The Role Of Polyphenols in Regulation Of Heat Shock Proteins And Gut Microbiota in Weaning Stress Part 2

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4.1. Weaning Stress in Pigs and Ruminants. Weaning pigs experience stressful periods that can alter intestinal and immune functions resulting in influencing animal health sta-tus.

Advanced tools have been employed to minimize wean-ing stress; however, more collective biological understanding is required to devise strategies to combat weaning stress [62]. The factors of weaning stress include physiological, environ-mental, and social challenges that occur when the pigs sepa-rate from the sow, thus making them vulnerable to diseases and production losses [62]. The gastrointestinal system per-forms various functions such as digestion and absorption of nutrients, electrolyte balance, and secretion of digestive enzymes and acts as a barrier against detrimental molecules [62]. Abrupt changes in the diet from milk to solids make pigs prone to declined growth rates [62]. A study by Mon-tagne et al. [63] demonstrated that reducing intake of feed during postweaning may contribute to intestinal inflamma-tion, influencing villous height and crypt depth. Pigs experi-ence low feed intake due to the alterations in absorption capacity of the small intestine [64]. Moreover, Rao [65]highlighted different intestinal markers linked with weaning stress, effectively reducing the physiological disturbance related to weaning stress. Weaning stress is also related to the overproduction of ROS and depletion of the antioxidant system [66]. The overwhelming status of ROS interferes with cellular function and subsequently affects TJ proteins result-ing in increased gut permeability [67]. Moreover, a signifi-cant impact of weaning stress in piglets has been well documented by numerous studies [68-71].

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Weaning stress is a crucial step in the calf farming sys-tem, which increases live weight gain and promotes gastroin-testinal development at the weaning stage [72]. Therefore, the presence of weaning stresses [73] may influence the dairy cow production system and increase calf mortality [74]. Cur-rently, limited literature is available on the subject of physio-logical and immunological responses in beef and dairy calves. Studies highlighted that weaning stress along with sudden housing reduced total leukocyte count,declined in vitro pro-duction of interferon-gamma, and enhanced the level of acute-phase proteins than with deferring housing for 35 days postweaning. Moreover, the transition period in cows pro-motes neutrophilia, suppresses interferon-y production, and enhances the level of acute-phase proteins that are prev-alent after the postweaning period. Hence, it is a long transi-tion suppression in immune response indicators in calves soon after weaning. Such immune biomarkers can be utilized in the future to predict the possible occurrences of weaning stress and for overcoming respiratory infections [75].

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Specific methods to improve gut health in the preweaning period are essential to reduce the calves'vulnerability against enteric infections. Gut health defines several factors which attribute to maintaining disease-free status in the GIT system [76]. Modification within the gut microbiome is an essential contributor that describes the effect on gut health [76] and is regarded as a window for improving calf gut health. Neonatal calves are most vulnerable to enteric infections, which are a pivotal cause of calf death; therefore, proper attention for improving gut health in particular calf health is required [77]. For further studies on the role of gut microbiota in weaning stress of dairy calves, a well-defined article is pre-ferred [77].

4.2. Gut Microbiota and Weaning Stress.

In the pig industry, the gastrointestinal tract of neonatal piglets is prone to post-weaning diarrhea [78, 79] and other intestinal disorders which may directly influence intestinal absorption, intestinal barrier injury, inflammation, oxidative damage,and altered microbial response [62, 78]. Previous literature revealed that the intestinal microbiome displayed a vibrant role in sustaining intestinal function and host health, while specific bacterial communities enable the capacity to suppress infection/pathogens and enhance mucosal immunity [71]. Hence, it considers a new strategy for gut microbiota mod-ulation to promote intestinal health.

However, the weaning stress declines the specific richness of the Lactobacillus group and enhances Clostridium spp. Prevotella spp.,Proteobacteriaceae, and E. coli, leading to the loss of microbial diversity [80]. Moreover, weaned piglets have shown diversity and composition of gut microbiota, which is largely influenced by the quantity and sources of die-tary proteins or fibres provided to postweaned pigs[81]. The interaction among nutritional constituents within intestinal cells and gut microflora is essentially vital for gastrointestinal tract function [82]. It is worth noting that the nutrition pool is pivotal for the renewal and proliferation of intestinal cells and an integral part of the microbial community [83]. The pathogenic bacteria enable to utilize proper nutrients which cannot catabolize via commensal bacteria, and it promotes the expression of virulent factors, for example, Salmonella, and enterohemorrhagic E.coli possess the capability to use ethanolamine as a source of carbon or nitrogen to obtain the benefit of nutrition in a competitive environment with other microflora [83, 84]. Enterohemorrhagic E. coli may consume fructose to stimulate a type III secretion system that favors the adhesion of pathogenic bacteria to host enterocytes [85]. As a consequence, weaned piglets are vulnerable to intestinal inflammation and postweaning diarrhea in response to the sudden proliferation of pathogenic bacteria and lack of microbial diversity [86]. The findings of the most recent article conclude that holly polyphenol(HP) enables attenuation of LPS-mediated intestinal injury via promoting intestinal disaccharidase activities, barrier function, and short-chain fatty acid (SCFA) production and suppresses intestinal inflammation [87].In a study by Liedel et al. [88], certain antioxidant substances revealed a significant relation-ship with beneficial bacteria and adverse relation with E.coli. However,specific substances and bacteria indicated an oppo-site relationship with pigs.

