Rabbits are raised primarily for their meat, hair, and fur. Rabbit meat is characterized by low contents of fat, cholesterol, and sodium. At the same time, it is rich in protein, polyunsaturated fatty acids (PUFA), minerals (potassium, phosphorus, and selenium), and vitamins (B₁₂ and niacin) [1]. With the worsening of climate change and the global warming phenomena, heat stress (HS) has become one of the most important types of stress that are challenging the rabbit industry, especially in hot and semi-hot regions of the world. The whole world is now suffering from high ambient temperatures, which have recently reached levels not seen before. HS is the highest serious stress and threat to the rabbit and poultry industry ^[2][3][2,3]. Rabbits are more susceptible to HS than other agricultural animals as they own fewer sweat glands and a thicker coat of fur, increasing the complexity of heat scattering ^[4][5][4,5]. Moreover, the genetically improved rabbits are characterized by rapid growth and higher metabolic rates, increasing their susceptibility to HS [6]. Thus, HS leads to significant economic losses in rabbit production as it elevates body temperature and disturbs normal physiological status, deteriorating growth performance, meat characteristics, reproductive traits, antioxidative properties, and immune responsiveness ^[7][8][7,8] (Figure 1).

Moreover, HS hurts the intestinal histomorphology and microbiome in rabbits [9]. The negative effects of HS on rabbit productivity can be mitigated with the help of cooling systems, ventilation, and management strategies. Implementing cutting-edge technology into the building infrastructure can be challenging under extreme conditions. Thus, nutritional manipulation to relieve the unfavorable influences of HS is an effective additional approach [10]. Nutraceuticals are dietary components that offer additional health benefits that override their nutritional benefits. Due to their potential impacts on maintaining normal physiological situations, strengthening the immune system, and preventing illness—which ultimately lead to an increase in productivity—nutraceuticals have recently attracted a lot of attention in rabbit farms (Table 1 and Figure 2). Nutraceuticals include vitamins, minerals, antioxidants, organic acids, fatty acids, probiotics, prebiotics, synbiotics, enzymes, medicinal plants, etc. [11]. Natural antioxidants are crucial in safeguarding the animal against the damage caused by free radicals. Weaned rabbits become extremely vulnerable to enteric infections due to the prevention of using antibiotics as growth enhancers because they have a very complicated and distinctive digestive system ^[12][13][12,13].

Moreover, there is a growing interest in natural alternatives to antibiotics that could be used in rabbit production and antibiotic-free rabbit meat. Several dietary supplements—including vitamins, minerals, and enzymes—are already utilized to preserve the normal physiological status, support immunological responsiveness, and improve rabbit productivity in thermo-neutral and HS circumstances ^{[14][15][16][17]}[14,15,16,17]. It has been suggested that probiotics, prebiotics, synbiotics, and organic acids could replace antibiotic growth enhancers in rabbit production because they promote a healthy intestinal environment ^{[18][19][20][21]}[18,19,20,21]. Furthermore, phytobiotics or phytogenics are being utilized more frequently in rabbit nutrition as antioxidants, physiological stimulants, flavorings, digestive aids, and colorants, and for protecting and treating different pathological troubles ^[22][23][24][22,23,24].

2. Effect of HS on Growth Performance

It is well known that HS is the highest hazard factor deteriorating growing rabbits’ growth performance and viability ^{[4][8][25][26][27][28][29]}[4,8,25,26,27,28,29]. Farghly et al. [8] reported that rabbits were susceptible to HS, which resulted in deteriorating growth performance indicators in terms of body weight (BW), body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR). Similarly, Matics et al. [3] noted that HS negatively influenced the growing rabbits’ FI, BWG, BW, and fat deposits. During HS circumstances, rabbits attempt to disperse the extra heat generated inside the body by reducing FI, and this FI decline could be about 28–38% ^[4][25][4,25]. Besides, under HS conditions, growing rabbits prefer to direct energy toward heat dissipation rather than the growth and building of muscles and tissues [30]. Moreover, HS suppresses the hypothalamus’s appetite–satiety center and enhances leptin and adiponectin secretion, decreasing FI ^[30][31][30,31]. Furthermore, elevating the ambient temperature reduced digestion [32] and absorption of nutrients [33], which, coupled with decreasing FI, almost resulted in reducing the supply of essential nutrients, leading to a deteriorating growth rate, final BW, meat quality traits, antioxidative status, and immune responsiveness in fattening rabbits ^[4][34][4,34]. Sirotkin et al. [26] pointed out that exposure to HS resulted in suppressing growth parameters (FI, FCR, and viability), reducing serum insulin-like growth factor 1 (IGF-I) content, and increasing serum corticosterone concentration and mortality of growing rabbits. From another point of view, several studies elucidated that HS harmed thyroid activity in the form of reducing serum concentrations of triiodothyronine (T₃) and thyroxine (T₄), which resulted in retardation of protein synthesis and an increase of protein destruction, leading to the suppression of the growth rate in growing rabbits ^[29][35][29,35].

