Effect of diet on gut microbiota as etiological factor in Autism spectrum

disorder

By

Prof. Afaf El-Ansary

Lorenza Putignani(2014) 76, 2-10. doi:10.1038/pr.2014.49

Early colonization and homeostasis of gut microbiota:

Homeostasis of gut microbiota, can be defined as the property of this ecosystem to maintain a balance between the different bacterial species colonized the gut, the epithelial tissue of the gut, and the immune system of the host over a period of time.

Disturbance of one or more of these factors usually leads to dysbiosis causing a shift or imbalance in the microbial groups and this is commonly associated with pathological states.

•

Figure 5Lorenza Putignani

(2014) 76, 2-10. doi:10.1038/pr.2014.49

• Gut microbiota colonization of the infant usually affected by many extrinsic factors most important of which is the mother who represents the most influential factor due to the intimate contacts during birth, nursing, and early feeding.

Factors affecting infant gut microbiota

The microbial populations in amniotic fluid and placenta are similar and highly consistent across individuals.

Proteobacteria was the most prevalent phylum in amniotic fluid and placenta samples with particularly high abundance of species belonging to enterobacteriaceae, enterobacter.

Propionibacterium was the second most predominant genus present in the amniotic fluid and placenta. These genera were also present in colostrum, meconium and infant faeces but in lower abundance (Collado et al., 2016).

Shared features between the microbiota detected in the placenta and amniotic fluid and in infant meconium suggest microbial transfer at the foeto-maternal interface.

At the age of 3-4 days, the infant gut microbiota composition begins to resemble that detected in colostrum.

Infant gut colonisation process may be initiated already prenatally by a distinct microbiota in the placenta and amniotic fluid.

The link between the mother and the offspring is continued after birth by microbes present in breast milk.

Microbiota and maternal stressMaternal prenatal stress has been often related to

infant general health, as well as psychological behavior.

In a recent study done by Zijlmans et al (2015) a

strong relationship between infant altered gut microbiota and basal maternal salivary cortisol level as marker of stress was ascertained.

Vaginally born infants of mothers with high

cumulative stress during pregnancy had significantly higher relative abundances of Proteobacterial groups known to contain pathogens (related to Escherichia, Serratia, and Enterobacter), and lower relative abundances of lactic acid bacteria (i.e., Lactobacillus, Lactoccus, Aerococcus) and Bifidobacteria.

Breast feeding and gut microbiota

Colostrum = Baby’s first vaccination

Is the special milk that is secreted in the first 2–3 days after delivery.

It is produced in small amounts, about 40–50 ml on the first day, but is all that an infant normally needs at this time.

Colostrum is rich in white cells and antibodies, especially IgA, and it contains a larger percentage of protein, minerals and fat-soluble vitamins (A, E and K) than later milk.

Anti-microbial Activity of Breast Milk

•Breast milk contains many factors that help to protect an infant against infection including:

Immunoglobulin, principally (IgA), which coats the intestinal mucosa and prevents bacteria from entering the cells.

White blood cells which can kill micro-organisms.

Whey proteins (lysozyme and lactoferrin) which can kill bacteria, viruses and fungi.

Oligosaccharides in mothers milk-bind to microorganisms and bar them from attaching to mucosal surfaces.

Omega 3s in mother’s milk-promote cognitive ability and visual acuity.

Anti-microbial Activity of Breast Milk

Destruction of Built-In Safety Systems by Pasteurization

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ComponentBreast

MilkRaw Milk

Pasteurized Milk

Infant Formula

B-lymphocytesMacrophagesNeutrophilsLymphocytesIgA/IgG AntibodiesB12 Binding ProteinBifidus FactorMedium-Chain Fatty AcidsFibronectinGamma-InterferonLactoferrinLactoperoxidaseLysozymeMucin A/OligosaccharidesHormones & Growth Factors

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inactivatedinactivatedinactivatedinactivatedinactivatedinactivatedinactivated

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Gut microbiota of autistic patients:

The brain and the gut communicate closely with one another via the gut-brain axis. What this means is that if the gut is unhealthy or ‘leaking’, it will promote the formation of inflammatory cytokines which are able to reach the brain by crossing the blood brain barrier.

