There’s a delicate dance among the way our genes are expressed, the contents of our digestive systems, and the development of our brains. While scientists have long known these three things are closely linked, a new study from The Chinese University of Hong Kong (CUHK) sheds welcome light on how they interact. The results could give us a way of assessing which infants are more likely to develop certain neurodevelopmental conditions – and, potentially, a way to intervene early.
Decoding the gene-microbiome axis
“Although many studies have shown that healthy microbiome development in early life is crucial for later health, the precise mechanisms by which the epigenome interacts with and influences this process have remained unclear,” says the study’s co-senior author, Professor Tun Hein-min, Associate Professor of the Jockey Club School of Public Health and Primary Care at CU Medicine and Associate Director of the Microbiota I-Center (MagIC).
Genes themselves are fixed, but their expression can be altered without changing the DNA sequence. This process, known as epigenetics, involves chemical modifications to DNA and associated proteins that influence gene activity.
For the study, Professor Tun and his team, a hyper-diverse group of microbiome scientists, computational biologists, gastroenterologists, obstetricians, paediatricians, psychiatrists, research nurses and study assistants, looked at 969 families. They measured DNA methylation – a chemical process that can effectively switch genes off – in umbilical cord blood of 571 infants and compared the results with gut microbiome samples collected at birth and at two, six and 12 months of age. They also collected microbiome samples from parents in the third trimester of pregnancy.
Early-life factors leave lasting imprints
The researchers found that several early-life factors were associated with epigenomic patterns, including mode of delivery, gestational age, maternal allergies and the presence of older siblings. Caesarean section, in particular, was associated with changes in immune-related genes.
A similar pattern was seen in the microbiome data. Mode of delivery and sibling exposure remained important, while breastfeeding and antibiotic use were also associated with differences in microbial development.
By six months of age, infants with higher levels of DNA methylation in immune-related genes – meaning their ability to recognise various germs had been switched off – tended to have less diverse gut microbiomes. According to Professor Tun, those early differences are likely to persist, underscoring the importance of gut health during the first few years of life.
“The first 1,000 days of life represent a critical window for long-term health and development,” he explains. “Epigenetic changes present at birth can programme the infant onto a subtly different developmental trajectory. These early changes may lead to lasting functional effects that increase disease risk later in life.”
Links to neurodevelopment
When the children were assessed at age three, the researchers found associations between earlier epigenomic and microbiome data and higher scores suggestive of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Children with higher scores suggestive of ASD or ADHD showed differences in more than 12,000 DNA epigenetic markers, as well as in a handful of types of gut bacteria.
Importantly, the findings also suggest that the associations are not fixed. Exposure to certain bacteria in the first year of life was associated with a lower likelihood of neurodevelopmental conditions. Lachnospira pectinoschiza, which helps break down plant fibre, was associated with a lower autism risk, while Parabacteroides distasonis was associated with a lower ADHD risk.
Translational potential and next steps
That holds out the hope that probiotic supplements based on those bacteria could one day be given to at-risk babies to help prevent neurodevelopmental conditions. The team is currently conducting preclinical experiments to evaluate the potential benefits of those bacteria, with a view to moving towards a clinical trial. They will also keep monitoring the development of the children from the study – but that’s far from the only research the study has inspired.
For a start, there’s no reason to assume that the associations end with neurodevelopmental conditions. “In a parallel study, we are also examining the associations between early-life factors and allergic diseases, including eczema and food and inhalant sensitisation, which are highly prevalent in our infant population,” says Professor Tun.
The team also plans to investigate whether the results can be replicated with groups of children from other parts of the world; and to explore the biological roles of specific epigenomic and microbiome markers identified in the study.
“The ultimate goal is to translate these mechanistic insights into safe, evidence-based early interventions that support optimal neurodevelopment, particularly for at-risk children,” says Professor Tun. “I am optimistic but at the same time cautious – this field requires rigorous, longitudinal data and strong preclinical evidence before moving into clinical trials.”
