Camel Milk as a Potential Nutritional Therapy in Autism

C H A P T E R

30 Camel Milk as a Potential Nutritional Therapy in Autism Laila AL-Ayadhi, Dost M. Halepoto King Saud University, Riyadh, Saudi Arabia

INTRODUCTION Camel milk has been known in Asia and Africa for 5000 years for its benefits for human health. Camel milk has been used medicinally for centuries by people (Yagil, 1982a, 2013a; Levy, 2013; Nikkhah, 2014; El-Agamy, 2006). It is the closest to human mother’s milk and safe for children (Hosseini et al., 2015; Yadav et al., 2015). Research studies around the world have confirmed that camel milk has better nutritional value as it exhibits many unique and amazing health-promoting properties as compared to cow milk (Kumar et al., 2016). Camel milk has been used in some parts of the world to treat certain diseases such as diabetes, allergies, cancer, arthritis, tuberculosis, autism, and hepatitis (Abdelgadir et al., 1998; Attia et al., 2001). Medicinal properties suggest that camel milk contains protective proteins that may have a possible role for enhancing immune defense mechanisms. Camel milk is a rich source of insulin, containing approximately 52 units of insulin in each liter of milk, making it a great treatment option for type 1 or type 2 diabetes as well as gestational diabetes (Gizachew et al., 2014). Camel milk is considered a complete food and can be consumed exclusively while meeting all nutritional requirements. Camel milk is most frequently consumed raw and unpasteurized, because the raw milk contains the most nutritional and immune properties (www.nourishinghope.com). Many studies have reported that camel milk has very high concentrations of mono- and polyunsaturated fatty acids, low fats, cholesterol, and lactose (Mohamed et al., 2005; Al-Humaid et al., 2010). It contains higher amounts of minerals (calcium, iron, magnesium, copper, zinc, and potassium) and vitamins A, B2, E, and C as compared to cow milk, and it contains no beta lactoglobulin and beta casein that are present in cow milk and that are the main cause of allergy in humans (Shabo et al., 2005). Furthermore, camel milk contains various protective proteins, mainly enzymes that exert antibacterial, antiviral, and immunological properties (AL-Ayadhi and Elamin, 2013; El-Agamy et al., 1992; Al Haj and Al Kanhal, 2010). It possesses unique, powerful immune system–boosting components that would exert potential health benefits. It is an alternative for people suffering from cow milk allergy. In view of its health benefits, there is fast-growing demand for raw camel milk around the world and it was introduced recently as a new functional food in the European market (Faye and Bonnet, 2012) and is available in pharmacies (El-Agamy, 2006). Studies confirmed that the composition of camel milk is unique in terms of antioxidative factors, antibacterial, antiviral, antifungal, and antitumor activity, and hypoglycemic effect (Kula, 2016).

Physicochemical Properties of Camel Milk Camel milk is generally opaque white in color, foamy, and slightly salty to taste (Abbas, 2013). Its density ranges from 1.026 to 1.035 and the pH from 6.2 to 6.5; both are lower than those of cow milk. It can be kept longer without refrigeration as compared to cow milk (Gul et al., 2015). The unprocessed camel milk has a shelf life of 5 days at 7°C, whereas the shelf life of pasteurized milk is 22 days, when heated at 65°C for 20 min and kept at 7°C. The fresh milk can also be stored for 1 year if it is frozen (Panwar et al., 2015). Nutrients in Dairy and Their Implications for Health and Disease http://dx.doi.org/10.1016/B978-0-12-809762-5.00030-9

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30.  CAMEL MILK AS A POTENTIAL NUTRITIONAL THERAPY IN AUTISM

TABLE 30.1  Chemical Composition of Camel Milk Components

Mean (SD) (g/100 g)

Protein

3.71 (0.16)

Fat

2.21 (0.16)

Lactose

3.36 (0.25)

Ash

0.48 (0.05)

Total solid

11.26 (0.69)

Water

88.3 (1.67) %

The most important component of camel milk is water content, which is about 84%–90% (Saitmuratova et al., 2015; Ohri and Joshi, 1961). It has been reported to be less viscous than bovine milk (Laleye et al., 2008). The freezing point of camel milk is between −0.57°C and −0.61°C. The camel milk has a calorific value of 665 kcal/L versus 701 kcal/L for cow milk. The production of milk in camels has been found to be in the range of 17–26 L per day (Knoess et al, 1986). Milk yield varies with breed, stage of lactation, management conditions, and feeding.

Camel Milk Composition Camel milk composition was found to be less stable than other species such as bovine milk. It is very rich in nutrients and different from other ruminant milk. The main constituents of camel milk composition (Al-Juboori et al., 2013) are depicted in Table 30.1. Milk Proteins The main component of milk, which has a major impact on its nutritional value, is protein. Milk proteins are a heterogeneous group of compounds that differ in composition and properties. The average protein in camel milk reported is 3.71%. Camel milk proteins can be divided into two groups: caseins and whey proteins. These proteins are important components of camel milk and have different functions. The amount and type of amino acids in camel milk are high except for lysine, glycine, threonine, and valine. The most important proteins in camel milk are whey proteins, which contain albumin, lactoferrin, immunoglobulins, etc., (Konuspayeva et al., 2009; Al haj and Al Kanhal, 2010; Shamsia, 2009). Casein content of camel and cow milk is quite similar; however, the whey protein fraction is higher in camel milk. The ratio of whey protein to casein in camel milk is higher than cow and human milk proteins. Casein is the major protein in camel milk and constitutes about 52%–87% of the total proteins. The β-casein content is higher than casein, and constitutes about 65% of total casein, compared with 38% in bovine milk. The κ-casein content of camel milk is about 3.47% of the total casein compared with 13% in bovine milk. Whey proteins constitute about 20%–25% of the total proteins and 0.63%–0.80% of the milk. Of the two major whey proteins, α-lactalbumin is the main component in camel milk and β-lactoglobulin is deficient (Laleye et al., 2008). Other whey proteins present in camel milk are serum albumin, lactoferrin, immunoglobulins, and peptidoglycan recognition protein. Protective Proteins in Camel Milk Camel milk contains various “protective proteins” (lysozymes, immunoglobulins, lactoferrin, lactoperoxidase, peptidoglycan recognition protein, and N-acetyl-β-glucosaminidase (NAGase)), which have antiviral, antibacterial, and immunological properties (Shabo et al., 2005; Kappeler, 1998; Konuspayeva et al., 2007). The presence of these proteins has explained some of the natural healing properties of the camel milk (Kappeler, 1998). The known protective proteins and their immunological action in camel milk are described in the following sections. Lysozymes A lysozyme is an enzyme that is part of the innate immune system that targets gram-positive bacteria. According to Singh et al. (2006), lysozyme activity is 0.03–0.65 mg/dL. Lysozymes participate in many primary immune systems, which are based on targeting of structures common to invading pathogens. Camel milk lysozymes showed a higher lyses value toward Salmonella typhimurium compared to egg white and bovine milk lysozymes.