Well, research indicates that individuals with autism are more likely to suffer from increased intestinal permeability compared to healthy subjects (36.7% vs. 4.8%).

Besides increasing inflammation, a leaky gut will also provide optimal conditions for pathogens to thrive in the gut.

One of the most important characteristics of fecal samples of autistic children is the significantly large amount of Clostridium genus (10 times more) (Finegold et al. 2002; Song et al. 2004; Parracho et al. 2005).

Composition of gut microbiota of autistic patients demonstrates a remarkable imbalance between Bacteroidetes and Firmicutes. (Finegold et al. 2010; Adams et al. 2011; Kang et al. 2013; Wang et al. 2013; Williams et al. 2012).

Modulation of transmitters such as serotonin, melatonin, gamma-aminobutyric acid (GABA), histamines, and acetylcholine within the gut provide another mechanism of action that could mediate the effects of the gut microbiota.

It is well documented, that some patients with autism suffer from gastrointestinal (GI) symptoms, with the severity of autistic behaviours associated with the severity of GI dysfunction (Adams et al. 2011).

Alteration of the composition of the gut microbiota, may contribute to intestinal inflammation and development or maintenance of autistic features (Bartlett & Gerding 2008; Bennet et al. 2002).

Dietary factors affecting gut biota1. Under-nutrition and gut microbiota

Undernutrition may delay the maturation of the infant’s gut microbiota or induce dysbiosis toward a persistent abnormal composition that either lacks necessary functions for healthy development or increases the risk for disease, including immunoinfammatory disorders among which is autism.

Under this condition, sometimes, nutrient repletion return the gut microbiota to the normal state, but in severe cases, persistent abnormal gut biota usually require continued nutritional supplementation in order to be corrected.

There is a growing evidence that pregnancy and the first 2 years of life are the most critical time period for interventions to improve child growth and development.

In addition, the gut microbial community is established within the first 3 years of life, and repair of defects in the development of this metabolic “organ” during this time period may promote healthy growth.

The first 1000 days.

As beneficial bacteria in the autistic guts are depleted, so fewer vitamins which are normally produced by these bacteria (vitamin B12, biotin, and vitamin K) are deficient.

Based on this, it is acceptable that some of autistic children can benefit from multivitamin supplementation (Rimland 2002).

In 2004, Adams et al. reported on a double-blind, placebo-controlled trial that multivitamin-mineral complex supplemention to 16 autistic children for three months, significantly increased their blood levels of vitamins B6 and C with remarkable improvement of sleep and bowl pattern.

Hildebrandt et al (2009) found

remarkable changes in the gut

microbiota when switching to a

high-fat diet with an increase in

Firmicutes and Proteobacteria

together with a decrease in

Bacteroidetes.

2. Dietary composition and gut microbiota:

In relation to this point, food selectivity is one of the most important problems faced by autistics parents. Ledford & Gast (2006), reviewed all studies on feeding in autism and they reported that difficulties in food selectivity by type and texture was documented.

Many autistic children demonstrate a preference for starches, snack foods, and processed while refuse to eat fruits, vegetables, and proteins.

How diet might affect the composition of the gut microbiota?

Williams et al. (2010) reported that Chronic eating/feeding problems can put children at risk for medical and developmental problems, including under- nutrition, suboptimal growth, social deficits and poor Academic progress, as well as risk of nutrient deficiencies, such as vitamins, minerals and amino acids (Sharp et al. 2013).

In an attempt to understand the role of diet on gut microbiota as etiological factor in autism, the effect of high carbohydrate diet can be highlighted.

It is well known that children with autism have many thousand folds higher gram negative bacteria than healthy controls. This can be attributed to the fact that gram negative bacteria that contain LPS are carbohydrate eaters and that many autistic children suffer from carbohydrate malabsorption and thus have problems digesting starch and other complex carbohydrates due to the extreme damage of their gut.

Unabsorbed carbohydrates become available food for pathogenic gut bacteria. Only monosaccharide do not become food for the bacteria because once they are absorbed, they vanish into the blood before the bacteria can access those (Finegold et al. 2012).