3. Effect of HS on Reproductive Performance

In general, HS negatively impacted reproductive performance in female and male rabbits, which posed a danger to the rabbit business in hot and semi-hot climates ^[36][37][36,37]. Rabbits subjected to HS conditions had a decrease in fertility, embryo development, litter size, litter weight, and milk production ^[28][37][28,37]. Marco-Jimenez et al. [37] reported that maternal exposure to high environmental temperatures decreased litter weight, litter size, and kit weight at birth, while the stillborn rate was greater in heat-stressed does during pregnancy. SOD-Superoxide dismutase, TAC-total antioxidant capacity, IFN-γ-interferon-gamma, TNF-α- tumor necrosis factor-alpha, IL-10-interleukin 10, HSP70-heat shock protein 70, GSH-glutathione, GSH-Px-glutathione peroxidase, CAT- catalase, GST-glutathione S-transferase, MDA- Malondialdehyde, TBARS-thiobarbituric acid reactive substances, ALT- Alanine aminotransferase, AST- Aspartate transaminase, T3-triiodothyronine, T4-thyroxine. García and Argente [61] elucidated that rabbits’ dams exposed to HS had minor ovulation rate, normal embryo %, embryo quality, zona pellucida thickness, and later embryogenesis. Several studies documented that a long exposure to thermal stress resulted in oxidative stress, consequently deteriorating rabbit females’ endocrine system and ovarian physiological functions ^[26][62][26,62]. It was noted that exposure to HS reduced the relative weight of the ovary ^[62][63][62,63]. Additionally, exposure to HS resulted in the impairment of ovarian granulosa cells’ responsiveness, reducing plasma progesterone concentration, destructing the ovarian cell nucleoli, and weakening the responsiveness of ovarian granulosa cells to follicle-stimulating hormone (FSH) in rabbit does [26]. Moreover, HS increased mortality in both adult mothers and offspring and deteriorated offspring growth [26]. Tang et al. [63] pointed out that HS had a negative influence on the physiological performance of female rabbits in terms of ovary weight % and plasma contents of interleukin (IL)-2, IL-8, catalase (CAT), and glutathione peroxidase (GSH-Px), and accelerated ovarian apoptosis and unhealthy follicles, as well as altered miRNAs expression in rabbit does. The CAT and GSH-Px play a vital role as antioxidative enzymes in rabbits’ earlier phases of folliculogenesis; therefore, exposure to HS suppressed ovarian folliculogenesis, maturation, and ovulation [64]. Regarding gene expression, Marco-Jiménez et al. [65] explained that the harmful effect of HS on live-born kits and litter size is attributed to a disruption in gene expression pattern, including the up-regulation of vascular endothelial growth factor (VEGF) and octamer-binding transcription factor 4 (OCT-4), and the down-regulation of Ifn-γ in endometrial tissue and embryos leading to retardation of fetal development during gestation. From another point of view, HS during pregnancy and lactation might affect the fetal growth and postnatal development of newborn kits through the lactation period ^[26][37][66][26,37,66]. This retardation in postnatal development might be attributed to HS hurting milk yield ^[25][31][25,31]. Therefore, kits suckled less milk, reducing weight gain [25]. Male rabbits are more oversensitive to HS than other male farm animals [67]. HS deteriorated sexual desire (libido) and semen quality characteristics, including concentration, motility, viability, morphological parameters, and metabolic activity ^[68][69][68,69]. Maya-Soriano et al. [67] reported that rabbit bucks subjected to HS (30 °C) had a lower sperm total motility, progressive motility, and specific motility parameters. Sabés-Alsina et al. [68] documented that HS had a negative effect on rabbit spermatozoa parameters, including viability %, acrosome abnormalities %, presence of distal cytoplasmic droplets %, motility parameters (total motility %, curvilinear velocity, average path velocity), and sperm metabolic activity. The exposure of male rabbits to HS reduced viable spermatozoa % and increased acrosome abnormalities % [69]. HS affects male rabbits with temporary infertility or sub-fertility and libido during the hot season ^[70][71][70,71]. Under high ambient temperatures, hypothalamic GnRH secretion is blocked, significantly impacting spermatogenesis and testicular function, and lowering semen quality in male rabbits [72]. HS also causes oxidative stress and reactive oxygen species (ROS) generation that damages sperm’s DNA, mitochondrial, and smooth endoplasmic reticulum, altering its cytoskeleton and axoneme and decreasing motility ^[73][74][73,74]. In testis, the excellent result of HS is a devastation of spermatogonia and the later stages of spermatogenesis by apoptosis and histomorphological modifications in seminiferous tubules and seminiferous epithelium in male rabbits [71].