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Immunoglobulins Immunoglobulins give immune protection to the body against infections such as tuberculosis and some other bacterial and viral infections (Mal et al., 2006). Lactoferrin Camel milk has higher concentration of lactoferrin compared to bovine milk (Yagil et al., 1994; Morin et al., 1995). Lactoferrin activity varies from 95 to 250 mg/dL (Morin et al., 1995). Camel milk is rich in lactoferrin with potent antimicrobial and antiinflammatory properties, including bacterial inhibition (Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Clostridium, and Helicobacter pylori), antiviral effects [HBC, CMV, herpes simplex virus-1, and human immunodeficiency virus (the virus responsible for AIDS)], antifungal effects (Candida albicans), immunosupportive and immunomodulating functions (regulates the maturation and activation of neutrophils and macrophages), the maturation and function of lymphocytes (antioxidant and antiinflammatory), and anticancer actions (Habib et al., 2013; Kanwar et al., 2015). Iron-saturated lactoferrin (from second-week lactation) prevents microbial growth in gut and participates in primary immune system, which is based on targeting of structures common to invading pathogens. Lactoperoxidase Lactoperoxidase is found in milk, tears, and saliva. It contributes the nonimmune host defense system, exerting bactericidal activity, mainly on gram-negative bacteria like E. coli, Salmonella, and Pseudomonas. According to Ueda et al. (1997), lactoperoxidase activity is 2.23 ± 0.01 U/mL of milk. It has growth promotion activity and antitumor activity (Ueda et al., 1997). It has close relation (71%) to human thyroid peroxidase, which is involved in iodination and coupling in the formation of the thyroid hormones. Peptidoglycan Recognition Protein Camel milk has the highest concentration of this protein (Kiselev, 1998). It stimulates the host immune response and it has broad antimicrobial activity (Kustikova, 1996). N-Acetyl-β Glucosaminidase Camel milk is rich in NAGase, which has antibacterial and antiviral activity. It is noteworthy that the NAGase activity is similar to that in human milk, confirming the nutritional advantage of camel milk over cow milk (Morin et al., 1995). Milk Fat Milk fat serves as an energy source, acts as a solvent for fat-soluble vitamins, and provides essential fatty acids. The fat content of camel milk is between 1.2% and 6.4% consisting of unsaturated fatty acids, volatile fatty acids, mainly linoleic acid, making the milk more digestible and more cardiovascular friendly. Camel milk fat contains six to eight times less of the short-chain fatty acids (C-4–C-14) compared to milk from cows, goats, sheep, and buffalo (Ceballos et al., 2009; Narmuratova et al., 2006). However, the long-chain fatty acids (C-14–C-18) are higher in content than the cow milk (Omar and Abdurahman, 2004). Linoleic acid and unsaturated fatty acids in camel milk are very important for nutrition (Konuspayeva et al., 2009; Al haj and Al Kanhal, 2010; Abdoun et al., 2007; Shamsia, 2009). Fat globules consist of a triglyceride core surrounded by a natural biological membrane with the biggest average diameter found in buffalo milk (8.7 μm) and the smallest in camel (2.99 μm). Therefore, camel milk is more digestible for humans (D’Urso et al., 2008). Compared with bovine milk, camel milk has a lower content of carotene (Stahl et al., 2006). The milk fatty acids present in camel milk (Stahl et al., 2006; Singh et al., 2006) are shown in Table 30.2. Milk Sugar/Lactose The major carbohydrate fraction in milk is lactose. Lactose present in the milk is readily digested by human enzyme lactase and does not produce signs of lactose intolerance in humans. The total amount of camel milk lactose also has been reported between 4.8% and 5.8% (Omar and Abdurahman, 2004; Konuspayeva et al., 2009; Al haj and Al Kanhal, 2010; Shamsia, 2009). The lactose content of camel milk remains almost unchanged over a season and under hydrated or dehydrated conditions (Kumar et al., 2016). Mineral Components of Milk Milk is an important source of mineral substances, especially calcium, phosphorus, sodium, potassium, chloride, iodine, and magnesium. Camel milk is the richest in these minerals (Al-Wabel, 2008; Mal et al., 2007).

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TABLE 30.2  Fatty Acids in Camel Milk Fatty Acid

Value % by Weight

Butyric acid

0.31–0.75

Caproic acid

0.2–0.6

Caprylic acid

0.2–0.3

Capric acid

0.2–0.4

Lauric acid

1–1.8

Myristic acid

15.9–25.2

Myristoleic acid

1.7–4.5

Palmitic acid

25–29.5

Palmitoleic acid

6.1–19.1

Stearic acid

1.9–11.7

Oleic acid

6.8–24.9

Linoleic acid

0.9–0.2

Arachidic acid

0.6–3.4

TABLE 30.3  Mineral Profile of Camel Milk Parameters

(%) Mean (SD)

Phosphorus (P)

0.05 (0.01)

Potassium (K)

0.19 (0.04)

Calcium (Ca)

0.11 (0.02)

Sulfur (S)

0.03 (0.02)

Sodium (Na)

0.14 (0.02)

Iron (Fe)

