MS, the gut, and Autism in males and females

 

There is quite a lot in this blog about MS (multiple sclerosis) because it is the classic myelin disorder and so is well researched. Many other neurological conditions, including some autism, also feature impaired myelination. 

One of the very cheap myelin therapies is the old anti-histamine drug Clemastine. I learnt this week that it will be trialed in children with Pitt Hopkins syndrome. It is a very logical choice and some parents have already trialed it. I used it for a few years and did feel there was a benefit. The key is to keep the dose low enough not to cause drowsiness. Very long term use may reduce acetylcholine in the brain, so it is not a forever medicine.

Then I saw some interesting research from Japan showing that it appears that multiple sclerosis starts in the gut.

We already know from interesting US research that you must have had the Epstein-Barr virus (EBV) to be able to develop MS. It also depends on the age at which you caught the virus. The older you were, the bigger the risk of later developing MS. So it is best to get EBV very young, or avoid it entirely by vaccination (expected to be available in 10 years). EBV is also known to increase the risk of certain cancers, so I guess the vaccination will get adopted.

 

The role of the gut

For years, researchers have suspected that the gut plays an important role in neurological conditions. What has been missing is a clear explanation, a step-by-step account of how something happening in the intestine could influence the brain.

A recent study provides exactly that for Multiple Sclerosis.

 

How Intestinal Cells Trigger Multiple Sclerosis

Summary: For years, scientists have suspected that the gut plays a role in Multiple Sclerosis (MS), but the “smoking gun” linking the two has been elusive. A landmark study has finally identified the cellular mechanism: Intestinal Epithelial Cells (IECs)—the cells lining your gut—are acting as “accidental” messengers.

The study found that in patients with MS, these gut cells abnormally express MHC II, a protein that “presents” antigens to the immune system. This interaction mistakenly transforms ordinary immune cells into pathogenic Th17 cells, which then migrate from the gut directly to the central nervous system to attack the brain and spinal cord.

Key Facts

·         The Accidental Messenger: IECs do not normally “talk” to the immune system in this way. In MS, they begin expressing MHC II, which “primes” CD4+ T cells to become aggressive.

·         The Th17 Migration: Using “Kaede” protein tracking (which changes colour under light), researchers proved that these gut-primed Th17 cells physically travel from the intestine to the spinal cord to drive neuroinflammation.

·         Human Connection: The team used single-cell RNA sequencing on human biopsies to confirm that the same inflammatory patterns seen in mouse models are present in the intestines of human MS patients.

·         New Treatment Target: Most current MS therapies target B cells in the blood; this study suggests that treating the gut environment or blocking the antigen-presenting activity of gut cells could stop MS at its source.

 

This new knowledge should shift the focus of treatment away from simply suppressing the immune system after damage has started, toward stopping the problem earlier at its source. Future therapies may aim to block these abnormal gut signals, target specific inflammatory pathways, and use gut-focused treatments such as microbiome modulation and diet. Overall, the goal is to prevent the immune system from being mis-trained in the first place, rather than just managing the consequences later.

  

The actual study:-

Intestinal epithelial MHC class II induces encephalitogenic CD4 T cells and initiates central nervous system autoimmunity

The gut as an immune training ground

The key finding is that cells lining the gut, intestinal epithelial cells, can act as unexpected immune instructors.

In MS, these cells begin expressing MHC class II, a molecule normally used by immune cells to “present” antigens. This abnormal behavior turns the gut lining into a kind of misguided training center.

The result is:

• Activation of Th17 cells
• These cells become highly inflammatory
• They migrate from the gut to the brain and spinal cord
• They drive autoimmune attack on myelin

This is a causal pathway from gut to brain.

 

A shared biological axis

The gut is not just influencing the brain, it is actively programming immune cells that control it.

This gut-immune-brain axis likely operates across multiple conditions, including autism, asthma, and ADHD.

 

Intestinal epithelial cells and autism

Intestinal epithelial cells sit at the center of the gut–immune interface and may also play a role in Autism.

They have three key functions.

 

1. Barrier control

IECs regulate what passes from the gut into the body.

If this barrier is altered, microbial products and metabolites may enter circulation and immune activation may increase

Some studies in autism report increased gut permeability, suggesting altered epithelial function.

 

2. Immune signaling

IECs actively communicate with the immune system. They release cytokines, influence T-cell behavior and potentially affect pathways like Th17 cells

In MS, abnormal IEC signaling directly drives inflammation.

