What link between autism and the microbiota?

Numerous studies show a link between autism and the microbiota, i.e. the population of microbes contained in the intestines.

A treatment based on Lactobacillus reuteri, a species of intestinal bacteria contained in yogurt and maternal milk, could improve social interactions.

Already in 2016, a team of researchers (Buffington S.A. et al. Cell 165, 1762-1775, 2016) demonstrated that this same bacterium could normalize social behavior in mice. This is also consistent with the results of a 2018 study showing that the bacteria improve social behavior in mice carrying a mutation in SHANK3, a major autism gene. So autism and the microbiota appear to be linked.

Definition of the microbiota: the set of microorganisms (bacteria, microfungi, protists, viruses) living in a specific environment called the microbiome in a host.

In all the models we tried, the bacteria were effective (…) it’s not a miracle that happened in my laboratory, I think it’s very general (…), says lead investigator Mauro Costa-Mattioli, professor and Cullen Foundation Chair of Neuroscience at Baylor College of Medicine in Houston, Texas. The work suggests that bacteria cause behavioral changes through signals sent by the vagus nerve – which connects the gut to the brain – which increases the hormone oxytocin in the brain. The findings were published today in Neuron.

These results confirm the crucial role of bacteria in the functioning of autism and the microbiota, and opens possibilities for a treatment of one of the main characteristics of autism: disorders of social interactions.

However, the researchers do not recommend the use of over-the-counter L. reuteri supplements to treat autism, as no one knows if all strains are effective or what dose to use in humans

Autism and the microbiota influences the social network
Costa Mattioli and colleagues conducted trials on three types of mice:

Mice with a mutation in the SHANK3 gene (known as a marker for autism)
Mice exposed in utero to Valproate (a substance that significantly increases the risk of autism)
BTBR mice that show autism-like traits
In all three cases the mice had an unusual mircrobiome in their intestines. Mice with SHANK3 and BTBR have a smaller proportion of L. Reuteri than the control mice.

The mice absorbed L. Reuteri for four weeks in the water they drank when they were 3 weeks old. The researchers then tested their social behavior.

Unlike the control subjects, the mice with autistic tendencies preferred objects to contact with other mice before taking L. Reuteri.

After taking the bacteria, the social behavior of the autistic mice tended to develop. Autism and microbiota are linked to the social aspect of relationships.

The results would be more convincing if the researchers could replicate the effects of the treatment at different ages and in mice with mutations in other autism genes, says Yong-Hui Jiang, a professor of pediatrics at Duke University in Durham, North Carolina, who was not involved in the study.

“The VPA and BTBR models are complicated because the consistency of these models remains questionable.”

Nevertheless, the results seem to confirm the 2018 results.

Another consideration is that the results could be biased by certain characteristics of the mice. For example BTBR mice have a poor sense of smell and mice with SHANK3 are slower. However, these traits remain even after treatment, while social behavior develops.

The treatment improves social interactions even in mice lacking a microbiome. This result suggests that L. reuteri acts independently of other gut microbes to influence social behavior.

A connection between gut and brain

The researchers experimented with cutting the vagus nerve of the mutant mice while continuing to feed them L. reuteri.

Definition of the vagus nerve: It is a very important pathway for vegetative regulation (digestion, heart rate…) but also for the sensorimotor control of the larynx and thus of phonation. The vagus nerve is the cranial nerve with the largest territory (hence its name). It is a mixed nerve that conveys motor, sensory, sensory and especially vegetative parasympathetic information.

When the vagus nerve is cut, the bacterial treatment does not work. Suggesting that the bacteria sends signals between the gut and the brain.

The vagus nerve connects to an area of the brain called the hypothalamus, which produces the hormone oxytocin. The researchers found that SHANK3 mice had unusually low levels of oxytocin in the hypothalamus. And the neurons in the oxytocin-driven reward circuit in the mutant mice had weak connections or synapses. These were measured by electrical currents in brain slices.

A 2013 study (Poutahidis T. et al. 2013) researchers showed that feeding mice with L. Reuteri increases the level of oxytocin in the blood.

In the new study, Costa-Mattioli’s team found that L. reuteri normalizes oxytocin levels in the brains of SHANK3 mice. It also boosts the strength of their neuronal connections. The bacterial treatment does not work if the mice lack oxytocin receptors in the reward neurons or if they first get a drug that blocks oxytocin receptors.

All of this research shows that L. Reuteri alters the social behavior of mice with autistic features via the vagus nerve. The next step is to identify the bacterial composition that activates this nerve.