By Gabi Giacomin, Dr. of Naturopathic Medicine, Member Trisomy21 Research Foundation, SAC

THE FDA PROHIBITS EVEN INDIVIDUALS FROM MAKING CLAIMS FOR NUTRITIONAL SUPPLEMENTS IN THE POTENTIAL TREATMENT OF DISEASE. THE FOLLOWING MENTION OF NUTRIONAL SUPPLEMENTS IS PROVIDED BASED ONLY ON THE ATTACHED RESEARCH TO EXPLAIN HOW THE HUMAN GENOME RESPONDS TO FOOD SUBSTANCES AND IS NOT INTENDED AS MEDICAL OR CURATIVE ADVICE.

Most citations used are taken from the NLM database and are in the public domain.

Gut Bacteria

Gut microbes influence epigenetics by changing the way DNA is copied to RNA (transcription) and making DNA more accessible (chromatin accessibility) 8, 14. Does this mean we can change the expression of genes by treating the gut? Yes. All genes go through the process of transcription from DNA to RNA, even genes on chromosome 21, and epigenetics influence the way transcription occurs.

Pathogenic bacteria produce various toxic agents such as ammonia, D-lactate, ethanol and peptidoglycans 9. These toxic substances stimulate TNFalpha and IL-6  which cause permeability of the intestinal barrier, as well as the blood brain barrier and progression to Alzheimer’s disease 8. Children with Down Syndrome have high levels of TNFalpha and IL-6 compared to typical children. 31

TNFalpha expression upregulates DYRK1A – and cognitive delay in DS 13. It stimulates the expression of APP and BACE1 – and development of Alzhemier’s in DS 15. TNF alpha increases CBS activity – and methylation issues in DS 16. TNF alpha stimulation increases the activity of MicroRNA and gut permeability 11 TNFalpha has been linked to Type 1 diabetes and obesity and stimulates the production of leptin. Curcumin, CoEnzyme Q10, Quercetin, Vitamin D, Glutathione and fish oil inhibit TNF alpha and IL-6, reducing inflammation and preserving gut integrity 17.

Early clinical trials reveal that Enterobacter overgrowth in the gut (Klebsiella, Escherichia, Shigella) increase TNF alpha levels affecting neurodegeneration associated with AD 18. Maintaining gut microbial diversity and richness and reducing levels of inflammatory microbes, improves AD outcomes 12.

There is a significant relationship between the dominant bacterial phyla (classes) in the gut – Bacteroides, Firmicutes and Proteobacteria – and Methylation 8. B vitamins are produced by our gut microbes. Human cells cannot make B vitamins and rely on microbes to meet some nutritional requirements. B vitamins are necessary for Methylation. When our gut produces enough Bifidobacteria bifidum and longum, methylation works well and we are less vulnerable to viruses, our attention improves and nerve transmission is better. When B vitamin synthesis is low, methylation slows down its production of T cells (white blood cells which are important for immunity) and our B cell production increases. When B cells dominate we are more likely to develop autoimmunity, allergies and food sensitivities 8.

Genetics

Working with clients who have Down Syndrome (DS) and addressing gene over expression using Targeted Nutritional Intervention (TNI) is a crucial step in ensuring good gut health.

Attached to chromosome 21 are several microRNA’s which are overexpressed in DS. Increased expression of microRNA 155 is associated with intestinal permeability, irritable bowel disease, chrohn’s disease and ulcerative colitis – diseases caused by high levels of inflammation in the body 1. Research shows that Resveratrol, Quercetin and Vitamin D decrease levels of MicroRNA 155, reducing progression of intestinal permeability and inflammatory bowel disease 2, 3, 4.

Increased activity of antioxidant enzymes such as Superoxide Dismutase (SOD), result in high levels of ‘oxidative stress’ in DS. Oxidative stress reduces Glutathione 5 – a substance  which controls inflammatory chemicals like TNF alpha. When glutathione levels are low, TNF alpha secretion from gut microbes isn’t regulated, and gut permeability occurs. One of the main outcomes of the Miguid study (2015) showed an increase in glutathione production and decreased SOD after supplementation with TNI 7.

Where does Gut Dysbiosis begin?

A foetus has its first contact with microbes via amniotic fluid and the placenta 22. It’s thought bacteria travels from the mothers mouth through her bloodstream to the placenta, or from her vagina to her womb. Following birth the newborn contacts microbes as it passes through the birth canal and then from skin-to-skin contact with mother and from its environment. Breastmilk contains staphylococci, streptococci, and lactic acid bacteria that are found in the infant gut 23. The mother’s health and the microbes she carries have an enormous impact on her child’s health and development and the disease’s it will be vulnerable to later in life.

Research reports that 79% of children born with Down Syndrome are transferred to Neonatal Intensive Care Units at birth 24. Some of these newborns will receive what’s known as universal prophylaxis – routine administration of antibiotics given within one hour of birth to babies with a risk for early onset neonatal infection.

Antibiotic use heavily disrupts the gut micro-biome. An imbalanced gut cannot perform vital functions such as nutrient supply, vitamin production and protection from pathogens. Gut imbalance is associated with a high percentage of health issues and is implicated in metabolic, immune and developmental disorders as well as vulnerability to infectious diseases 25. Antibiotics also cause a reduction in the number of mitochondria and their expression.

Poor gut integrity leads to inflammatory bowel conditions which eventually impact immunity, metabolism and neurotransmitter production. Poor gut health means children are constantly getting sick with colds and flu’s, they are more likely to develop weight issues such as obesity or failure to thrive and poor production of neurotransmitters impacts their sleep, ability to focus and behaviour. After three days without fibre (raw fruit and vegetables), metabolic syndrome, weight gain and poor gut barrier integrity begin to develop 26.

