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Friday 18 October 2024

The role of the microbiome in aggression. Gut microbe imbalances that predict autism and ADHD. Biogaia trial for Autism.

 


By December 2020 7.3% of the Swedish cohort born in 1997-9 had been diagnosed with a Neurodevelopmental Disorder (ND). This can be predicted by samples previously collected.

Today’s post is all about the microbiome and covers three different areas covered recently in the research. Eight years after I wrote a post about our informal trial of Biogaia probiotics for autism, we now have a published paper.

Aggression and self injurious behavior (SIB) affects at least half of those diagnosed with level 3 autism at some point in their lives. SIB can become the overriding concern for care givers.

Our first paper looks at the role of the microbiome in aggression.

Gut-brain axis appears to play a critical role in aggression

A series of experiments on mice has found that they become more aggressive when their gut microbiome is depleted. Additionally, transplanting gut microbiota from human infants exposed to antibiotics led to heightened aggression in mice compared to those receiving microbiome transplants from non-exposed infants. The research was published in Brain, Behavior, and Immunity.

In the past decade, scientists have discovered a complex communication pathway linking gut microbiota—the trillions of microorganisms living in the human gut—with the brain. This pathway is called the microbiota-gut-brain axis. It regulates various physiological functions, including digestion and immunity, but also affects mood and behavior. The gut microbiota produces neurotransmitters and other metabolites that can influence brain function through neural, immune, and endocrine pathways.

Recent studies have demonstrated that symptoms of various disorders, once considered primarily psychological or neurological, can be transferred to rodents by transplanting gut microbiota from humans with these disorders. For example, researchers have shown that transplanting gut microorganisms from people with Alzheimer’s disease into mice (whose gut microbiota had been depleted to enhance transplant effectiveness) resulted in cognitive impairments in the mice. Similarly, symptoms of anxiety have been induced in mice by transplanting gut microbiota from humans with social anxiety.

For the humanized mice, the researchers obtained fecal samples from infants who had been exposed to antibiotics shortly after birth, as well as from unexposed infants. These samples were transplanted into five-week-old germ-free mice. The researchers then waited for four weeks before testing the mice for aggression.

To measure aggression, the researchers employed the resident-intruder test, a well-established behavioral assay in which a male mouse (the “resident”) is introduced to another unfamiliar male mouse (the “intruder”) in its home cage. Aggression was quantified based on the latency to the first attack (how quickly the resident mouse attacked the intruder) and the total number of attacks during a 10-minute period.

The results showed that mice raised without gut bacteria (germ-free) and those treated with antibiotics exhibited higher levels of aggression compared to the control group. These mice attacked more frequently and were quicker to initiate aggressive behavior in the resident-intruder test.

The researchers found that humanized mice receiving fecal microbiota from antibiotic-exposed infants were significantly more aggressive than those receiving transplants from non-exposed infants. Even though the infants’ microbiomes had a month to recover after antibiotic exposure, the aggressive behavior was still evident in the recipient mice.

Biochemical analyses revealed that aggressive mice (both germ-free and antibiotic-treated) had distinct metabolite profiles compared to control mice. Specifically, levels of tryptophan—a precursor to serotonin, a neurotransmitter associated with mood and behavior—were elevated in these mice. Additionally, the levels of certain metabolites associated with microbial activity, such as indole-3-lactic acid, were reduced in the aggressive mice, suggesting that the absence of a healthy microbiome might alter key biochemical pathways involved in aggression.


Here is the link to the original paper:

A gut reaction? The role of the microbiome in aggression

Recent research has unveiled conflicting evidence regarding the link between aggression and the gut microbiome. Here, we compared behavior profiles of control, germ-free (GF), and antibiotic-treated mice, as well as re-colonized GF mice to understand the impact of the gut microbiome on aggression using the resident-intruder paradigm. Our findings revealed a link between gut microbiome depletion and higher aggression, accompanied by notable changes in urine metabolite profiles and brain gene expression. This study extends beyond classical murine models to humanized mice to reveal the clinical relevance of early-life antibiotic use on aggression. Fecal microbiome transplant from infants exposed to antibiotics in early life (and sampled one month later) into mice led to increased aggression compared to mice receiving transplants from unexposed infants. This study sheds light on the role of the gut microbiome in modulating aggression and highlights its potential avenues of action, offering insights for development of therapeutic strategies for aggression-related disorders

Note the ABX means antibiotics

We include a study of humanized mice using unique fecal samples of 1-month-old infants, collected nearly a month after early-life ABX administrationIn previous work (Uzan-Yulzari et al. 2021, Nat Comm), we have demonstrated that ABX in this critical period of life can have lasting effects of childhood growth. Here, we extend these findings using samples from the same cohort. Using fecal samples collected weeks after ABX administration also reduces the direct chemical effects of ABX on the host, highlighting the causative role of the dysbiotic host microbiome and associated metabolome in driving aggressive behavior. We demonstrate that infant microbiota, perturbed within the first 48 h of life, has a lasting signature through 1 month of age that, when transplanted into GF mice, results in increased aggression (3–5 weeks after transplant) when compared to effects of stools of infants not exposed to any early-life antibiotics. The findings are revolutionary as they show how ABX-altered microbiota during a critical development window can lead to persisting behavioral deficits.

