Originally featured in the April 2014 issue of IHCAN magazine

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Researchers have proposed for more than a decade that low vitamin D plays an important role in the development of autism, and there have been confusing findings related to disordered serotonin levels as well. Now a remarkable new paper from Prof Bruce Ames has solved some major problems in our understanding of autism. Naturopath Ben Brown, ND, reports.

Prof Bruce Ames is arguably one of the greatest thinkers and innovators in nutritional medicine of our age, so his most recent contribution concerning vitamin D, serotonin synthesis and autism will undoubtedly make big waves in the world of autism research, and beyond.

A recent, groundbreaking scientific publication helps solve a number of mysteries that have faced autism researchers over the years. By exploring new nutrient-gene interactions, Prof Ames and co-author Rhonda Patrick reveal new biological mechanisms underlying autism that will undoubtedly help pave the way for new preventive approaches and better treatment.

Bruce Ames is a professor of biochemistry and molecular biology at the University of California, Berkeley. Throughout his long and distinguished career (he is an active professor at age 85), he has received a plethora of prestigious awards, and was described by the founder of functional medicine, Jeff Bland, PhD, as “the Linus Pauling of our time”. Notably, he has been instrumental in pioneering – and substantiating through meticulous experimental work – some of the greatest paradigms shifts in nutritional wisdom in recent times. So when Prof Ames publishes new scientific work it pays to take heed, and his most recent publication is one of his most important.

Unifying mechanism
In the words of Ames and Patrick, the new publication “presents a unifying mechanistic hypothesis that links vitamin D and serotonin concentrations to these disparate observations and to the increased autism incidence”. Using the University of California – Santa Cruz’s genome database, they identified three genes that are abnormally expressed in autism and then went on to show for the first time that these genes are responsive to regulation by vitamin D. This then helped them solve some important problems in autism.
More specifically, what they discovered was that vitamin D activates the gene for the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase (TPH), in the brain and inhibits the gene for TPH in tissues outside the blood-brain barrier.

Low vitamin D is a frequently-reported problem in autism, and researchers have proposed for more than a decade that this plays an important role in the development of autism. There have also been confusing findings related to disordered serotonin levels in people with autism, suggesting this neurotransmitter plays an important role. Remarkably, what this new discovery does is help to fit pieces of the puzzle together and solve some major problems in our understanding of autism. Here are four of the major breakthroughs:

Upside-down serotonin
One of the confusing observations in
autism is that brain levels of serotonin are typically low, yet blood levels outside the brain are high. The new research suggests that adequate vitamin D increases serotonin synthesis in the brain, and decreases it in peripheral tissues. So low vitamin D status helps to explain why children with autism tend to have high levels of serotonin in their blood, but unusually low brain serotonin. Disordered serotonin levels are thought to play a role in abnormal brain development and behavioural symptoms.

Boyish bias
There is a preponderance of autism in boys, who are five times more likely to develop the disorder than girls. But the female sex hormone oestrogen is known to increase the expression of TPH in the brain, so it may be that the female brain is protected against the adverse effects of vitamin D deficiency on serotonin synthesis and the risk of developing autism. In other words, boys’ brains are more sensitive to low vitamin D and thus at greater risk.

Maternal attack
“Maternal autoimmunity has been strongly associated with the development of autism during pregnancy, although no satisfactory explanation of this phenomenon has been put forward”, point out Ames and Patrick.Their discovery also helps explain this association. A protein called kynurenine plays an important role in preventing autoimmune responses to the foetus during pregnancy, by generating regulatory T-cells in the placenta. It turns out that the amino acid required for serotonin synthesis, tryptophan, is also a precursor to kynurenine. So low vitamin D and increased expression of TPH may shunt tryptophan away from the kynurenine pathway and decrease placental production of kynurenine. Low kynurenine means low regulatory T- cells and a higher risk of developing autoimmunity.

Inflamed gut
Chronic gastrointestinal inflammation and digestive disorders are characteristic of autism. In the gut, excess serotonin can result in immunological changes and increased gastrointestinal inflammation. Ames and Patrick propose that the “gastrointestinal (GI) inflammation observed in individuals with autism may be a direct result of elevated serotonin in the GI tract, due to increased TPH expression as a consequence of low vitamin D hormone levels”, And they go on to propose, “that raising vitamin D concentrations should help lower GI inflammation by decreasing serotonin concentrations in the GI cells through transcriptional repression of TPH.” The increased production of serotonin production in the gut may also shunt it away from the brain, as we will see later.

Social connection
Low vitamin D may directly explain social deficits associated with autism. Ames and Patrick examined the genes responsible for the production of the neuropeptide hormone oxytocin. Oxytocin is known to play an important role in social behaviour; low levels have been associated with autism, and administration of oxytocin to adults with autism has been shown to improve several aspects of socialisation. They also discovered that the vitamin D receptor is an activator of the oxytocin gene, suggesting that low vitamin D would result in low oxytocin production.

New understanding, new hope
As you can see, this remarkable work takes us several strides forward in our understanding of the mechanisms underlying the biology of autism, but what about the practical implications? What makes this publication exceptional is that beyond the exploration of molecular pathways and nutrient-gene interactions, it concludes with a detailed discussion of therapeutic implications.
Firstly, Ames and Patrick discuss the implications for autism prevention; the most obvious implications are of course treatment of vitamin D deficiency: “The vitamin D-dependent regulatory mechanisms of serotonin synthesis and their relationship to the underlying causes of autistic spectrum disorders (ASD) suggest that risk of ASD may be decreased by a practical and affordable solution: adequate vitamin D supplementation during pregnancy and early childhood.”

They say: ‘The vitamin D hormone levels of a developing embryo and neonate are completely dependent on those of the mother. It is known that 25(OH)D3 plasma concentrations in the foetus reflect those of the mother. In the United States, 25(OH)D3 concentrations are surprisingly low during pregnancy, despite some supplementation with prenatal vitamins.” So appropriately they point out that “the American College of Obstetricians and Gynaecologists recommends that pregnant women use 1000–2000iu of vitamin D, instead of the 400iu currently present in prenatal vitamins.

Nutritional treatment
But most interesting is their discussion around implications for treatment. “Understanding the mechanism by which vitamin D levels regulate serotonin synthesis in different tissues gives some insight into therapeutic treatment, with the goal of improving a wide-range of social behaviours”, they state. Some of the key implications for therapeutic intervention are:

L-tryptophan supplementation – which may help increase brain serotonin and reduce social anxiety without negative side-effects.
Avoiding the use of 5-hydroxytryptophan (5-HTP) – as it may rapidly convert to serotonin in the gut and increase gastrointestinal inflammation while limiting delivery of tryptophan to the brain.
Administering L-tryptophan with vitamin D, as vitamin D will enhance serotonin synthesis in the brain and limit its production in the gut. Vitamin D will also improve oxytocin production.
Avoiding selective serotonin reuptake inhibitors (SSRIs) – they have been used in autism with mixed results, likely because their effect on serotonin is unclear. L-tryptophan and vitamin D would have a more direct effect on serotonin.
Consider vitamin B6, folate, iron and omega-3 fatty acids – they are cofactors in serotonin synthesis and may help improve symptoms.
Intriguingly, this seminal publication is Part 1 of a series. I am very excited to see where Prof Ames takes us next.

Reference:
Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J 2014, epub Feb 20.

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