers in Brazil [ , ] and Argentina [ ].

In conclusion, the addition of low-dose tannins to ruminant diets in intensive fattening is an available tool to increase nutrient use efficiency, improving daily weight gain and feed conversion, through different metabolic mechanisms.

The estimated level of animal feed supplemented with tannins produced in the world in was 15 tonnes, reflecting the acceptance of tannins as an important tool in animal husbandry.

The available scientific information about mechanism of action, the observed animal response and the accumulated experience in the use of tannins as feed additive confirms that tannins are a valuable alternative to complement or replace the use of AGPs in industrial livestock production.

Designing an antibiotic alternative to address several components of gut health may work better than using a single approach to reduce negative consequences of gut damage caused by complex etiologies such as those that cause diseases such as NE.

perfringens produces several exotoxins, including α-toxin and NE toxin B NetB , that disrupt the intestinal epithelium, causing necrotizing lesions that constitute the characteristic sign of NE [ 21 , ].

For complex disease like NE, it takes a multi-faceted approach to decrease the effects of disease on gut health. For example, a commercial product Varium ® was designed to improve barrier function by removing pathogens by agglutination, removing biotoxins via adsorption, priming immune development, and providing energy to the enterocytes [ ].

Varium ® has been tested in vitro for its ability to bind biotoxins of pathogenic bacteria i. perfringens and E. coli such as α-toxin, NetB toxin, lipopolysaccharide, heat-labile toxin and Shiga-like type 2 toxin.

Two large broiler trials have been conducted to test the hypothesis that CaMM, or its blends with other materials e. The two trials evaluated CaMM-based dietary products on growth performance, clinical signs, immunopathology, and cytokine responses of young broilers using disease challenge models with avian NE [ ].

When tested in unchallenged birds, Varium exerted an effect similar to an in-feed AGP on body weight, feed intake, and FCR. Chickens fed a diet supplemented with CaMM plus a fermentable fiber and an organic acid showed increased body weight gain, reduced gut lesions, and increased serum antibody levels to C.

perfringens α-toxin and NetB toxin compared with chickens fed the basal diet alone. Levels of transcripts for inflammatory cytokines such as IL-1β, IL-6, inducible NO synthase, and TNFSF15 were significantly altered in the intestine and spleen of CaMM-supplemented chickens compared with unsupplemented controls [ ].

perfringens under subclinical infection conditions to elicit NE. Compared with unsupplemented controls, broilers fed with CaMM plus a fermentable fiber and an organic acid showed increased body weight gain, reduced FCR, mortality, and intestinal lesions, compared with chickens fed an unsupplemented diet.

Based on both broiler trials, it is recommended that dietary supplementation of CaMM or CaMM plus a fermentable fiber and an organic acid is useful to decrease negative effects of avian NE in the field. Future studies are needed to characterize further the CaMM-regulated physiological and immunological mechanisms that are activated in response to avian NE.

Yet, most of the technologies discussed here have proposed or known mechanisms of action that involve inhibition, alteration or killing of one or more bacteria. In general, it appears that most people equate the phrase with something not termed an antibiotic that can be substituted for low level feeding of broad-spectrum antibiotics used to promote growth in livestock.

The reason there is a need for alternatives to AGP is the recognition that the practice can lead to development of infective bacteria that are resistant to many of the current antibiotics available to human medicine.

The rising incidence of superbugs globally and the rising human deaths from multiple drug-resistant bacteria have alerted WHO, CDC and UN to release strict action plans on reducing the use of antibiotics in animal production.

Regardless of which side of the argument over whether AGP use in animals is contributing to the problem of resistant bacteria in humans you are on, the sociopolitical momentum has created a marketing opportunity for selling meat from animals claimed to have never received antibiotics during production.

This in turn creates a market for products that can provide the benefit of AGPs but not be antibiotics used in human medicine, or sometimes any antibiotic at all. The alternative to antibiotics market is growing rapidly and attracting interest from companies and organizations of all sizes and capabilities.