 

Gut microbe imbalances could predict a child’s risk for autism, ADHD and speech disorders years before symptoms appear.

Study Identifies Gut Microbe Imbalances That Predict Autism And ADHD

We are researchers who study the role the microbiome plays in a variety of conditions, such as mental illness, autoimmunity, obesity, preterm birth and others. In our recently published research on Swedish children, we found that microbes and the metabolites they produce in the guts of infants – both found in poop and cord blood – could help screen for a child’s risk of neurodevelopmental conditions such as autism. And these differences can be detected as early as birth or within the first year of life. These markers were evident, on average, over a decade before the children were diagnosed. 

The imbalance in microbial composition – what microbiologists call dysbiosis – we observed suggests that incomplete recovery from repeated antibiotic use may greatly affect children during this vulnerable period. Similarly, we saw that repeated ear infections were linked to a twofold increased likelihood of developing autism.

Children who both repeatedly used antibiotics and had microbial imbalances were significantly more likely to develop autism. More specifically, children with an absence of Coprococcus comes, a bacterium linked to mental health and quality of life, and increased prevalence of Citrobacter, a bacterium known for antimicrobial resistance, along with repeated antibiotic use were two to four times more likely to develop a neurodevelopmental disorder.

Antibiotics are necessary for treating certain bacterial infections in children, and we emphasize that our findings do not suggest avoiding their use altogether. Parents should use antibiotics if they are prescribed and deemed necessary by their pediatrician. Rather, our study suggests that repeated antibiotic use during early childhood may signal underlying immune dysfunction or disrupted brain development, which can be influenced by the gut microbiome. In any case, it is important to consider whether children could benefit from treatments to restore their gut microbes after taking antibiotics, an area we are actively studying.

Another microbial imbalance in children who later were diagnosed with neurodevelopmental disorders was a decrease in Akkermansia muciniphila, a bacterium that reinforces the lining of the gut and is linked to neurotransmitters important to neurological health.

Even after we accounted for factors that could influence gut microbe composition, such as how the baby was delivered and breastfeeding, the relationship between imbalanced bacteria and future diagnosis persisted. And these imbalances preceded diagnosis of autism, ADHD or intellectual disability by 13 to 14 years on average, refuting the assumption that gut microbe imbalances arise from diet.

We found that lipids and bile acids were depleted in the cord blood of newborns with future autism. These compounds provide nutrients for beneficial bacteria, help maintain immune balance and influence neurotransmitter systems and signaling pathways in the brain.

The full paper is here: 


Infant microbes and metabolites point to childhood neurodevelopmental disorders 

Highlights

Infant microbes and metabolites differentiate controls and future NDs

Early-life otitis lowers Coprococcus and increases Citrobacter in future NDs

Preterm birth, infection, stress, parental smoking, and HLA DR4-DQ8 increase ND risk

Linolenic acid is lower and PFDA toxins higher in the cord serum of future ASD

Summary

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immune-dysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.



ABIS = All Babies in Southeast Sweden cohort

NDs = Neurodevelopmental disorders

Young children later diagnosed with ASD or exhibiting significant autistic traits tend to experience more ear and upper respiratory symptoms. In ABIS, infants who had otitis in their first year were found to be more prone to acquiring NDs if they lacked detectable levels of Coprococcus or harbored Citrobacter. The absence of Coprococcus, despite comparable levels in controls irrespective of otitis, raises questions about microbial community recovery. This potential failure of the microbiome to recover following such events may serve as a mechanism connecting otitis media to ND risk. Moreover, antibiotic-resistant Citrobacter was more prevalent in these infants. The presence of strains related  to Salmonella and Citrobacter, labeled in this investigation as SREB, was significantly higher in infants who later developed comorbid ASD/ADHD (21%), compared to controls (3%). This disruption may have consequences on neurodevelopment during a critical period. Salmonella and Citrobacter have shown the ability to upregulate the Wingless (Wnt) signaling. The Wnt pathway is vital for immune dysregulation and brain development, and its disruption has been implicated in ASD pathogenesis. 