14.65 (7.70)

Copper (Cu)

0.42 (0.02)

Zinc (Zn)

8.19 (0.01)

The total mineral content of camel milk varies from 0.60% to 0.90%. The values of trace minerals (iron, zinc, and copper) are significantly higher in camel milk as compared to bovine milk (Singh et al., 2006). The ratio of Ca:P is 1.5 for camel milk compared to 1.29 and 2.1 for cow and human milk, respectively. Camel milk is also a rich source of chloride (Yagil, 1982a) and this might be the cause of the salty taste in camel milk. The mineral composition of camel milk (Al-Juboori et al., 2013) is summarized in Table 30.3. The present findings revealed that camel milk is rich in minerals and can be considered as a good source of these minerals for humans (Al-Juboori et al., 2013). Milk Vitamins Milk is a valuable source of vitamins. Camel milk has a lot of fat and water-soluble vitamins from different groups such as vitamins A, E, D, B, and C (Abbas, 2013; Konuspayeva et al., 2009; Al haj and Al Kanhal, 2010; Shamsia, 2009). Camel milk is a kind of exception because of its high concentration of vitamin C. The vitamin C levels in camel milk are three times that of cow milk (Farahi et al., 1992) and one-and-a-half times that of human milk (HamersCasterman et al., 1993). The availability of a relatively higher amount of vitamin C in raw camel milk is of significant relevance from the nutritional point as vitamin C has powerful antioxidant action (Al-Ayadhi and Elamin, 2013). The levels of vitamin A and E were reported to be low in camel milk compared to the cow milk, however; β-carotene is not detected in camel milk. The content of vitamin A camel milk ranges between 100 and 380 μg/L (Kumar et al., 2016). The low pH of camel milk is due to the vitamin C content, which stabilizes the milk and so it can be kept for relatively longer periods (Panwar et al., 2015).

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Introduction

Vitamins B1, B2, folic acid, and pantothenic acid are low in camel milk; B6 and B12 content are quite similar to those of cow milk and higher than in human milk. According to the United States Department of Agriculture (USDA, 2009), camel milk (250 mL) provides an adult with about 15.5% of cobalamin (B12), 8.25% of riboflavin (B2), 5.25% of vitamin A, and 10.5% of ascorbic acid (C), thiamin (B1), and pyridoxine (B6) of the recommended daily intake. Vitamin contents in camel and cow milk (Stahl et al., 2006) are given in Table 30.4. Camel Milk Enzymes Camel milk contains various proteins, mainly enzymes. The main camel milk enzymes and their activity (NRCC, 2006–07) are depicted in Table 30.5. Milk enzyme gamma glutamyl transferase plays an important role in the keeping quality of camel milk and can be used as indicator for the proper heat inactivation of camel milk because it is destroyed between 10 and 20 min at 72°C (Wernery, 2007). Antimicrobial and Antiviral Properties of Camel Milk Camel milk has been reported to have a higher antimicrobial activity compared to bovine milk (Yagil et al., 1994). Antibacterial activity of camel milk is due to the presence of antimicrobial substances such as lysozyme, hydrogen peroxide, lactoferrin, lactoperoxidase, and immunoglobulins. These antimicrobial agents were reported to completely lose their activity in camel milk if heated at 100°C for 30 min (El-Agamy, 2000a). Camel milk was reported to have an antimicrobial effect against gram-positive and gram-negative bacteria, including E. coli, Listeria monocytogenes, S. aureus, and Salmonella typhimurium (Benkerroum et al., 2004; El-Agamy et al., 1992). The inhibitory action of camel milk against L. monocytogenes, S. aureus, and E. coli might be attributed to the presence of lactoperoxidase, hydrogen peroxide, and lysozyme, respectively (Benkerroum et al., 2004). The growth of S. typhimurium was inhibited by lactoferrin in camel milk through binding iron and making it unavailable for its growth (El-Agamy et al., 1992; Ochoa and Cleary, 2009). The stronger antirotavirus activity was reported in camel milk and colostrum (El-Agamy et al., 1992; El-Agamy, 2000b). This indicates that raw camel milk is considered a strong viral inhibitor to human rotavirus. The ability of camel milk proteins to inhibit and/or block the hepatitis C virus entry and replication inside the cell system has been explored (El-Fakharany et al., 2008; Redwan and Tabill, 2007).

TABLE 30.4  Vitamin Content in Camel and Cow Milk Vitamin

Camel

Cow

β-Carotene (μg%)

Absent

99.60 ± 62.00

A (μg%)

20.10 ± 10.00

60.90 ± 25.60

E (μg%)

32.70 ± 12.80

171.00 ± 114.40

B1 (mg%)

19.60 ± 6.40

34.70 ± 8.10

Niacin (mg/mL)

4.60 mg/mL

0.60 mg/mL

Vitamin C (mg/mL)

35.00

10.00

TABLE 30.5  Milk Enzyme and Their Activity in Camel Milk Enzymes

Activity (IU/L)

Aspartate aminotransferase

7.98–9.21

Alanine transferase

9.49–11

Gamma glutamyl transferase

254–296

Acid phosphatase

2.74–3.08

Alkaline phosphatase

16.04–24.93

Lactate dehydrogenase

132–168

Catalase

0.083–0.193 mol/min/g of protein

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TABLE 30.6  Compositional Differences of Camel and Cow Milk Parameters

Camel Milk

Cow Milk

Parameters

Camel Milk

Cow Milk

Water (%)

90

87

Pantothenic acid (mg/mL)

0.90

3.80

Total solids (%)

10.00

13.00

β-Lactoglobulin (mg/mL)

0

3500

Fat (%)

2.00

4.00

Whey acidic protein (mg/mL)

157

0

Insulin (μu/mL)

40.50

16.30

Peptidoglycan recognition protein (mg/mL)

107

0

Iron (mg/100 g)

0.05

0.27

β-Lactalbumin (mg/mL)

3500

1200

Calcium (mg/100 g)

132

120

Kappa casein (%)

5.00

14.00

Potassium (mg/100 g)

