It has been previously suggested that a high-fibre diet can prevent neurodegeneration by increasing gut microbiota derived butyrate in the colon, but how changes in gut bacteria could influence brain development and function is still poorly studied.
A recent study, led by Dr. Mauro Costa-Mattioli from the Baylor College of Medicine in Houston, Texas (USA), has found that the reintroduction of a commensal bacterial strain can reverse asocial behaviours in mice that are seen in autism spectrum disorders (ASDs).
Previous human epidemiological studies that have found that maternal obesity during pregnancy could increase children’s risk of neurodevelopmental disorders, including ASDs. Besides this, recurrent gastrointestinal problems are frequently reported in individuals with ASDs. Based on these observations, the researchers sought to explore the connections between changes in diet, the gut microbiome, and social behaviours.
First of all, female mice were fed either a regular diet (RD, consisting of 13.4% kcal from fat, 30% kcal from protein, and 57% kcal from carbohydrates) or a high-fat diet (HFD, consisting of 60% kcal from fat, 20% kcal from protein, and 20% kcal from carbohydrates) for 8 weeks. Females then were paired with males to produce offspring that all were given RD after weaning. Maternal high-fat diet (MHFD) significantly increased maternal weight. At 7-12 weeks of age behavioural and electrophysiological experiments were performed in order to study social behaviour in maternal regular diet (MRD) and maternal high-fat diet offspring. Maternal high-fat diet offspring displayed impaired sociability and dysbiosis of the gut microbiota.
Buffington and colleagues next tested whether the gut microbiota mediated MHFD-induced social deficits. To this end, at 3 weeks an MHFD mouse was co-housed with three MRD mice. As a result, co-housing MHFD with MRD offspring rescued both social dysfunction and the microbiota phylogenetic profile of the socially impaired mice born to mothers on a high-fat diet. Taken together, these data indicate that gut microbiota mediates MHFD-induced social deficits and suggest that MHFD offspring may lack one or more beneficial bacterial species required for normal social behaviour. Faecal transplant experiments in germ-free mice suggested that dysbiosis of the gut microbiota in the mice born to mothers on a high-fat diet could be involved in their social deficits.
In order to elucidate the specific bacterial species involved in social deficits of the mice, the researchers performed metagenomic sequencing of faecal samples from both MHFD and MRD offspring. Lactobacillus reuteri was the most drastically reduced in the gut microbiota of mice born to mothers on the high-fat diet.
In the high-fat-diet fed offspring, elective reintroduction of L. reuteri originally isolated from human breast milk restored the social deficits in the mice-but not repetitive behaviours and anxiety- and it also restored levels of oxytocin, a hormone that plays a crucial role in social behaviours and has been associated with autism in humans.
The reward circuitry in the socially impaired mice was also assessed. According to Dr. Costa-Mattiol, “in response to social interaction there was a lack of synaptic potentiation in a key reward area of the brain that could be seen in the normal control mice.” It is noteworthy that the reintroduction of L. reuteri in the maternal-high-fat-diet offspring also restored the changes in synaptic function in the reward circuitry.
On the whole, a maternal high-fat diet may lead to dysbiosis of the gut microbiota of offspring and induce behavioural alterations that can be restored via selective reintroduction of L. reuteri.
Based on the hypothesis that changes in the gut microbiota may be relevant to the development of behavioural symptoms associated with ASD, interventional studies are currently being developed. For instance, a pilot study that is currently underway, led by Dr. Filippo Muratori from the IRCCS Stella Maris Foundation and University of Pisa, aims to explore supplementation with a probiotic mixture in pre-schoolers with ASD. As some ASD patients may have some gastrointestinal problems that may be associated with a higher rate of irritability, aggressive behaviours and sleep disturbances, therefore the treatment of these symptoms with probiotics opens a new therapeutic approach in ASD. Intervention studies in humans are warranted to develop evidence-based guidelines for the use of probiotics as a non-pharmacological option complementary to the recommended treatments for ASD, which are based on an integrated approach including behavioural treatments, drugs and other options.
Buffington SA, Di Prisco GV, Auchtung TA, et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016; 165(7):1762-75. doi:10.1016/j.cell.2016.06.001.
Santocchi E, Guiducci L, Fulceri F, et al. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016; 16:183. doi:10.1186/s12888-016-0887-5.