In autism, similar immune pathways are implicated, though less directly established.

 

3. Microbiome interpretation

IECs “read” signals from gut microbes.

·        balanced microbiome produces healthy regulatory signals

·        dysbiosis produces inflammatory signals

 

In autism, microbiome differences are common, meaning IEC signaling may be altered.

 

Autism - same axis, different outcome

In autism, we see:

• altered microbiome
• gut inflammation
• immune activation (including Th17/IL-17 in some cases)

 

The difference is timing and target.

 

Step	MS (Adult)	Autism (Early Life)
Gut signal	IEC activation	Dysbiosis / gut inflammation
Immune response	Pathogenic Th17 cells	Altered immune signaling
Brain effect	Myelin attack	Developmental disruption
Timing	Adulthood	Early childhood

 

Why more females have MS

Multiple Sclerosis is 2–4 times more common in females.

Females have:

• stronger immune responses
• two X chromosomes (more immune genes)
• greater responsiveness to immune signals

When the gut sends the wrong signal, females are more likely to amplify it into autoimmunity.

Hormonal shifts (e.g., pregnancy/postpartum) further support an immune-driven mechanism.

 

Why more males have Autism

Severe autism is 3–4 times more common in males.

Males show:

• higher vulnerability during early brain development
• only one X chromosome (less genetic backup)
• less regulated early-life immune signaling

When the gut–immune system is activated early, males are more likely to cross the threshold into neurodevelopmental disruption.

Females appear more protected via:

• neural resilience
• better early immune regulation
• genetic redundancy

 

The EBV connection: a required trigger

One of the most important recent discoveries is the role of Epstein-Barr Virus infection in MS.

Large longitudinal studies show:

• individuals not infected with EBV almost never develop MS
• after EBV infection, the risk of MS increases dramatically (around 30-fold)

This suggests EBV is a necessary but not sufficient factor.

 

How EBV fits the model

EBV infects and persists in B cells, altering immune behavior. It may:

• create immune cells that recognize both viral proteins and brain proteins (molecular mimicry)
• keep B cells chronically activated
• prime the immune system toward autoimmunity

 

A multi-hit model of MS

The emerging picture is that MS requires multiple aligned factors:

1.     EBV infection
creates autoreactive immune potential

2.     Gut immune dysregulation
generates inflammatory Th17 cells

3.     Environmental modifiers (e.g., low vitamin D)
reduce immune regulation

Together, these drive immune attack on the brain

EBV loads the gun, the gut pulls the trigger, and the immune system fires at the brain.

 

Why MS varies by latitude

MS prevalence increases with distance from the equator.

• Lower rates near the equator
• Higher rates in northern regions

This reflects environmental effects on immune regulation.

 

Vitamin D and sunlight

Reduced sunlight lowers vitamin D, which normally:

• suppresses excessive Th17 cells activity
• promotes immune tolerance

Low vitamin D removes a key brake on autoimmunity.

 

Infection timing

Epstein-Barr Virus infection often occurs later in higher latitude regions, triggering stronger immune responses.

 

Microbiome differences

Geography affects diet and microbial exposure, shaping the gut–immune axis.

 

Hygiene effects

Reduced early microbial exposure may impair immune training.

 

Why some conditions improve with age

A striking observation across medicine is that many children “grow out of” certain conditions.

This includes:

• Mild autism (in some cases)
• Asthma
• Attention Deficit Hyperactivity Disorder

This reflects a shared biological pattern.

 

The dynamic regulation model

Early life is a period of high instability:

• the gut barrier is still developing
• the microbiome is fluctuating
• the immune system is learning tolerance
• the brain is highly sensitive

This creates a system that is:

• more reactive
• more inflammatory
• more vulnerable

 

What Changes Over Time

Three stabilizing processes occur:

1. Gut stabilization

• microbiome becomes more consistent
• fewer abnormal immune triggers

2. Immune regulation improves

• better control of inflammation
• reduced overactivation (including Th17 pathways)

3. Brain maturation

• circuits strengthen
• compensatory pathways develop
• regulation improves

 

The threshold effect

Symptoms can be viewed as crossing a threshold:

• Above threshold → visible condition
• Below threshold → mild or no symptoms

As stability improves:

• inflammation ↓
• regulation ↑

The individual may drop below the clinical threshold (unless they keep lowering the diagnostic threshold, as with autism)

 

Implications for Treatment

Focus on stabilizing the system, not just suppressing symptoms.