5. Polyphenols, Heat Shock Proteins, and Gut

Microbiota in Weaning Stress

Dietary approaches modify HSP expression in vivo and increase host health response via targeting specific immune responses such as Tregs. Oral induction of carvacrol in mice causes enhanced expression of HSP70 in Peyer's patches and Tregs and inhibited induced arthritis in an animal model 89]. Numerous nutritional compounds have also been doc-umented to influence HSP expression in the GI tract in vitro and in vivo [90-92]. The anthocyanin cyanidin-3-O-β glucopyranoside and its aglycon form,cyanidin chlo-ride, were documented to show antioxidant effects partially via induced expression of HSP70 in Caco2 cells [93]. The same effect was also reported using naringenin at 10-100wM [94].In addition to that, in vitro studies on polyphe-nols have documented that flavonoid quercetin at 30-100μM and others such as flavone at 150uM， kaempferol at 100μM， and genistein at 100μM are known to be the potent inhibitors of iHSPs specifically iHSP70 [95,96]. The grape seed extract (polyphenols) was also demonstrated to suppress iHSP70 in a bovine GECline [97],suggesting a neg-ative impact of several polyphenols on iHSPs. Resveratrol-triggered HSP70 expression declines the temperature rise of heat shock response and prepares cells to overcome the det-rimental effects of stress levels [98]. Moreover, resveratrol brings GSH in a reduced form to suppress ROS-mediated cel-lular damage [99] and ameliorate H,O,-induced lipid perox-idation via decreasing MDA levels and enhancing SOD activity and mitigating the intracellular expression of ROS in Caco2 cells[100]. Resveratrol-induced HO-1 signaling is pivotal for the expression of TJ proteins through suppressing PKCactivity and P38 phosphorylation[100]. Further, resver-atrolactivated HSP that is known to be the stimulator of anti-inflammatory regulatory T cells to protect intestinal integrity. HSP stimulation blocks the NF-xB stimulation via regulating IKBα[101].

There are several factors to be involved in stimulating HSP expression in swine production such as high tempera-ture, transportation, weaning, exercise, and cell exposure to toxins. The HSPs such as HSP27, HSP60, and HSP70 are overwhelmed in heat stress conditions. The expression of HSP in GIT is modified by weaning and depends upon the site of GIT and stage of postweaning [102].Apart from that, HSPs are the conserved proteins that showed their expres-sion in gut epithelial cells such as HSP25, HSP27,and HSP 70 and contributed to numerous cellular functions [103, 104]. It is noteworthy that iHSPs regulate barrier function via mediating TJ proteins and reverting the insult induced by oxidative and inflammatory stress on cells [26]. The intes-tinal and colonic epithelial cells both give similar responses against iHSP stimuli. Gut iHSP vanishes in germ-free ani-mals [105,106]. Further, comprehensive knowledge on the dietary intervention of heat shock proteins and gut microbi-ota is well documented by [51]. The animals experience different stresses during their adaptations as depicted in Figure 2.

6.Regulation of Polyphenols in Weaning Stress

Mediated by Gut Microbiota

Nutritional research is continuously improving with particu-lar feed additives [107]. Recently, food producers and con-sumers have attracted interest in promoting feed additives and prioritizing natural compounds. Polyphenols are highly effective and exhibit antimicrobial [108], antioxidative [109, 110],and antiviral [11l] activities and are the large groups of natural bioactive compounds that originated from plants. The antioxidant compounds are rich in polyphenols, which can also be applied to attenuate oxidative stress in animals and enhance the antioxidant potential of animal origin prod-ucts[112]. However, some scientists suggest that polyphe-nols do not have antioxidant capacity in the body because of their poor absorption eficacy, but they could perform other bioactivities through affecting cell signaling or micro-bial metabolites[113]. For example, the flavonoid could act at protein kinase and lipid kinase pathway to affect cancer and heart disease progress[114].As for polyphenols'antiox-idative activity, the polyphenol protective effect on regulation

of the gut microbial community has been well deciphered by previous studies[109,115]. The different sources of plant polyphenols have been discussed above. The vibrant activi-ties of these compounds observed in in vitro and in vivo stud-ies are reported to have antioxidative, immune-stimulatory, and anti-inflammatory activities [116-120].