This can be treated with Specific Carbohydrate Diet (SCD) that targets the malabsorption.

By removing the undigested food the energy source for the

pathogenic bacteria is eliminated, they die off, and the proper gut biota balance can be restored.

Inulin as a water soluble storage polysaccharide belongs to a group of non-digestible carbohydrates (NDO) called fructans. It is available in about 36,000 species of plants, such as wheat, onion, garlic, and bananas.

Commonly, inulin is used as a prebiotic, fat replacer, sugar replacer, texture modifier and for the development of functional foods in order to improve health due to its beneficial role in gastric health (Shoaib et al. 2016).

Fructo-oligosaccharide or inulin as types of non-digestible carbohydrates are known to enhance the growth of bifidobacteria and may yield high SCFA/low PH which are not suitable environmental conditions for the growth of certain pathogenic bacteria.

Manipulation of imbalanced gut microbiota

Role of colostrum:Early after birth the gut microbiota can

be protected through the use of Colostrum, as an amazing fluid expressed by the nursing breast for the first few days following birth.

It provides another immune support agent of high benefit to autism (Kirkman Laboratories. 2002). Colostrum contains a wide range of immunoglobulins that generally stimulate immunity; antibodies, and other less specific antiviral factors; glycoproteins that inhibit the attachment of pathogenic bacteria to the intestinal mucosal lining.

Studies have shown that some of the typical behavioral and physiological abnormalities associated with autism can be modulated by restoring the normal gut microbiota composition (Sampson & Mazmanian 2015; Koufaris & Sismani 2015; Mangiola et al. 2016; Reddy & Saier 2015; Liu et al. 2015; Frye et al. 2015).

Role of probiotics, prebiotics and synbiotics: The gut microbiota can be manipulated

by the use of probiotics that have many health benefits which can be demonstrated as suppression of the adhesion of pathogenic bacteria to the epithelium.

Regulation of the immune cells, and decrease colonization of the pathogens in gut microbiota (BENGMARK 1998; Doron S. 2006).

In order for probiotics to restore a healthy gut microbiome many factors must be present. The probiotics microorganisms have to be able to survive the passage through the intestinal tract, able to grow in the presence of bile (Sanders & Ellen. 2006).

Probiotics are beneficial bacteria and yeast that helps in the process of digestion and improves health whereas prebiotics are non-digestible fiber compounds that stimulate the growth of these helpful bacteria.

Probiotics can be included either from natural food sources or supplements. The best natural source of probiotics is yogurt, loaded with lactobacillus or bifidobacteria that improves gut health. But the best way to utilize the benefits of both probiotics and prebiotics can be achieved only through supplements.

Two commonly used types of probiotics are lactobacillus and bifodobacterium. They can stop the spreading of pathogenic bacteria in the body, can produce vitamins and enzymes, and change the the acidic environment (AFRC 1989).

It is important to note that findings on the success of probiotics are still in the process and many other factors could be at play such as how long will the new bacteria survive, and if the effects are possibly from the healthy food itself.

Prebiotics are food supplements that are generally non-digestible and can be given to stimulate the growth and/or activity of beneficial bacterial species (Gupta & Garg 2009).

A synbiotic, on the contrary, represents a defined supplement comprised of a mixture of probiotics and prebiotics purposed to enhance the survival and colonization of the supplemented species in the GI tract (Rauch & Lynch 2012).

Lactobacillus species produce lactic acid, acetic acid, and propionic acid. These acids suppress the growth of pathogenic bacteria by lowering the pH value in the intestinal tract and thereby re-establish the balance of GM.

They also produce hydrogen peroxide, which change the environment from aerobic to anaerobic and thereby inhibits bacterial growth (Doron S. 2006; Williams 2010).

Furthermore, LABs strengthen the barrier of the intestinal mucosa by stabilizing tight-junctions (Otte 2004).

Bifidobacterium are important in regards to the development of the newborn’s mucosal immune system and microbiota, where it becomes dominant after birth until the weaning period (Salminen et al. 2006).