Down Syndrome associated pathology

Gut dysbiosis aggravates Non-alcoholic Fatty Liver disease, which is as high as 82% in overweight children with DS. High TNF alpha causes immune dysregulation which is thought to be the underlying cause of Obesity in DS 19.

Gut imbalance plays a major role in the progression of autoimmunity 20. High levels of TNF alpha coming from the gut alter the balance of T regulatory cells, increasing the risk of developing type 1 diabetes, Coeliac disease and Hashimoto’s Thyroiditis. Blood tests can detect circulating levels of antibodies many years before autoimmunity develops. Finding and removing the triggers such as food sensitivities and gut pathogens, can reverse and eliminate autoimmunity. Probiotics balance the immune response in children with coeliac disease by reducing TNF-alpha, according to a recent double-blind placebo-controlled trial 21.

Antibiotics reduce populations of butyrate producing bacteria such as Roseburia and Ruminococcus which protect us against inflammation and autoimmunity. Butyrate levels are low in the micro-biome of children with T1D. When butyrate producing bacteria are low, species like Bacteroides Dorei and Bacteroides Vulgatus proliferate and an imbalance in Short Chain Fatty Acid production occurs, favouring acetate, propionate and succinate which increase gut permeability and initiate autoimmunity 27.

People with autoimmune hypothyroidism reportedly have reduced levels of Prevotella and Dialister bacterial species, while Escherichia-Shigella, Esherichia coli and Parasutterella were elevated causing imbalances. Individuals with Down syndrome (DS) are at an increased risk of developing thyroid disease, primarily autoimmune, with a prevalence ranging from 13% to 63% 28.

Pulmonary hypertension patients have profound gut imbalances, increased inflammation and gut permeability. DNA analysis of faecal samples report a significant decrease in abundance, diversity and homeostasis, with significant increases in inflammatory gram-positive bacteria and lipopolysaccharides 29. Zonulin, a marker of leaky gut was increased up to 81% in people with PH.

Current research points to the gut as the organ responsible for most disorders affecting brain function, hence, processing disorders are likely to be caused by a gut dysfunction. Allergies, which develop as a result of poor gut health, block the nose and ears making it difficult for a child to process sensory inputs. Treating the gut is the first step towards improving sensory processing functions 30.

In the United States and New Zealand, guidelines for treating children with autism include the recommendation to assess each child on the spectrum for gastrointestinal problems, as the rate is so high. The pain and inflammation caused by digestive issues can result in behavioural difficulties that cannot be improved by behavioural approaches. They only respond with appropriate treatment of gut issues and pain 31.

Conclusion

TNI provides us with the tools to regulate gene overexpression. Increasing evidence reveals that epigenetics, such as gut health, also play a big role in the development and cognition of people with Down Syndrome. Until recently, epigenetics weren’t widely studied in relation to DS. Pharmaceutical treatment hasn’t been successful in reducing DS associated pathologies, and epigenetics offer new avenues of treatment. Gut repair, increasing SCFA production and beneficial bacteria levels will reduce the production of inflammatory chemicals coming from the gut. Having a healthy microbiome is essential for the health of our children.

References 

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881531/

2. https://www.sciencedirect.com/science/article/pii/B978012809965000015X

3. https://www.researchgate.net/publication/44801790_Effect_of_quercetin_and_its_metabolites_isorhamnetin_and_quercetin-3-glucuronide_on_inflammatory_gene_expression_Role_of_MIR-155

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647642/

5.https://www.sciencedirect.com/science/article/pii/S0024320513004839

6. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.27489

7. https://www.researchgate.net/publication/274714596_Antioxidant_activity_in_Egyptian_children_with_Down_syndrome_before_and_after_nutritional_supplementation

8. http://clinical-epigenetics.imedpub.com/dysbiosis-of-gut-microbiome-and-its-impact-on-epigenetic-regulation.pdf

9. https://www.wjgnet.com/1007-9327/full/v16/i24/2978.htm

10. https://www.ncbi.nlm.nih.gov/pubmed/29137441

11. https://www.ncbi.nlm.nih.gov/pubmed/21062749

12. https://www.nature.com/articles/s41598-017-13601-y

13. https://www.researchgate.net/publication/51823900_Dyrk1A_Positively_Stimulates_ASK1-JNK_Signaling_Pathway_during_Apoptotic_Cell_Death

14.https://www.biorxiv.org/content/biorxiv/early/2018/01/26/210294.full.pdf

15. https://www.ncbi.nlm.nih.gov/pubmed/17255335

16. https://www.ncbi.nlm.nih.gov/pubmed/12615917

17. https://www.ncbi.nlm.nih.gov/pubmed/20354351

18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135029/

19. https://www.jpeds.com/article/S0022-3476(17)30945-9/fulltext

20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036413/

21. https://www.intechopen.com/books/probiotics-and-prebiotics-in-human-nutrition-and-health/probiotics-in-childhood-celiac-disease

22. https://www.nature.com/articles/d41586-018-00664-8

23. https://www.ncbi.nlm.nih.gov/pubmed/14620455

24. https://www.ncbi.nlm.nih.gov/pubmed/25282970

25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831151/

26. http://www.gutmicrobiotaforhealth.com/en/recent-mouse-studies-lend-insights-mechanisms-dietary-fibres-benefits/

27.  https://www.ncbi.nlm.nih.gov/pubmed/26711739

28.  https://www.ncbi.nlm.nih.gov/pubmed/29320965

29. http://hyper.ahajournals.org/content/70/Suppl_1/AP134

30. https://mindd.org/auditory-processing-disorder-children/

31. https://mindd.org/healthy-gut-flora-childrens-behaviour/

32. https://www.ncbi.nlm.nih.gov/pubmed/27770619