4. Effect of HS on Carcass Traits and Meat Quality

Carcass characteristics and meat quality parameters of rabbits are very important criteria for consumer acceptance. Several studies elucidated that HS negatively affected carcass and meat quality traits ^[3][66][3,66]. Matics et al. [4] noted that a high ambient temperature hurt slaughter weight, hot carcass weight, chilled carcass weight, and reference carcass weight in growing rabbits. Zeferino et al. [66] observed that HS reduced slaughter weight, carcass weight, and relative weights of internal organs (thoracic viscera, liver, and kidneys), decreasing meat juiciness and meat color (redness and yellowness) while increasing cooking loss. HS did not influence other meat quality characteristics, including pH (24 h and 48 h), water-holding capacity, and the Warner–Bratzler force [66]. Contrarily, Dahmani et al. [27] postulated that HS did not significantly influence the carcass yield %, forelegs %, hind legs %, and loin %. In contrast, the liver %, kidney %, peritoneal fat %, and inter-scapular fat % were reduced in fattening rabbits. Similarly, Matics et al. [4] noted that HS harmed perirenal and scapular fat percentages in growing rabbits. Additionally, Zeferino et al. [66] concluded that heat-stressed rabbits had lower fat depots. Meanwhile, Liu et al. [29] elucidated that chronic HS decreased the liver index (%), while the shoulder fat % and kidney fat % were increased.

5. Effect of HS on the Intestinal Microbiome

The intestinal microbiome performs a vital task in gut action and health and is involved in nutrient digestion, immune response, and productiveness ^[75][76][75,76]. The highest percentage of digestive disorders is noticed in juvenile rabbits, mostly during the weaning period (feed transmission, handling, stressful factors, etc.). Such disturbances might be linked to unbalance and instability in intestinal microbiota and the inability of nonspecific and specific immune responses to combat harmful pathogens effectively [77]. Environmental stressors, mainly HS, can modify the balance of the gut flora in growing rabbits ^[78][79][80][78,79,80]. Bai et al. [79] postulated that thermal stress increased the number of Firmicutes, Proteobacteria, and Verrucomicrobiota at the phylum class, while reducing the Bacteriodota number in growing rabbits. Liu et al. [29] reported that HS affected the cecal microflora and increased the number of cecal Proteobacteria of Proteus, and reduced the number of Lachnospiraceae, Ruminococcaceae, and Candidatus saccharimonas, which may lead to inflammatory diseases in growing rabbits. Yasoob et al. [81] demonstrated that HS induced an imbalance in cecal microbiota by increasing the quantity of Proteobacteria in growing rabbits. El-Badawi et al. [9] noted that HS increased the total count of pathogenic bacteria such as Salmonella, E. coli, Staphylococcus aureus, Clostridium perfringens, and molds in the small intestine and cecum of growing rabbits. Moreover, Patra and Kar [82] documented that HS causes injury to the mucosal epithelia’s structure and deteriorates the intestinal barrier function, increasing intestinal permeability to toxins and pathogens in farm animals. This damage increased the sensitivity to oxidative stress insults and inflammation.