152

140

Casein micelles (μm)

320

160

Zinc (mg/100 g)

0.50

0.40

Whey protein (%)

1.00

0.80

Vitamin C (mg/mL)

35

10

Omega 6 (%)

3.50

5.20

Niacin (mg/mL)

4.60

0.60

Omega 7 (%)

11.60

2.30

Protein (%)

2.80–3.60

3.40

Lactose (%)

2.80–4.20

4.80

Comparison of Camel Milk With Bovine Milk Yagil (2000) reported that camel milk composition is vastly different from that of ruminant milk, having low cholesterol, low sugar, high minerals (sodium, potassium, iron, zinc, and magnesium), high vitamin C, low protein, and large concentration of insulin. The values of trace minerals were significantly higher in camel milk as compared to bovine milk (Agrawal et al., 2004a; Arrowal et al., 2005). The specific gravity of camel milk is less than that of cow, sheep, or buffalo milk (Shalash, 1979). The levels of vitamins A, E, and B1 were reported to be low in camel milk compared to the cow milk (Stahl et al., 2006). Cow milk contains a carotene that is lacking in camel milk. The compositions of cow and camel milk (Singh et al., 2006; Yagil, 2000) are given in Table 30.6.

MEDICINAL PROPERTIES OF CAMEL MILK Camel herders and indigenous cultures have known about the power of camel milk for a long time (Abdel Gader and Alhaider, 2016). It has been consumed for centuries by nomadic peoples due to its nutritional and medicinal properties (Yagil, 1962, 1978). To this day, Bedouin parents send their children to drink camel milk for a couple of weeks in their childhood, as they know that it sets up a strong immune system for life. The Arabs in several districts use camel milk extensively (Price, 2008). The long-standing practice of using camel milk for medicinal purposes in the Middle East, parts of Africa and Asia, and the former Soviet Union was without scientific rationale for centuries. However, based on the existing information about bovine milk as a functional food, camel milk, in a similar way, could serve not only as a source of nutrients but also as a source of bioactive agents with therapeutic properties. The current scientific evidence for the therapeutic actions of camel milk continues to unfold, and efforts are underway to more precisely identify the therapeutic constituents. In the beginning of the early 1980s, several published reports identified specific diseases and medical conditions that have been treated by camel milk (Abdel Gader and Alhaider, 2016). El-Agamy et al. (1992) reported that camel milk possesses antibacterial and antiviral activities and they suggested that this milk contains protective proteins that may have a possible role for enhancing immune defense mechanisms (Sharma and Singh, 2014). Camel milk is used for treating dropsy, jaundice spleen ailments, asthma, anemia, and piles (Rao et al., 1970; Abdelgadir et al., 1998). The patients suffering from chronic hepatitis had improved liver function after drinking camel milk (Sharmanov et al., 1978; Saltanat et al., 2009). Among the diseases successfully treated with camel milk are cirrhosis of the liver, constipation, tuberculosis, autoimmune diseases, diabetes mellitus, Crohn’s disease, and autism (Wernery, 2006). Historically, camel milk has been used for a number of medical problems (Khan, 1974; Yagil, 1982b). Recently, Zibaee et al. (2015) reviewed nutritional and therapeutic characteristics of camel milk in children. Tezera (1998) reported the importance of camel milk for treating malaria, jaundice, gastrointestinal disorders, and strong cough

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Medicinal Properties of Camel Milk

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(pneumonia). Research by Indian scientists supports the therapeutic value of camel milk in the treatment of several diseases including tuberculosis (Ilse, 2004). Camel milk and its components was also reported to have other potential therapeutic properties, such as anticarcinogenic (Magjeed, 2005; Habib et al., 2013), antihypertensive (Quan et al., 2008), and renoprotective potential (Afifi, 2010). It has been also recommended to be consumed by children who are allergic to bovine milk (El-Agamy et al., 2009; Shabo et al., 2005). It has also been reported to improve oxidative stress and lipid peroxidation in rats (Al-Hashem, 2009). Camel milk works as a laxative on people unused to drinking this milk (Rao et al., 1970). The milk also apparently has slimming properties (Yasin and Wahid, 1957). Camel milk is given to the sick, the elderly, and the very young because of the belief that it is not only healthier but works especially well in bone formation (Gast et al., 1969). Camel milk contains antibacterial and antifungal agents that boost immunity to fight bacterial and yeast infections (Al-Qahtani, 2007). This is partially due to higher concentration of lactoferrin in its milk compared to bovine milk (Yagil et al., 1994). Camel milk colostrum is of superior nutritional value, making it a potent immune booster for recovering patients and sufferers of nutrient deficiencies and bone loss. The medicinal properties of camel milk could also be related to the gamma globulins and other immune components, including immunoglobulins, present in camel milk (Alhaider et al., 2013). It was found that relatively large concentrations (45–128 U/L) of insulin are present in camel’s milk (Singh, 2001; Zagorski et al., 1998; Yagil, 1962, 1978) and it has been used as an antidiabetic (Agrawal et al., 2007, 2011; Mohamad et al., 2009). Recent randomized human studies revealed that regular consumption of camel milk by diabetics resulted in a substantial reduction in the mean dose of insulin needed to obtain glycemic control and improve fasting blood sugar and glycosylated hemoglobin (HbA1c) (Agrawal et al., 2011; Ajamaluddin et al., 2012). In clinical trials, 30%–35% reduction in doses of daily insulin in patients of type 1 diabetes receiving camel milk was reported (Agrawal et al., 2002a,b, 2003). A significant hypoglycemic effect of raw camel milk is decreased when camel milk is boiled and insulin-like activity decreases even on pasteurization. Hence, use of raw camel milk or sterilized camel milk through UV rays has been suggested. An epidemiological study of the Raica community revealed zero prevalence of diabetes in camel milk–consuming Raica community versus 3%–4% prevalence of diabetes from other communities living in the same environment, having the same life style, except that they were not drinking camel milk (Agrawal et al., 2004b). Several review articles reported on camel milk, citing that it can be used in metabolic and autoimmune diseases, hepatitis, rotavirus diarrhea, tuberculosis, cancer, diabetes, liver cirrhosis, rickets, autism, and Crohn’s disease (Yagil, 2004; Asresie Leme and Adugna Mulugojjam, 2014; Sharma and Singh, 2014; Mullaicharam, 2014). An animal study indicated that fermented camel milk had a higher content of sodium and potassium and stopped diarrhea in model rats (Mona, 2010). Camel milk was reported to cause significant improvement in the clinical symptoms and investigative tests of patients suffering from drug-resistant tuberculosis (Mal et al., 2006). In addition, camel milk has been used to reduce cholesterol levels in the blood, to avoid psoriasis disease, to heal inflammation in the body, help to strengthen the human immune system, and to reduce growth of cancer cells (Kaskous, 2015). A significant therapeutic effect of raw camel milk is decreased on boiling even on pasteurization. Thus if camel milk is used raw, there is less chance of transmission of infection. This concept is consistent with the historic belief that natural substances play an important role in preventative and therapeutic treatment (Agrawal et al., 2005).

