Targeting microbial metabolites to treat autism

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In summary, recent research has shown that the gut microbiome, specifically the metabolites produced by gut microbes, may play a crucial role in regulating brain activity and behavior, particularly in relation to autism spectrum disorder (ASD). This is supported by studies that have identified changes in the gut microbiome and gut-derived metabolites in individuals with ASD. In this week's issue of Nature Medicine, two articles explore this link in more detail. One article presents the first clinical evidence that a gut microbiome-targeting therapeutic can improve ASD-associated behaviors, while the other provides a deeper understanding of the mechanisms behind this effect in mouse models. This research provides a promising avenue for potential treatments for ASD, but larger, placebo-controlled trials are needed to confirm the efficacy of
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A pair of new papers published this week explores the how metabolites produced by gut microbes might be important regulators of brain activity and behavior, especially in relation to autism spectrum disorder. A News and Views article in Nature Medicine accompanies the articles and provides a nice summary:

Autism spectrum disorder (ASD) is a group of heterogenous neurodevelopment conditions, characterized by deficits in social communication and interaction in conjunction with restricted, repetitive patterns of behaviors and interests. Many affected individuals experience gastrointestinal (GI) dysfunction, as well as a range of comorbidities including sleep disorders, epilepsy and anxiety. Currently, there are no approved drugs for treating the core symptoms of ASD. Although the etiology remains poorly understood, it is widely recognized that genetic and environmental factors and their interactions contribute to ASD phenotypes. One such environmental risk factor is the gut microbiome, a key regulator of brain development and behavior1.

In this issue of Nature Medicine, Campbell et al2. provide the first preliminary clinical evidence that AB-2004, a first-in-class molecular therapeutic that prevents the absorption of neuroactive microbial metabolites from the GI tract, can help improve ASD-associated behaviors (Fig. 1). In this and a companion article by Needham et al. (published in a concurrent issue of Nature)3, the group also describe preclinical studies in mouse models that provide a rationale for taking this therapeutic approach into the clinic.

Here are the articles referenced:

Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.

A gut-derived metabolite alters brain activity and anxiety behaviour in mice

Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut–brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte–neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9,10,11,12,13,14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

There are, of course, limitations to the studies. The study in Nature was done solely in mice, so it's not yet clear how well the findings translate to humans. The clinical trial published in Nature Medicine was phase 1 study meant solely to evaluate safety of the treatment, not efficacy. Furthermore, the study was small (n = 30), not placebo controlled and the data showing that the treatment modifies behavior does not look very strong to me, so larger, double-blind, placebo-controlled phase 2 trials are needed to better evaluate the efficacy of the treatment. Lastly, the treatment seems likely to only be able to modify the symptoms of ASD and not necessarily treat the underlying condition.

See also this previous PF thread for more discussion of the link between ASD and the gut microbiome:
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The lack of bio-diversity in the contents of the gut is associated with a number of disorders. It seems the microbiome is needed to produce important molecules that the brain and body needs.

There is a known correlation between abnormal gut microbiome profiles and inflammatory conditions (see for example: and ).

The association of abnormal gut microbiome with brain disorders is discussed in this recent Nature article: How gut microbes could drive brain disorders. Such disorders appear to be related to bacterial metabolites produced in the gut: "small molecules produced by bacteria that can enter the bloodstream and travel around the body. At least half of all small molecules in the blood are either made by microbes or modulated by microbes".

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Related to Targeting microbial metabolites to treat autism

1. What are microbial metabolites?

Microbial metabolites are small molecules produced by microorganisms such as bacteria, fungi, and viruses as a byproduct of their metabolism. These molecules have various functions, including communication, defense, and nutrient acquisition.

2. How can microbial metabolites be used to treat autism?

Recent research has shown that the gut microbiome, which is composed of various microorganisms, plays a significant role in the development of autism. By targeting specific microbial metabolites through diet, probiotics, or other interventions, it is possible to modulate the gut microbiome and potentially improve symptoms of autism.

3. Are there any microbial metabolites that have been identified as potential treatments for autism?

Yes, several microbial metabolites have been identified as potential treatments for autism. Some examples include short-chain fatty acids, which are produced by gut bacteria and have anti-inflammatory properties, and tryptophan metabolites, which have been linked to neurotransmitter production and brain function.

4. Is there evidence that targeting microbial metabolites can improve symptoms of autism?

While the research is still in its early stages, there is some evidence that targeting microbial metabolites can improve symptoms of autism. For example, a small study found that a probiotic treatment containing specific bacterial strains and their metabolites led to improvements in social behavior and communication in children with autism.

5. Are there any potential risks or side effects associated with targeting microbial metabolites for autism treatment?

As with any medical treatment, there may be potential risks or side effects associated with targeting microbial metabolites for autism treatment. However, more research is needed to fully understand the safety and efficacy of this approach. It is important to consult with a healthcare professional before starting any new treatment for autism.

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