6. Effect of HS on Antioxidative Properties

Under thermoneutral conditions, there is an equilibrium between the generation and elimination of free radicals (e.g., ROS) by the antioxidative system. Enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) scavenge reactive oxygen species (ROS), which are neutralized by the antioxidative defence system [83]. While under HS conditions, the redox balance is disturbed, and consequently, the ROS generation is elevated, leading to oxidative stress in rabbits ^[62][79][84][62,79,84]. Saghir et al. [34] indicated that exposure to HS resulted in reducing the activities of antioxidative enzymes, including GSH-Px, SOD, and CAT, and increasing serum oxidative markers such as protein carbonyl (as an index of amino acids oxidation) and malondialdehyde (MDA, as an index of lipids peroxidation) in growing rabbits. Similarly, several studies revealed that the plasma concentration of GSH-Px, SOD, and CAT was significantly minimized, while the plasma level of MDA was elevated in heat-stressed rabbits ^[84][85][84,85]. Likewise, Madkour et al. [86] observed that HS at 36 °C lessened the amounts of SOD, GSH, and CAT, and elevated the MDA concentration in the blood plasma and muscle of broiler rabbits. Bai et al. [79] postulated that the plasma total antioxidant capacity (TAC) concentration was reduced in growing rabbits under HS conditions. Moreover, thermal stress hurts metabolism by increasing the contents of 4-pyridoxic acid, kynurenine, 20-OH-leukotriene B₄, and dopamine. It reduces pyridoxal’s value, making rabbits susceptible to inflammatory and oxidative stress [79]. Yasoob et al. [81] noted that HS generated cecal oxidative stress, whereas the MDA concentration in cecal mucosa was elevated in growing rabbits subjected to HS conditions. Madkour et al. [87] elucidated that HS had an unfavorable effect on hepatic antioxidative status, including reduced glutathione (GSH), SOD, and CAT concentrations, while the MDA concentration was increased in fattening rabbits. In female rabbits, Mutwedu et al. [62] demonstrated that exposing rabbits to HS (35–36 °C) caused oxidative stress, reduced the renal values of CAT, SOD, and GSH-Px, and raised the renal content of MDA.

7. Effect of HS on Immune Responsiveness

Inhibition of humoral and cell-mediated immune responses was seen in rabbits exposed to cyclic or chronic HS ^[87][88][87,88]. HS inhibits the immune system components and disturbed homeostasis in rabbits [89]. Liu et al. [29] noted that HS harmed growing rabbits’ thymus index (%). Saghir et al. [34] indicated that HS induced the raising of pro-inflammatory cytokines containing tumor necrosis factor-α (TNF-α), IL-1β, and interferon-gamma (IFNγ) in growing rabbits. These results conform with reports postulated that HS stimulated inflammatory signaling, including TNF-α, IL-1β, and IFNγ in heat-stressed rabbits ^{[43][79][87][89]}[43,79,87,89]. Yasoob et al. [81] noted that HS adversely affected the mucosal immune response and increased cecal concentrations of TNF-α, IL-1α, and IL-1β as markers of cecal mucosa inflammation in growing rabbits. Additionally, in fattening rabbits exposed to HS, the serum lysosome activity and nitric oxide levels were reduced [34]. Moreover, HS disturbed the equilibrium between anti-inflammatory and pro-inflammatory cytokines [34], which might be connected with a progressive inflammation response [86]. Abdel-Latif et al. [39] observed that HS had a negative influence on IFN-γ, TNF-α, and heat shock protein 70 (HSP70) expression leading to affect the infiltration of regulatory T cells adversely and NK cells in New Zealand White (NZW) growing rabbits. From another point of view, normal thyroid hormone concentrations are essential for the proper function of the immune system [35]. Exposure to HS suppresses the hypothalamic–pituitary–thyroid axis and reduces the serum concentrations of T₃ and T₄ ^[29][61][29,61], and, finally, depressing the immune response in growing rabbits. Furthermore, considering the link between oxidative stress and inflammation, it might be indicated that rabbits exposed to HS are under a penalty of oxidative stress, which might adversely affect their health status.