Camel Milk Therapy in Autism Autism is a severe neurodevelopmental disorder that is characterized by impairment in verbal and nonverbal communication, imagination, reciprocal social interaction, and evidence of developmental delay within the first 3 years of life (Baird et al., 2006; American Psychiatric Association, 2000; Hollander et al., 2004; Ivarsson et al., 1990). The etiology of autism is not yet well understood, although there is growing evidence that autism can be caused by a variety of factors including genetic (De la Torre-Ubieta et al., 2016), environmental (Vijayakumar and Judy, 2016), autoimmunity (Al-Ayadhi and Mostafa, 2012a), food allergy (Millward et al., 2004; Jyonouchi, 2009), and oxidation stress (AL-Ayadhi and Elamin, 2013). While several intervention methods have been used to treat children with autism, very few have been subjected to careful scientific investigation. To date there is no known effective approved intervention method for autism. Consequently, this creates many challenging issues and it has become an area of a major controversy. Camel milk has emerged to have potential therapeutic effects in patients suffering from autism. Children suffering from autism who consumed camel milk showed reduced autism symptoms and improved motor skills, language, cognition, joint coordination, and skin health (Panwar et al., 2015). To date, a few studies have reported some improvements in symptom scores in autistic children who were treated with camel milk (Shabo and Yagil, 2005a,b). E.  MILK AS A FUNCTIONAL FOOD FROM NONBOVINE SOURCES

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Some have believed that all dairy, regardless of the source, is harmful to the immune systems, brains, and bodies of children with autism (www.carinsmit.co.za). A study by Shabo and Yagil (2005b) showed that children suffering from severe food allergies who did not respond to conventional treatments were given camel milk. Within 24 h of starting to drink the milk, all the children showed diminished symptoms. Within 4 days, all symptoms had disappeared. No recurrence of allergic reactions was reported. Professor R. Yagil in his personal communication (www.carinsmit.co.za) explained that unpasteurized frozen camel milk had been given to a number of autistic children. The outcomes were beyond belief. Children who were highly allergic to dairy, and a variety of other foods, lost their allergies within hours of consuming camel milk; children who had severe behavioral issues, calmed down within a very short period of time. Dr. Pritpal Singh, leader of the clinic in Faridkot, India, also confirmed (www.carinsmit.co.za) that unpasteurized, frozen camel milk is healing allergic gastritis and a plethora of immunity related issues. The autistic children especially were doing very well and the children with the 20+ bouts of diarrhea per day were cured with much more normal bowel movements. Shabo and Yagil (2005a) reported different healing stories of people with autism who were given camel milk instead of cow milk and recovered well from autism. Another autistic child’s parent’s story (www.carinsmit.co.za) described that on the very first day of using camel milk their daughter (age 11) showed huge improvements in all areas of her development. Children with severe symptoms of autism showed improved cognitive and communication skills after 1 month of drinking camel milk. An autistic youth hostel, with an average age of 21 years, replaced all dairy milk with camel milk for 2 weeks, and the children appeared to be calmer and stopped self-mutilation (Shabo and Yagil, 2005a). Furthermore, a study concluded that young children secreting casomorphin and with no brain damage could show complete recovery by drinking camel milk, and it showed the same effect as intravenous immune-globulin treatment in the reduction of aggravation, cognitive, and behavioral symptoms of autism (Shabo and Yagil, 2005a). A study published in 2005 (Shabo and Yagil, 2005c) reported the effects of camel milk consumption, instead of cow milk, on several cases of children and adults with autism. The authors reported in the study that camel milk consumption in children under 15 has been effective in controlling some of the symptoms. Some parents reported that children suffering from autism used camel milk and some of their symptoms improved such as better sleep, increased motor planning and spatial awareness, increased eye contact, better language, and improved gastrointestinal function (Shabo and Yagil, 2005c). In a case report published in 2013, a boy had was diagnosed with autism in the third year of his life. The mother of this boy started, from the age of 9 years, to give him a glass of camel milk at night for 6 years (2007–13). She observed positive improvement in the symptoms of autism (Adams, 2013). Bashir and Al-Ayadhi (2014) investigated the role of the effectiveness of camel milk (raw and boiled) on thymus and activation-regulated chemokine (TARC) serum levels and Childhood Autism Rating Scale (CARS) score in subjects with autism and compared to placebo group (cow milk). The results suggested that camel milk therapy over the course of 2 weeks significantly decreased the serum levels of TARC among the study subjects and also improved clinical measurements of autism severity (CARS score). This research was further supported by another study, in which Al-Ayadhi et al. (2015) investigated the behavioral benefits of camel milk. Forty-five children diagnosed with autism were randomly assigned to receive boiled camel milk, raw camel milk, or a placebo (cow milk). Significant differences in behavior were detected among children with autism using CARS, the Social Responsiveness Scale, and Autism Treatment Evaluation Checklist scales, following 2 weeks of camel milk therapy. The study by Wernery et al. (2012) revealed that after consuming pasteurized camel milk on a regular basis, a positive effect on impairments of various nature and proportions appeared to be apparent amongst a group of children with autism. Fourteen days after the consumption of 500 mL of pasteurized camel milk, the probands exhibited regular bowel movements and five of eight probands developed a normal sleep pattern. The overall observation revealed also a decreased hyperactivity, increased alertness, and better social interaction, and many parents observed a newly expressed effort by their children to obey instructions. In light of these just-discussed studies, the use of camel milk appears to be a promising treatment for children with autism. Camel milk therapy was safe and well tolerated. None worsened and no side effects were reported.