Two fatty acid differences were notable in the stool of future ASD versus controls: omega-7 monounsaturated palmitoleic acid, (9Z)-hexadec-9-enoic acid (below the level of detection in 87.0% of future ASD but present in 43.5% of controls), and palmitic acid (elevated in future ASD). Palmitoleic acid has been associated with a decreased risk of islet and primary insulin autoimmunity. Conversely, palmitic acid, a saturated fatty acid, has been linked to neuronal homeostasis interference. Its effects are partially protected by oleic acid, which although approaching significance, was lower in the cord serum of future ASD.

Few metabolites were higher in stool of infants with future ASD, but there are a few notable examples: α-d-glucose, pyruvate, and 3-isopropylmalate. Coprococcus inversely correlated with 3-isopropylmalate, suggesting gut-brain connections and a possible imbalance in branched-chain amino acid (BCAA) pathways given the role of 3-isopropylmalate dehydrogenase in leucine and isoleucine biosynthesis. An increase in dehydroascorbate suggests potential disruptions in vitamin C metabolism, crucial for neurotransmitter synthesis and antioxidant defense, while elevated pyruvate suggests disturbance of neurotransmitter synthesis or energy production early in life. Pimelic acid elevation, found in disorders of fatty acid oxidation, suggests disruption of mitochondrial pathways for fatty acid oxidation.

Akkermansia and Coprococcus, absent or reduced in infants with future NDs, positively correlated with signals in stool representing neurotransmitter precursors and essential vitamins in stool. Specifically, Akkermansia correlated with tyrosine and tryptophan (i.e., catecholamine and serotonin precursors, respectively) and Coprococcus with riboflavin. Disruption of BCAA metabolism in ASD has been documented, involving coding variants in large amino acid transporters (LATs) and reduced utilization of trypotphan and large aromatic amino acids along with increased glutamate and decreases in tyrosine, isoleucine, phenylalanine, and tryptophan in children with ASD. Oxidative stress, a diminished capacity for efficient energy transport, and deficiencies in vitamins (like vitamin B2) essential for neurotransmitter synthesis and nerve cell maintenance have been implicated. Riboflavin as an antioxidant reduces oxidative stress and inflammation, demonstrating neuroprotective benefits in neurological disorders, possibly through maintenance of vitamin B6, which is necessary for glutamate conversion to glutamine and 5-hydroxytryptophan to serotonin.

Together, these findings support a hypothesis of early-life origins of NDs, mediated by gut microbiota. This provides a foundation for research and for developing early interventions for NDs.

 

Today’s final paper was highlighted recently in a comment on a post I wrote eight years ago, when we were trialing Biogaia probiotics. This original interest was prompted by a reader sharing her successful experiences of treating her son with severe autism. Perhaps she left the recent comment?

The two bacteria involved are both types of L. reuteri.

L. reuteri 6475 is sold as Biogaia Osfortis

L. reuteri 17938 is sold Biogaia Protectis

The combination of L. reuteri 17938 and L. reuteri 6475 is sold as Biogaia Gastrus.

My old post from 2016:-

Epiphany: Biogaia Trial for Inflammatory Autism Subtypes



The recently published trial:

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial -

Highlights

L. reuteri (6475 + 17938) improves social functioning in children with autism

L. reuteri does not improve overall autism severity or repetitive behaviors

L. reuteri does not significantly alter microbiome composition or immune profile

  Only the 6475 strain reverses the social deficits in a mouse model for autism



we performed a double-blind, randomized, placebo-controlled, parallel-design pilot trial in children with ASD. Importantly, we found that L. reuteri, compared with placebo, significantly improved social functioning, both in terms of reducing social deficits, as measured by the social responsiveness scale (SRS31,32), and increasing adaptive social functioning, as measured by the social adaptive composite score of the Adaptive Behavior Assessment System, Second Edition (ABAS-233). L. reuteri did not improve overall autism severity, restricted and repetitive behaviors, and co-occurring psychiatric and behavioral problems, nor did it significantly modulate the microbiome or immune response. Thus, this safe microbial manipulation has the potential for improving social deficits associated with ASD in children.

I had to amend my old post with a warning long ago.

UPDATE: A significant minority of parents report negative reaction to Bio Gaia, this seems to relate to histamine; but more than 50% report very positive effects without any side effects; so best to try a very small dose initially to see if it is not well tolerated. 

Histamine Reaction to BioGaia gastrus

Conclusion

The gut microbiota does indeed play a key role in how your brain functions, but the gut-brain axis works in both directions. What goes on in your brain can affect your gut and not just the other way around. It is called bidirectional signaling.