Potential approaches:

• improve gut health and microbiome stability
• reduce inappropriate immune activation
• support metabolic resilience
• ensure adequate vitamin D and environmental exposure
• minimize chronic inflammatory triggers

 

For MS:

• targeting EBV and gut immune programming may prevent disease at its source

 

For autism and related conditions:

• early stabilization of the gut–immune axis may improve outcomes

 

Does severe autism improve with age?

Severe autism is not a fixed condition where everything is determined at the start of life. While some children begin with greater challenges than others, what happens over time depends heavily on how skills develop during the long period of childhood and adolescence. These include communication, social interaction, emotional regulation, and daily living abilities. Early progress in these areas can create a positive ripple effect, making future learning easier and more natural.

If certain skills are delayed or missed early on, development may be slower—but this does not mean progress is impossible. The brain remains capable of learning and adapting, even later in life. This means that outcomes are not set in stone, much is up to the parents.

What shapes these outcomes is a combination of factors. Biology plays an important role—things like brain plasticity, energy levels, and overall health can influence how easily a child can learn. Biology can be modified pharmacologically, which is what EpiphanyASD is all about.

Biology is only part of the picture. Therapy, education, and the home environment are equally important. Structured teaching, repetition, encouragement, and meaningful interaction all create opportunities for skills to develop.

Importantly, these factors interact with each other. When a child’s biological state improves, they become more receptive to learning. In turn, effective therapy and support can help build new abilities, which further improves confidence, behavior, and engagement. This creates a positive cycle where progress builds on progress. Nothing changes over night, it is a slow process. Increasing skill acquisition rate by just 10% can lead to a massive difference over a decade.

This is why outcomes in autism are so variable. Two children who start at a similar level can follow very different paths depending on the opportunities they have and how their abilities are supported over time.

There are also important developmental windows, particularly in early childhood, when learning certain skills is easier. However, these windows do not fully close. Progress may become slower later, but it is still very much possible. Many individuals continue to gain skills well into adolescence and adulthood.

In this way, severe autism is better understood as a dynamic developmental process rather than a fixed outcome. The trajectory can be changed, sometimes substantially, depending on how biology, learning, and environment come together over time.

 

A note on EBV

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a common virus that infects most people and remains in the body for life. It is best known for causing infectious mononucleosis (“glandular fever”), especially when infection occurs in adolescence.

EBV spreads via saliva.

Childhood transmission is very common globally, but as hygiene increases it gets caught at older ages. In western countries kissing during adolescence is a major route.

90-95% of adults carry the EBV, the only question is at what age they were exposed.

Early exposure to EBV is less risky than late exposure. This fits the hygiene hypothesis, which has been covered in this blog and my book.

The hygiene hypothesis proposes that reduced exposure to microbes in early life results in less “training” of the immune system and causes higher risk of immune dysregulation in later life.

Exposure to pets at home will help train a young child’s immune system, but does not expose him/her to EBV, which is exclusively a human virus. 

Improving the Blood–Brain Barrier and Cognitive/Mitochondrial Function in Alzheimer’s, and some Autism: Linking TNAP, GPLD1, Vitamin B6 and Exercise

 

 

Scientists Find a Mechanism for How Exercise Protects the Brain

UCSF study finds that an exercise-induced liver protein strengthens the blood-brain barrier, improving memory and slowing age-related decline.

Researchers at UC San Francisco have discovered a mechanism that could explain how exercise improves cognition by shoring up the brain’s protective barrier of blood vessels.

With age, this network of blood vessels — called the blood-brain barrier — gets leaky, letting harmful compounds enter the brain. This causes inflammation, which is associated with cognitive decline and is seen in conditions like Alzheimer’s disease.

Six years ago, the team identified a brain-rejuvenating enzyme called GPLD1 that mice produced in their livers when they exercised. But they couldn’t understand how it worked, because it can’t get into the brain.

The new study reveals that GPLD1 works through another protein called TNAP. As the mice age, the cells that form the blood-brain barrier accumulate TNAP, which makes it leaky. But when mice exercise, their livers produce GPLD1. It travels to the vessels that surround the brain and trims TNAP off the cells.

“This discovery shows just how relevant the body is for understanding how the brain declines with age,” said Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute.

 

Every few months Alzheimer’s research produces another “breakthrough.” Most focus narrowly on the brain — amyloid, tau, synapses.

Recent Alzheimer’s drugs, like lecanemab and donanemab represent a scientific advance, but their real-world impact remains modest. They cost about $30,000 a year, require intensive monitoring, and typically slow decline by only a few months.