Camel Milk and Food Allergy in Autism Milk protein allergy is an allergic reaction to proteins commonly found in cow milk. It is caused by the immune system reacting to the milk proteins as they would present a threat to the body. An activated immune system reacts just as it would to a foreign virus or a toxin. Several studies have demonstrated that the majority of children with cow milk protein allergy synthesize antibodies predominantly against α-casein and β-lactoglobulin (Lara-Villoslada et al., 2005).

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Various foods can cause allergies, especially consumption of ruminant milk and milk products (Shabo et al., 2005). The effect of camel milk on food allergies is based on the fact that it does not contain allergens that are so potent in cow milk. There is no β-lactoglobulin and a different β-casein (Beg et al., 1986; Merin et al., 2001)—the two powerful allergens in cow milk—which make camel milk a potent alternative for children suffering from milk allergies (Makinen-Kijunen and Palosne, 1992). Another pertinent fact is that the components of camel milk include immunoglobulins similar to those in mother’s milk, which reduces children’s allergic reactions and strengthens their future response to foods (Makinen-Kijunen and Palosne, 1992). Camel milk has been used to treat food-allergic children (Shabo et al., 2005; El-Agamy et al., 2009; Al-Hammadi et al., 2010). Restani et al. (1999) and El-Agamy et al. (2009) found that IgE of children who were allergic to cow milk, only unreacted with camel milk. Eighty percent of the treated children, who were food-allergic, had positive results after using camel milk. Children with cow milk allergy could safely take camel milk as an alternative nutrient. El-Agamy et al. (2009) indicated that the absence of immunological similarity between camel and cow milk proteins can be regarded as important points of nutrition for children allergic to cow milk. Results of a prospective cohort study, performed in children with a cow milk allergy, indicated that 80% of children were safely able to consume camel milk without developing any adverse allergic reaction (Ehlayel, 2011a). In the second study, children with cow milk allergy were evaluated by being given camel and goat milks. The tests in the children showed less allergic reaction to camel milk (Ehlayel, 2011b). In another two studies, researchers tested patients, with cow milk allergy, using a prick test with food antigens and prick-by-prick test with camel and cow milks. The patients were positive for the cow milk and negative for the camel milk in the prick test (Rubino, 2014; Zibaee et al., 2015). Results of these studies show that camel milk could represent a possible alternative to infant formulas for those with cow milk allergy. It appeared that camel milk has a positive effect in children with severe food allergies. The reactions are rapid and long lasting. Milk proteins of camels, cows, and humans, extracted by two different methods of electrophoresis, were investigated by El-Agamy et al. (2009) who revealed that, when applying camel milk protein–specific antisera in immunoblotting analysis, there was no immunologic cross-reactivity between camel and cow milk proteins. This study obtained a better understanding of the capability of the camel milk for food allergies in children. For this purpose, molecular and immunological similarities of milk were evaluated. The results showed that camel milk proteins can be used as a new protein source for food allergies (El-Agamy et al., 2009). A group of children with severe food (mainly milk) allergies who failed to respond to all modern therapies recovered fully after the daily administration of camel milk (Shabo et al., 2005). Dairy food allergy in autistic children is very common. Milk protein casein plays an important role in the food allergies–related disorders including autism. Reduction in dairy food allergy in autistics has been shown to reflect improvement in behavioral areas (Shabo and Yagil, 2005a). Many children with autism may have gastrointestinal difficulties that make it hard for them to digest milk protein properly (Galiatsatos et al., 2009; Evans et al., 2008; Murch, 2005). The most studied theory is that milk protein casein leads to high levels of protein by-products, including one called casomorphin. Some scientists have concluded that they are leaking from the intestines into the blood of these children (Reichelt and Knivsberg, 2003; Horvath and Perman, 2002). Specifically, in autistic children, casomorphin could affect brain areas that are involved in autism (Sun et al., 1999), reduce their desire for social interaction, block messages, and increase confusion (Millward et al., 2004; Reichelt and Knivsberg, 2003). Autism can be caused by food allergy (Millward et al., 2008). It has been believed that normal dairy food is harmful to the immune systems, brains, and bodies of children with autism (Sun et al., 1999) and has a significant impact on behavior, cognition, socialization, and health/physical traits associated with an autism diagnosis. Camel milk can certainly play an important role in the prevention of dairy food allergies and has been used to treat children with autism (Shabo et al., 2005). Potential effect of camel milk is due to its inflammation-inhibiting proteins, and hypoallergenic properties, in addition to its smaller-size nanobodies, which are different than those found in humans. Casein molecules are actually micelles, and camel micelles have been found to be larger in size (15 nm) than those of cow milk or human milk (Kappeler, 1998). Therefore, it is not reactive to children with the most sensitive allergy to milk and casein. Children with severe food allergies react well to the camel milk (Habib et al., 2013). Camel milk has a lower pH than other milk, so that upon entering the stomach the casein micelles do not break down into casein and whey, and therefore do not break into casomorphin (www.australiancamelindustry.com).