Antibiotics taken during pregnancy, or during early childhood, will have unintended consequences. Often there is no choice, like for those readers whose baby experienced sepsis at birth (bacterial blood stream infection); you have to give antibiotics to avoid death.

In today’s second paper we see that the researchers are thinking about therapeutical implications. Perhaps the newborn’s gut flora should be repopulated during the weeks after the antibiotic treatment?

I receive many questions about how to treat self injurious behavior that does not respond to anything the doctor has prescribed. Rifaximin, an antibiotic used to treat irritable bowel syndrome with diarrhea, is one therapy that does help some types of SIB (and SIBO, small intestinal bacterial overgrowth, of course). This probably would not surprise the authors of today’s first paper.

Biogaia Gastrus (L. reuteri 6475 + 17938) from today’s third paper worked wonders for the SIB of one reader’s child.

Not surprisingly fecal microbiota transplantation (FMT) can improve SIB in some people.

The Swedish data shows interesting insights such as that lipids and bile acids were depleted in the cord blood of newborns with future autism. The researchers think they can predict the diagnosis of autism or ADHD. The question is and then what? Even when there is a diagnosis of autism, not much changes for most children.





Wednesday 2 October 2024

Educating children with level 3 Autism

 


Some people do not like South Park, but it is a good example of genuine inclusion


The number of children with autism and intellectual disability continues to rise and this is putting a strain on government resources in many parts of the world. Increasing budgets can never match the increased perception of needs.

In spite of the vast amounts of money being spent very little attention is given to evaluating what gives the best results.

In the US it has long been put forward that the earlier the intervention starts the better the results will be and often it is stated that 40 hours a week of one-to-one therapy is needed.  This view is generally limited to the US.    

ABA therapy became a big business in the US and many providers are now owned by private equity investors.

I did point out that in the book the Politics of Autism, the author recounts her discussions with the founding father of ABA, Ivar Lovaas, that revealed he had rigged his clinical studies by excluding those children who did not respond to his 40 hours a week therapy from the final results. He just dropped them before the end of the trial. This would totally invalidate his conclusions.

There is a recent study on this very subject.


Rethinking the Gold Standard for Autism Treatment

Research shows some autistic children may get more treatment hours than needed.

The JAMA Pediatrics study looked at the relationship between the amount of intervention provided (hours per day, duration, and cumulative intensity) and the outcomes for young autistic children. Researchers analyzed data from 144 studies involving more than 9,000 children, making it one of the most comprehensive analyses of its kind.

Contrary to what many have long believed, the study found no significant association between the amount of intervention and improved developmental outcomes. As the authors write, “health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.”

Determining Associations Between Intervention Amount and Outcomes for Young Autistic Children A Meta-Analysis

A total of 144 studies including 9038 children (mean [SD] age, 49.3 [17.2] months; mean [SD] percent males, 82.6% [12.7%]) were included in this analysis. None of the meta-regression models evidenced a significant, positive association between any index of intervention amount and intervention effect size when considered within intervention type.

Conclusions and Relevance  Findings of this meta-analysis do not support the assertion that intervention effects increase with increasing amounts of intervention. Health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.


Some parents in the US get to the bizarre situation where their child can receive 40 hours of ABA for free, but if they say they want only 20 hours because they have other activities for the rest of the week, this is refused.  It is the full 40 hours or none.   


School segregation

Segregation is a word with negative connotations, but it is used when it comes to the merits of inclusive education versus special schools.

There are many ways in which schools are segregated, including

By sex

It is still very common to have separate boys' schools and girls' schools in many countries

By religion

Religious schools are common in both public and private sectors

By ethnicity

This was widely practiced in the United States and South Africa. The legacy of these policies is still evident today.

By ability

Selecting pupils by academic level is very common.

By disability

Segregation of those with learning disabilities into special schools or special classes within a mainstream school is widespread.

By socioeconomic status

Segregation by the ability to pay is common all over the world. In parts of the world there is no schooling for those whose family cannot afford it.

Homeschooling

In parts of the world homeschooling is legal and thriving. The US has by far the largest contingent, with 6% of children home-schooled.  In Germany it is illegal.


What is the best type of school for level 3 autism?

There is no “best” choice.

From the parents' perspective, some are desperate for their child to attend a special(ist) school and some are desperate not to attend such a school.

Some parents choose to home school.

Some parents look for some kind of hybrid solution.

Most parents just take what is given to them.


Inclusion vs segregation

The key issue here is whether the child is “includable”. It is fashionable in Western countries to be anti-segregation and pro inclusion.