A growing body of research is pointing somewhere else entirely.

Not just the brain, but the interface between the body and the brain.

At the center of this shift are three players:

• TNAP (tissue-nonspecific alkaline phosphatase)
• GPLD1 (an exercise-induced blood protein)
• Vitamin B6 (PLP)

Together, they connect:

• the blood–brain barrier (BBB)
• neurotransmitters
• mitochondrial function
• inflammation

This same network appears not only in Alzheimer’s disease, but also in subsets of autism.

 

The Blood–Brain Barrier: The Overlooked Gatekeeper

The blood–brain barrier is not just a passive wall. It is an active, living system that determines what reaches the brain.

When functioning properly, it:

• keeps out inflammatory molecules
• regulates nutrient delivery
• protects neurons from toxins

With age — and in many neurological conditions — this barrier begins to fail.

It becomes leaky.

This allows:

• cytokines
• immune cells
• metabolic toxins

to enter the brain.

The result is chronic low-grade inflammation, one of the key drivers of cognitive decline.

 

TNAP: A Double-Edged Enzyme

TNAP sits at a critical junction.

Inside the brain:

TNAP helps regulate vitamin B6 availability, which is essential for:

• GABA (the calming neurotransmitter, but excitatory in 30% of severere  autism)
• dopamine
• serotonin

Without sufficient active B6 (PLP), neurons become more excitable and unstable.

 

At the blood–brain barrier:

TNAP plays a different role.

With aging, TNAP accumulates in the BBB, where it begins to:

• weaken barrier integrity
• increase permeability
• promote inflammation entering the brain

So TNAP is both

• necessary for neurotransmitters
• but potentially harmful in excess at the BBB

This dual role is key to understanding the system.

 

GPLD1: The Exercise Signal

Recent research from the University of California in San Francisco has identified a protein called GPLD1, released into the bloodstream during exercise.

Its function is remarkable.

GPLD1 appears to:

• remove excess TNAP from the blood–brain barrier
• restore barrier integrity
• reduce inflammation entering the brain

In animal models this led to:

• improved cognition
• reduced amyloid pathology
• better overall brain function

This is one of the clearest mechanisms yet showing how exercise protects the brain.

 

Vitamin B6: The Neurochemical Link

Vitamin B6 (in its active form, PLP) sits downstream of TNAP.

It is essential for:

• converting glutamate → GABA
• stabilizing neuronal firing
• supporting mitochondrial enzymes

In some individuals — including subsets of autism — B6 metabolism appears to be impaired.

This can lead to:

• low GABA
• excess excitation
• sensory sensitivity
• tics or seizures

Correcting B6 availability can sometimes produce significant functional improvements.

 

Mitochondria: The Energy Perspective

All of this sits on top of a deeper requirement: energy

Neurons are extremely energy-dependent.

If mitochondrial function is impaired:

• ion gradients fail
• signaling becomes unstable
• excitability increases

Both Alzheimer’s disease and autism frequently show signs of:

• mitochondrial dysfunction
• impaired energy metabolism

Vitamin B6 supports mitochondrial enzymes.

Exercise increases mitochondrial number and efficiency.

Again, the same network appears.

Exercise is not just “burning calories.”

It is activating PGC-1α, the master regulator of mitochondrial production, effectively increasing the brain’s energy-generating capacity.

A brain with more mitochondria is more stable, more resilient, and less vulnerable to both degeneration and developmental disruption.

  

Why This Matters for Autism

At first glance, Alzheimer’s and autism may seem unrelated.

But both conditions often involve:

• neuroinflammation
• mitochondrial dysfunction
• synaptic instability
• blood–brain barrier disruption

The difference is timing:

• Alzheimer’s → degeneration of an aging system
• Autism → altered development of the system

Understanding one can illuminate the other.

If BBB dysfunction drives inflammation in Alzheimer’s, it may also contribute to instability in developing brains.

If mitochondrial support improves cognition in aging, it may improve resilience in autism.

 

Exercise: The Overlooked Multi-System Therapy

Exercise is unique because it affects all parts of this network simultaneously.

• increases GPLD1 → strengthens the BBB
• increases BDNF → improves synaptic plasticity
• improves mitochondrial function
• reduces inflammation
• enhances brain blood flow

It is not a single-target intervention.

It is a system-wide regulator.

Many autism interventions (e.g. Pentoxifylline, Agmatine and even beetroot juice) converge on improving cerebral blood flow.