Camel Milk and Immune Function in Autism Although there is no clear mechanism regarding the pathophysiology of autism, immune factors have been suggested as a causative factor responsible for the initiation of autism (Shabo and Yagil, 2005a; Vojdani et al., 2002). Some research suggested altered immune status in autistic children, indicated by higher levels of antibodies against

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gluten and cerebellar peptides, with the formation of IgA, IgM, and IgG autoantibody (Cohen and Shoenfeld, 1996), reflecting an autoimmune status. It is possible that immune factors initiate the neurological disorders of autism, but the mechanisms are not clearly understood (Vojdani et al., 2002). Children with autism routinely have immune system challenges: inability to fight bacterial, viral, and other infections, and states of chronic inflammation, allergy, and autoimmunity. Over the last few years, a number of research groups suggested possible autoimmunity as a significant etiological factor in autism (Al-Ayadhi and Mostafa, 2012a). Many immune factors, such as proinflammatory cytokines, immunoglobulins, antigangliosides, and progranulin (Mostafa and Al-ayadhi, 2011, 2012; Al-ayadhi and Mostafa, 2011a,b,c; Al-Ayadhi et al., 2011) blood levels in autistic children have shown abnormality compared to normally developing controls. The prevalent assumption that the neurological symptoms of autism are rooted to autoimmunity is given more weight by the findings that agitation, cognitive and behavioral symptoms are reduced by intravenous immunoglobulin treatment (Plioplys, 1998). Autoimmunity to CNS has shown evidence, by the presence of brain-specific autoantibodies in some autistic children, to play a role in the pathogenesis of autism (Coly and Panja, 2005; Mostafa and Al-Ayadhi, 2012; Singh, 2001). The reason behind the formation of some brain autoantibodies in some patients with autism is not fully understood. It is speculated that an autoimmune reaction to neurons might be triggered by some cross-reacting antigens in the environment resulting in the release of neuronal antigens. These neuronal antigens may result in induction of autoimmune reactions through the activation of the inflammatory cells in genetically susceptible individuals. The environmental antigens may include food allergies to certain peptides such as gliadin, cow milk protein, and soy (Jyonouchi et al., 2002). Several researchers have proposed (Galiatsatos et al., 2009; Evans et al., 2008; Murch, 2005) that children with autism have gut problems that are caused by an immune response (Ashwood et al., 2006) to proteins in the diet because they do not digest dairy products properly. Their intestines may leak protein by-products into their systems, and these by-products may act like a drug in their brains. The effectiveness of elimination diets in improving the behavior of children with autism has been scientifically researched (Millward et al., 2008). It has been believed that all dairy foods, regardless of the source, were harmful to the immune systems, brains, and bodies of children with autism spectrum (Sun et al., 1999). Hamers (1998) described the amazing camel immune system, different from all other mammalians. IgM, IgG, IgA, and even IgD have been detected in camel sera on the basis of cross-reactivity with human immunoglobulins (Abu-Lehiya, 1997). Many observations over the past years suggest that autoimmune diseases are controlled or even healed by drinking camel milk. The use of camel milk to strengthen the immune system has been tested in many studies (Yadav et al., 2015). El-Agamy et al. (2009) found that camel milk proteins have unique patterns that are totally different from cow and human milk. Studies indicated that camel milk contains immunoglobulins special to camels. The immunoglobulins are the same structure as human immunoglobulins but only one-tenth the size (Mullaicharam, 2014). Therefore, that enables easy targeting and penetration of foreign disease for destruction by the immune system, whereas human immunoglobulins cannot (Hoelzer et al., 1998; El-Agamy, 2000b; Hamers, 1998). In general, camel milk contains immune proteins in higher qualities than other milk (Conesa et al., 2008). Camel milk will provide a tool for fighting autoimmune diseases by rehabilitating the immune system (Muyldermans et al., 2001). In many Arab countries it is common practice, even today, to give camel milk to children to strengthen their immune system, without knowing how it works. During the past few years, publications have appeared concerning the use of camel milk for treating a number of primary and secondary autoimmune diseases including autism (Shabo et al., 2005; Shabo and Yagil, 2005a; Yagil, 2013b; Yagil et al., 1998; Agrawal et al., 2002a,b).

Camel Milk and Inflammation in Autism There is a theory that autism may be caused by some type of inflammation (www.healthline.com). Neuroinflammation Several studies have revealed that children with autism have evidence of neuroinflammation (Vargas et al., 2005; Pardo et al., 2005; Laurence and Fatemi, 2005). Marked activation of microglia and astroglia with elevations in IL-6 and macrophage chemoattractant protein-1 (MCP-1) were found in autistic brain samples upon autopsy, along with increased proinflammatory cytokines in the cerebral spinal fluid of living autistic children (Vargas et al., 2005). Some studies have demonstrated an increased neuroinflammation in children with autism (Mostafa and Al-Ayadhi, 2011; Al-Ayadhi and Mostafa, 2012b). Camel milk therapy most probably reduced thymus and TARC synthesis and secretion, and consequently, reduced the neuroinflammation and the autoimmune reaction, leading to improved behavior, reflected in improved CARS scores (Bashir and Al-Ayadhi, 2014). E.  MILK AS A FUNCTIONAL FOOD FROM NONBOVINE SOURCES

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Gastrointestinal Inflammation Some patients with autism have chronic ileocolonic lymphoid nodular hyperplasia (LNH) and enterocolitis characterized by mucosal inflammation of the colon, stomach, and small intestine (Wakefield et al., 2005; Uhlmann et al., 2002; Furlano et al., 2001). As many as 90% of autistic children with gastrointestinal symptoms have evidence of ileal LNH, with 68% having moderate to severe ileal LNH (Wakefield et al., 2005). One study demonstrated that the gastrointestinal mucosa in autistic individuals had evidence of increased lymphocytes and proinflammatory cytokines including TNF-a and interferon-c (IFN-c), and less of the antiinflammatory cytokine IL-10, which is counterregulatory (Ashwood et al., 2004). Camel milk is thought, by some, to have an ameliorative effect for symptoms of autism by reducing inflammation (www.camelmilkforhealth.com). Camel milk contains a high concentration of antiinflammatory proteins, which have a positive health effect on the stomach and intestinal disorders. The high proportion of mono- and polyunsaturated fatty acids and vitamin-rich composition provide improved carbohydrate metabolism (Karray et al., 2005; Konuspayeva et al., 2008). Moreover, it was found that fermented camel milk has angiotensin I-converting enzyme (Quan et al., 2008), which facilitates the digestion of the milk proteins (Alhaj et al., 2006). Recent reports on the application of camel milk for the health of the digestive system showed that camel milk has antidiarrheal properties; in one study, all the children, who had 20 bouts of diarrhea per day, who took camel milk were cured and returned to normal bowel movements (Yagil, 2013b).