Some children are not includable and some school environments are hostile rather than welcoming.  Even some children with level 1 autism struggle to cope in mainstream school.

Monty was lucky and completed all his schooling in a mainstream school with very small class sizes, about 12 pupils. He had his own teaching assistant throughout. Two of his former assistants later became class teachers at his school. We paid for the school and the assistants.

Had Monty attended a school with 30 children in the class with 3 other special needs kids, each with their own teaching assistant, the result would not have been so good.

As you can see it is a question of “inclusion in what” versus “segregation in what”.


What is the purpose of “school”

If you talk to parents of older children you will discover that over the years their view of schooling changes. It is an illusion, one grandfather told me. For many schooling is just daycare for the pupil and respite care for the parents.

Some parents do not want their child to be just taught daily living skills, they want the academic curriculum.

Some schools teach non-verbal children an alternative method of communication, whereas other do not bother.

It is not surprising that the result is often nobody is satisfied.


Peter’s idea about schooling for level 3 autism

I would require all children with level 3 autism to be taught at primary/elementary school a means of communication. Remarkably this is not done.

Proactive parents have been doing this for decades at home, but what if your parents are not proactive?

I read the other day that a mother commented that her non-verbal 7 year old daughter would greatly benefit from an augmentative communication device, but that the council/municipality did not want to provide one. In previous decades these were expensive devices, but nowadays these are just apps that you install on an iPad, or android device. Some of these apps are even free !!

Clearly, I would ensure all pupils with level 3 autism were screened and treated for any type of treatable intellectual disability, the most common one being elevated chloride inside neurons, which was the case for Monty.

I recently was contacted by a parent who, after trying to help his son for 7 years, has finally had success by increasing his dose of leucovorin (calcium folinate). Now his son responds to verbal instructions like "wash your hands".

Some of these children, once under medical treatment, will be able to follow much of the core academic curriculum and be genuinely included in mainstream classes. That was the outcome for Monty, now aged 21.

Children who remain with a lower IQ should not be in classes that teach academic concepts far above their level of understanding. This is pointless and will just lead to frustration.

One non-verbal child I know, who cannot read or write is “taught” a second language at school. How about teaching him a first language?

Children should be taught in groups of similar ability/functioning level, rather than grouping them by age. I thought this would be just common sense, but not in the world of education.

If the material has not been mastered there is no point moving forward, just repeat it. After 15 years at school there should have been measurable progress.

Beware of prompt-dependence and assistant-dependence. Skills learned at school need to be such that the child can apply them independently and can generalize them to new situations. Some wealthy schools provide very high levels of support and this risks that the child will become an adult dependent on a similar level of support. This is an example of “too much of a good thing”.

 

The services “cliff-edge”

Some people with autism, and their families, receive very considerable support for two decades and become dependent on it. At some point in early adulthood these supports may get abruptly withdrawn.

In other parts of the world, there was only ever very minimal support and the family became more self-reliant and so do not experience such a cliff-edge. The family and the young adult learnt to cope.


Level 1 autism / Asperger’s

This post is about level 3 autism, but I am always surprised how many people with level 1 autism write to me so here are some thoughts on them.

You would think that all people with level 1 autism should be able to thrive in mainstream education these days. There is so much in the media, or social media, about accommodating differences and promoting the “able disabled” who are featured everywhere, so how come kids at school are still bullying/tormenting their classmates who are 1% different. Times have not really changed as much as we might have thought.

Most kids with level 3 autism love going to school.  Monty adored it.

Many kids with level 1 autism clearly hate it.

During my time helping to run my children’s school one of the things teachers told me was that kids are actually very supportive of those who are clearly disabled but will delight in picking on kids who are a tiny bit different.

The net result is that many children with level 1 autism thoroughly enjoyed their on-line education during the pandemic away from all that awkwardness at school.

Many parents whose child goes to a special school for autism or Down syndrome are completely unaware that there are also some special schools for level 1 autism. It greatly surprised me.

 

Conclusion

The idea of trying to educate children with level 3 autism is relatively new. In the recent past they were just put aside in institutions and forgotten about.  Today much is possible, but a lot comes down to who the parents are and where they happen to live.

The Education for All Handicapped Children Act (EAHCA) of 1975 (later renamed the Individuals with Disabilities Education Act, or IDEA, in 1990) was the major turning point in the US. This ultimately opened the door to a flood of ABA, paid for by private health insurance, but only in the US.

My doctor mother once commented to me that we had shown that such children can be taught and can genuinely learn. This was a combination of personalized medicine and personalized learning.

Good things don’t just happen, you have to make them happen.

The outcome in level 3 autism is hugely variable and that is rather sad.