Better blood flow → more oxygen and glucose delivered to the brain.

This supports mitochondrial ATP production, improving brain energy and stability.

Exercise complements this by increasing mitochondrial number via PGC-1α and strengthening the BBB (GPLD1/TNAP).

Together, these interventions enhance neurovascular–metabolic function, leading to more stable cognition and behavior.

 

A Unifying Model

We can now sketch a simple framework:

• TNAP → Vitamin B6 → neurotransmitter balance (GABA)
• Excess TNAP (BBB) → barrier breakdown → inflammation
• Exercise → GPLD1 → removes excess TNAP → restores BBB
• B6 + exercise → support mitochondria and brain stability

This links:

vascular function + metabolism + neurotransmitters + inflammation

into a single system.

 

The Bigger Insight

For years, Alzheimer’s research has tried to isolate single causes:

• one gene
• one protein
• one drug target

But the brain does not work that way.

It is a network.

TNAP is not “the cause.”
GPLD1 is not “the cure.”

They are control points in a larger system.

Conclusion

This emerging biology suggests that:

• protecting the blood–brain barrier
• supporting vitamin B6 metabolism
• improving mitochondrial function
• and maintaining regular physical activity

may all be part of the same therapeutic strategy.

Not just for Alzheimer’s disease, but for understanding — and in some cases improving — aspects of autism.

The most sophisticated and expensive interventions may still lie in the future, but one of the most powerful has been available all along.

Exercise is not just good for the body. It is a direct regulator of brain biology.

  

A Final Thought: The Brain Is Only as Protected as Its Barriers

One of the more surprising directions in Alzheimer’s research is not a new drug or gene, but a shift in perspective.

The brain is not as isolated as we once thought.

It is protected by multiple biological barriers — and when these begin to fail, risk increases.

We have already looked at the blood–brain barrier, but this is not the only route.

There is also a direct pathway from the nose to the brain via the olfactory nerve — effectively bypassing the blood–brain barrier altogether. Animal studies have shown that certain bacteria can use this route, especially when the nasal lining is damaged, triggering immune responses in the brain that resemble early Alzheimer’s pathology.

(Note to self, don’t pick your nose!)

The gut can influence the brain through immune signaling and inflammation, particularly when the intestinal barrier is compromised.

Individually, these findings may seem unrelated — blood vessels, nasal tissue, gut bacteria.

But they point to the same underlying principle:

The brain depends on the integrity of the body’s protective barriers.

When those barriers are strong:

• inflammatory signals are controlled
• harmful agents are excluded
• neuronal function remains stable

When they weaken:

• the brain becomes exposed
• immune responses increase
• long-term damage may follow

This brings us back to the central theme of this article.

Exercise is not just improving fitness — it is helping to restore control over these systems:

• strengthening the blood–brain barrier (via GPLD1)
• reducing systemic inflammation
• improving metabolic function
• supporting mitochondrial health

In other words, it helps the body maintain the boundaries that protect the brain.

The emerging biology — TNAP, GPLD1, vitamin B6, mitochondria — is complex.

 

Oral bacteria and its link to brain function

Alzheimer’s and Parkinson’s research has also looked at the effect of the oral microbiome.

Tooth decay and gum disease are not just local problems — they influence whole-body inflammation.

·        Harmful oral bacteria (e.g. Porphyromonas gingivalis) increase with poor oral hygiene.

·        These bacteria can enter the bloodstream, especially when gums bleed.

·        This can contribute to systemic inflammation and stress the brain.

·        Inflammation may weaken the blood–brain barrier (BBB).

·        A weaker BBB allows more harmful molecules to reach the brain.

·        This links oral health to cognitive decline and dementia risk.

·        At the same time, some oral bacteria are highly beneficial.

o   These bacteria convert dietary nitrates into nitric oxide (NO).

o   Nitric oxide improves cerebral blood flow and brain function.

o   Overuse of strong antiseptic mouthwash can reduce these beneficial bacteria.

o   The goal is balance, not complete sterilization of the mouth.

·        Good oral hygiene reduces harmful bacteria without eliminating beneficial ones.

·        Healthy gums act as a barrier, preventing bacterial entry into blood.

·        Diet plays a major role in shaping the oral microbiome.

·        High sugar promotes tooth decay and harmful bacteria.

·        Nitrate-rich foods (e.g. vegetables, beetroot) support beneficial bacteria.

·        Maintaining teeth and gums is therefore part of protecting long-term brain health.