This is evident from the need for a meeting such as this and the plethora of products marketed, with or without credible data, to be alternatives to AGPs. Although the banning of AGPs has accelerated over the last few years, the search for alternatives started in earnest following the ban in the EU of avoparcin in The most important development in the search for credible alternatives is the increasing understanding in both human and veterinary medicine that the gastrointestinal tract is more than a nutrient-absorbing organ, but in fact is fundamental to health and development of humans and animals.

The scientific advancement in our understanding of the importance of the gut environment and its barrier function in health provide a way to develop products that can deliver the benefits of AGPs without causing an increase in the emergence of antibiotic-resistant bacteria.

This can be accomplished by using multiple technologies to maintain or strengthen gut barrier function. Scientific principles should be applied to the development of products such that they provide reliable positive benefits to the target animals. However, there are still many challenges remaining with the most consistent concerns being consistency, safety and solid scientific proof.

This is not surprising when you consider most of the popular alternative products marketed today modify the microbiota in some way to enrich beneficial bacteria.

We are just learning what the desirable microbiota is and how it works in given animal, and we have even less knowledge of the variations between different animals and the normal daily and lifetime changes in different ecosystem.

In addition to the microbiota, it will be necessary to understand clearly what impact the product has on the gut barrier which comprises the mucus layer, endothelial cells and attendant immunological cells and structures associated with the gut wall. This is a relatively new field of research and as time goes on, the industry, through application of good science, will learn more.

This will be both in the basic understanding of the gut environment, including the microbiota and the dynamic function of the gut barrier, and how to manipulate these structures in individuals, but as part of a population.

Because it is new and there are many unknowns, regulation of these products poses a challenge in different regions of the world.

What constitutes acceptable efficacy and what types of claims can be supported are largely unknown. However, there is little doubt that use of the FDA drug approval process is not a viable option today.

Perhaps as science defines ways to measure and test efficacy in a consistent manner across several mechanisms of action, a regulatory pathway can be established.

There will need to be tolerance and flexibility in the approval process for these products or the market will be flooded by products with no proof of efficacy or safety. At a minimum, these products should have scientific proof of efficacy in the target species for which they are marketed.

In vitro tests are insufficient to provide confidence that a product will work in an animal, let alone provide consistent value across a population of animals. Increasing concerns about the increase of superbugs and limited development of new drugs for livestock and humans necessitates the timely development of alternatives to AGPs.

With increasing availability of many different categories of antibiotic alternatives in the market for animal agriculture with various claims and efficacy, the industry needs to understand the mode of action associated with different types of antibiotic alternatives and the kind of synergy that can be offered by the combinations of different antibiotic alternatives, especially for prevention and treatment of complex diseases such as necrotic enteritis.

Furthermore, the definition of the phrase antibiotic alternatives should be better defined, although this terminology is now an accepted term to refer to non-antibiotic substances that can be substituted for low-level feeding of broad-spectrum antibiotics that promote growth in livestock.

Increasing marketing opportunity for selling animal meat products claimed to have never received an antibiotic antibiotic-free, ABF; no antibiotics ever, NAE has created a market for products that can provide the benefit of AGPs without using antibiotics that are used therapeutically in human medicine.

This new scientific knowledge in our understanding of the importance of the gut environment and barrier function in health should guide finding a future solution to develop novel products that can deliver the benefits of AGPs without causing an increase in the emergence of resistance.

Since using phytochemicals as antibiotic alternatives in agricultural animals is a relatively new field of research, regulation of these products poses a challenge. There is a timely need to provide increased public funding for mechanistic research for phytochemicals that include standard measurements to define the efficacy in a consistent manner across several regulatory pathways, to prevent false claims and yet have flexibility in the approval process for proof of efficacy or safety for commercialization.

Owing to the rise in consumer demand for livestock products from ABF production systems, scientists, regulatory agencies and commercial partners need to work together to develop effective antibiotic alternatives to improve performance and maintain optimal health of food animals.

Using optimal combinations of various alternatives coupled with good management and husbandry practices will be the key to maximizing performance and maintaining animal productivity, while we move forward with the ultimate goal of reducing antibiotic use in the animal industry.

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