Role of Camel Milk as Antioxidant in Autism Extensive studies have demonstrated that oxidative stress plays a vital role in the pathology of several neurological diseases including autism (AL-Ayadhi and Elamin, 2013). Oxidative stress occurs when reactive oxygen species levels exceed the antioxidant capacity of a cell. It acts as a mediator in brain injury, strokes, and neurodegenerative diseases (Shohami et al., 1997; El-Ansary et al., 2010). Over the last few years, studies have demonstrated increased oxidative stress in autistic subjects compared to normally developing controls (Al-Ayadhi, 2012; Damodaran and Arumugam, 2011; Al-Gadani et al., 2009; Yui et al., 2016; Frustaci et al., 2012; Rose et al., 2012). Furthermore, autistic children have evidence of increased oxidative stress including lower serum glutathione levels (James et al., 2004). Some autistic children have increased red blood cell nitric oxide, which is a known free radical and is toxic to the brain (Söğüt et al., 2003). Lower serum antioxidant enzymes, antioxidant nutrients, and glutathione levels, as well as higher prooxidants have been found in multiple studies of autistic children (McGinnis, 2004). Decreased activities of certain antioxidant enzymes have also been described in autistic individuals including superoxide dismutase, glutathione peroxidase (Yorbik et al., 2002), and catalase (Zoroglu et al., 2004). Some autistic children also have decreased activity of paraoxonase, an antioxidant enzyme that prevents lipid oxidation and also detoxifies organophosphates in humans (D’Amelio et al., 2005). Furthermore, in one study, treatment with antioxidants was shown to raise the levels of reduced glutathione in the serum of autistic children and appeared to improve symptoms (James et al., 2004). In another study, the use of antioxidants improved behavior in some autistic children (Dolske et al., 1993). Nutrition is the key to good health. Studies have shown that regular consumption of natural antioxidants is strongly associated with a reduced risk of developing chronic diseases. In the last few years intensive research has been conducted on the possibilities of designing new dietary foods containing high amounts of functional ingredients including natural antioxidant because different antioxidants serve different purposes in the body. The high content of vitamin C in camel milk gives it a strong antioxidant property (Hamers-Casterman et al., 1993; Gast et al., 1969) and could be a promising beneficial intervention approach in autism. The enzymatic digestibility and antioxidant activity of camel α-lactalbumin were studied recently by Salami et al. (2009). Camel α-lactalbumin has shown higher degrees of hydrolysis with both trypsin and chymotrypsin enzymes than bovine α-lactalbumin, but both proteins showed similar sensitivity to pepsin enzyme. The antioxidant activity of camel α-lactalbumin was greater than that of bovine α-lactalbumin because of the differences in structural and amino acid sequences of both proteins. AL-Ayadhi and Elamin (2013) evaluated the effect of camel milk consumption on oxidative stress biomarkers by measuring the plasma levels of glutathione, superoxide dismutase, and myeloperoxidase before and after 2 weeks of camel milk administration. All observations revealed that measured parameters exhibited significant increase after camel milk consumption. These findings suggest that camel milk could play an important role in reduction of oxidative stress by increase in antioxidant enzymes and nonenzymatic antioxidant molecule levels, as well as show improvement of autistic behavior in children. Similar results were shown by Wernery et al. (2012) that the autistic

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children after the use of camel milk have better social interactions and reduced hyperactivity and increased vigilance and regular bowel movements. Pathology and Mechanism of Action of Camel Milk as Antioxidant in Autism Low plasma antioxidant enzymes, superoxide dismutase (SOD) (Meguid et al., 2011) and glutathione peroxidase (GSH-Px) were reported (Al-Mosalem et al., 2009). Low level of antioxidant enzymes indicated increased vulnerability to oxidative stress due to impaired antioxidant defense mechanisms, which lead to harmful effects of free radicals that could have an important role in the etiology of autism. Moreover, increased oxidative stress in autistic subjects leads to a decrease in the levels of nonenzymatic antioxidants like GSH, vitamins E and C (Chauhan et al., 2004), which in turn leads to impairment of metabolic pathways and may contribute to the developmental delays that occur in autism; this could be corrected by micronutrient supplementation. In addition, lower plasma levels of glutathione and cysteine in subjects with autism were documented (Knivsberg et al., 1995, 2002). Camel milk has been reported to improve clinical outcomes of autism spectrum disorder (Yagil, 2004), as caseinand gluten-free diet has been reported to improve autistic behavior (Yagil, 2004), possibly by reducing excess central opioid effects (Al-wabel et al., 2012). Glutathione is one of the most important intracellular antioxidants, responsible for maintaining the reducing intracellular microenvironment that is essential for normal cellular function and viability. It also exerts neuroprotective properties and reduces neuropathy, hence decreasing oxidative stress. A significant increase in GSH level after camel milk consumption is reported, which was attributed to the antioxidant nutrient constituents of camel milk (AL-Ayadhi and Elamin, 2013). Magnesium is known to reduce oxidative stress and enhance vitamins E and C absorption (Ashwood et al., 2011), whereas zinc increases total glutathione, GSHPx, and SOD levels. Moreover, vitamin E has been suggested to enhance glutathione levels. Taken together, high levels of Mg and Zn and vitamin E in camel milk might help to increase glutathione production and enzyme production, and hence to decrease the oxidative stress in autistic subjects (AL-Ayadhi and Elamin, 2013).

Acknowledgments We thank Autism Research and Treatment Centre, Al-Amodi Autism Research Chair, King Abdul Aziz City for Science and Technology (KACST), National Plan for Science and Technology and Innovation (MAARIFAH), and Vice Deanship of Research Chairs, at King Saud University, Kingdom of Saudi Arabia for financial support.

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E.  MILK AS A FUNCTIONAL FOOD FROM NONBOVINE SOURCES