Eucommia ulmoides(EU)flavone, a Chinese herbal plant, contains several compounds which provide health-enhancing effects [121]. The leaf of this plant is a rich source of flavonoids[31,122] providing beneficial effects on health by direct scavenging of free radicals, inhibitingproinflamma-tory cytokines via suppressing ROS and nitric oxide, reduc-ing inflammatory genes encompassing cyclooxygenases (COXs) and inducible nitric oxide synthase(iNOS),upregu-lating antioxidative enzymes, manipulating transcription fac-tors such as NF-xB and AP-1, and increasing the Nrf2 signaling pathway[123, 124]. The in vitro protective effect of Eucommia ulmoides flavones against LPS-triggered enter-ocyte damage(intestinal porcine epithelial cell line(IPEC-J2))is wellillustrated by Hussain et al. [120]. The inclusion of 10ug/mL EUF provided beneficial effects on cell viability, proliferation, cell cycle and apoptosis, mitochondrial bioen-ergetics, and NF-xB protein pathway. EUF activated PI3K/AKT which serves as the cell survival and signaling pathway, ameliorated negative effects of LPS, and restored enterocyte integrity. Another study by Chun et al. [119] has shown that dietary supplementation of Eucommia ulmoides flavones (polyphenols)enhanced growth performance in weaned piglets which was challenged with the diquat model of oxidative stress. Eucommia ulmoides flavones further spec-ified fruitful results through attenuation of oxidative stress and inflammation in intestinal morphology, reduced inflam-matory cytokines, increased antioxidant response, and enhanced villi height, villus height, and crypt depth in weaned piglets.

The positive effect of tea polyphenols(TP) on a diquat-challenged model of postweaned piglets is well described by Fiesel et al.[125].Results demonstrated that dietary TP mit-igated oxidative stress and promoted growth performance to some extent. The ratio of CD4b/CD8b was increased suggest-ing the recovery of immune disruption induced by oxidative stress. Moreover, TP reduced the level of I-1 and IFN-y, which were increased by oxidative stress. However, TP enhanced the serum concentration of IL-4, indicating changes in the response of Thl to Th2. Thus, the results showed the immunomodulatory response of TP towards weaned oxidative stress.

The coix seed associated with the family Poaceae,a rich source of nutritional compounds including polyphenols, originates in China, Japan, Thailand, and Burma[126,127]. A study by Dairy [128] exhibited that coix seed extract signif-icantly enhanced growth performance,promoted density and

length of GIT villi, enhanced abundances of Bacteroidetes and genus Lactobacillus, and declined the richness of Prevo-tella in gut microbiota. Hence, it is a potential source of feed supplement in swine production. In a previous study, Ishi-hara et al.[129]used grape seed and grape marcmeal extract (GSGME)or spent hops(SH) to enhance animal perfor-mance. In his experiment, pigs who were offered GSGME or SH supplement disclosed an increased gain:feed ratio, reduced levels of volatile fatty acids, and decreased counts of Streptococcus spp.and Clostridium cluster XIVa in the fecal microbiota. Further,supplementation of both groups had the lowered expression of several proinflammatory genes in the duodenum, ileum, and colon. A study by Sarker et al.[130]exhibited that plant polyphenols affected the antioxidant sta-tus of weaned piglets. Results highlighted that optimized plant polyphenol supplementation may enhance plasma antioxidants by reducing the level of MDA. Other studies by Oliveira et al. [131] revealed that plant-derived polyphe-nols have gut health beneficialeffects. It was further indicated that polyphenols(apple and red wine pomace) had higher contents of flavonoids, implied as a feed additive,and pro-vided beneficial effects on villi morphology and gut-associated lymphoid tissue (GALT) activation and may increase pig health. The role of polyphenols in the regulation of gut microbiota is well ascribed in Table 1.

At present, a lot of studies on weaning stress in pigs and their successful nutritional intervention strategies with poly-phenol additives have been well documented, but unfortu-nately, such wide literature does not exist in buffalo, cattle, goats, and sheep. We tried our best to enumerate the evi-dence which highlights the importance of weaning stress and their possible dietary intervention with polyphenols to improve animal growth and production.

This Article is extracted from Hindawi Oxidative Medicine and Cellular Longevity Volume 2021, Article ID 6676444, 13 pages https://doi.org/10.1155/2021/6676444