Both LAB and Bifidobacterium species have shown to influence both the innate and the adaptive immune responses (Dongarrà et al. 2013).

Kern et al. (2016) recorded the association between elevated mercury level and behavioural autistic features.

Mercury toxicity can be through many routes among which is vapor from dental amalgams (elementary mercury), inorganic mercury (e.g., mercuric chloride), and organic mercury (e.g., methyl and ethyl mercury).

According to the US Environmental Protection Agency, all forms of mercury are highly toxic (Agency. 2016). Formation of methyl mercury as the most toxic form can initiated by bacteria (Lohren et al. 2015).

Based on this information, it is very interesting to know that probiotics Lactobacilli and Bifidobacteria was found to be successfully assist to detoxify mercury.

The hypothesis state that organic mercury is taken up by probiotics, converted from highly toxic Hg2+ to Hg(0) via a redox reaction. Hg (0) as hydrophobic and volatile form, can easily leave the bacterial cell into the intestinal lumen (Brudnak 2002).

Clostridia are normally found in the gut of healthy individuals, where their numbers are kept in check by other bacteria.

Overgrowth of clostridia in the ileum increases water absorption, and results in drying up the feces, causing constipation.

Furthermore, they can impair fat absorption through deconjugation with bile, metabolize tryptophan, and prevent vitamin B12 absorption in the ileum, causing anemia.

The synthetic sugar lactulose, which can only be digested by lactobacilli, can help displace the clostridia and resolve the constipation by causing the lactobacilli to produce short fatty acids that have the opposite effect to that produced by clostridia and their accomplices: they cause water retention in the intestines (Johnson 2001).

Seven Essential Keys to Rehabilitate Your Gut, from Birth to Death

1. Vaginal birthDo everything you can to avoid a Caesarian section. When you select to deliver a child via Caesarian section – and there are times when it needs to be done to save the life of the mother or the baby—understand that by and large, you're tripling the risk for attention-deficit hyperactivity disorder (ADHD) and doubling the risk for autism in your child.

2. BreastfeedingAside from providing the most appropriate nutrients, breast feeding also affects your child's microbiome via bacterial transfer from skin contact.

3. Antibiotics

It’s extremely important to avoid unnecessary antibiotic use.

4. Refined sugar and processed fructose Refined sugar preferentially increases the growth of pathogenic disease-causing bacteria, fungi, and yeast, so limiting the amount of refined and processed sugars in your diet is a key dietary principle for gut health.

5. Genetically engineered foods and pesticides

-Doctors and scientist call for rethink about the regulation on genetically engineered food because they negatively affect gut microbiota.

6. Probiotic foods

7. Prebiotic fiber

Researchers in Finland decided to explore the possibility that changing the microbiome might be associated with a reduced risk for autism. Their study, published just last month in the journal Pediatric Research, evaluated 75 infants who were randomized to either receive a specific probiotic, Lactobacillus rhamnosus, or a placebo during the first six months of life. The study then followed these kids for the next 13 years.

At age 13 years, autistic spectrum, was diagnosed in 17.1% of the children in the placebo group and

none in the group receiving the probiotic.

http://www.drperlmutter.com/probiotic-prevents-adhd-autism/#

sthash.3qk72w51.dpuf

Dose Probiotic supplementation Prevents Autism?

The conclusion of the study humbly stated:

Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in

childhood…

Conclusion-1Feeding in the first months and years of life is one of the

most important determinants of children’s health, and even the healthy status in adulthood.

Although significant understanding of the complexity of gut microbiota have been acquired, more detailed information on the effect of gut microbiota and their products on brain as a distant organ from the gut is needed.

Conclusion-2

Gastrointestinal disturbances and altered gut microbiota is ascertained in children with autism and can be directly related to the severity of their behavioral symptoms.

Conclusion-3

The suggestion of strategies which can reduce the gut production and absorption of toxins or restore normal gut microbiota, such as dietary intervention, probiotics, and prebiotics may represent a non-pharmacological option in the treatment of gastrointestinal disturbances in autistic patients.

Non Pharmacological : Referring to therapy that does not involve drugs.

Conclusion-4