• What is already known on this topic
  The prevalence of childhood obesity has been increasing in most countries across the globe in recent decades. The idea that the gut microbiota may play a vital and potentially etiological role in the development of obesity has gained traction. Differences in the gut microbiota have been associated with overweight/obesity in both adults and children and there is growing evidence of possible causal mechanisms.

• What this research adds
  Researchers studied the early-life gut microbiota at days 4, 10, 30, 120, 365, 730 and its association with body mass index (BMI) z-scores at the age of 12 years in a Norwegian prospective cohort. Researchers further evaluated how these BMI-associated taxa relate to maternal overweight/obesity (Ow/Ob) and excessive gestational weight gain (GWG).

• Conclusions
  In this cohort, the gut microbiota taxa at 2 years of age explained over 50% of the variation in childhood BMI. The subset of the early-life taxa within the gut microbiota predicted later childhood BMI. The preliminary results demonstrated that the infant gut microbiota, especially at the age of 2, may have the potential to help identify children at risk of developing obesity.

The infant gut microbiota is associated with later BMI and, particularly at 2 years of age, may have the potential to help identify children at risk for obesity. These are the conclusions of a study by M.A. Stanislawski and colleagues at the School of Public Health in Colorado, United States, published in the journal mBio.

Researchers examined the early-life gut microbiota at days 4, 10, 30, 120, 365, and 730 and the association with body mass index (BMI) z-scores at age 12 in a Norwegian prospective cohort (n=165), and evaluated how these BMI-associated taxa relate to maternal overweight/obesity (Ow/Ob) and excessive gestational weight gain (GWG) by performing 16S rRNA gene sequencing on the gut microbiota samples.

Infant gut microbiota and childhood BMI z-score

The overall infant gut microbiota taxonomic phylogeny at days 10 and 730 were significantly associated with sex and age-specific BMI z-scores at the age of 12 years. A specific subset of the taxa could be predictive of childhood BMI even though the overall composition is not considerably associated. Researchers further studied whether the gut microbiota taxa at each sampling time during the first 2 years of life can predict the later BMI.

The gut microbiota of infants during the first 4 months explained a considerable portion of the variation in BMI z-score. This association strengthened with age, and more than half of the variability in BMI z-scores at the age of 12 years was explained by the gut microbiota composition at 2 years of age.

This is substantially more than other predictors of child BMI. For example, taken together child BMI predictors like delivery mode, exclusive breast-feeding duration, antibiotic exposure, twin status, gestational age at birth, and maternal factors (including pre-pregnancy BMI and smoking during pregnancy) explained 15.2% of the variation in child BMI z-score.

The confounding variables of delivery mode, exclusive breastfeeding duration, antibiotic exposure, twin pregnancy, and gestational age included in the random forests were not among the most important predictors of later BMI; researchers estimated R2 values of the random forests both with and without these confounding factors and the values were comparable.

Association of maternal gut microbiota taxa with maternal Ow/Ob and excessive GWG

Maternal gut microbiota taxa associated with maternal Ow/Ob and excessive GWG showed substantial overlap at the species level with BMI-associated taxa in the infant.

In prior research work, researchers evaluated the association of maternal Ow/Ob and excessive GWG with maternal gut microbiota at the time of child birth in this cohort.

It was reported that maternal Ow/Ob was associated with alpha diversity and taxonomic differences in composition, while excessive GWG was associated only with taxonomic differences.

BMI-associated infant gut microbiota and the association with maternal characteristics of pre-pregnancy Ow/Ob and excessive GWG

Researchers studied the relationship between both excessive GWG and maternal pre-pregnancy Ow/Ob and the groups of infant gut microbiota taxa selected as most predictive of childhood BMI with permutational ANOVA. Maternal Ow/Ob was associated with the qualitative differences in the selected infant gut microbiota taxa at day 30; excessive GWG was associated with quantitative differences at day 730.

The gut microbiota, especially at 2 years of age, was strongly associated with later childhood BMI. Also, BMI z-scores at the age of 2 years were not considerably higher in the child population, who later became Ow/Ob, so the development of the gut microbiota composition that predicted later BMI preceded any measurable excess weight in children.

One avenue for the prevention of obesity would be through early detection of individuals/children at high risk for the development of obesity. The findings of this study suggest that fecal microbiota during early childhood may have the potential to be part of an obesity risk prediction algorithm, which could be especially advantageous given the ease of recovering samples from diapers. Dietary or other interventions could be considered for these individuals before they start gaining weight.

Both in this cohort and in many other studies, it was reported that maternal Ow/Ob and excessive GWG are the predictors of obesity in childhood. The maternal gut microbiota may contribute toward offspring risk of developing obesity through vertical transfer, as well as through in utero effects. There is strong evidence that many early infant gut taxa are transferred from mother to child. This is particularly true for certain taxa, including Bifidobacterium. Strain level similarity between mothers and infants decreases over the period, but species-level composition converges.

Overall, the findings of this study reveal a strong relationship between the infant gut microbiota at the age of 2 and the BMI at the age of 12. It also shows that the gut microbiota, a characteristic predictive of later BMI, precedes excessive weight gain. It suggests that the gut microbiota could have a potential role to help identify children at risk of developing obesity.

Researchers also found some support for the hypothesis that maternal Ow/Ob may influence some of the infant gut microbiota taxa that are associated with later BMI.

Further research studies especially focusing on the specific group of bacteria may also lead to greater explanation and clear understanding of the etiology of obesity. Additional research work would be required to extend these findings to other populations and to explore how the patterns may vary with early-life exposures.

• What is already known on this topic
  Epilepsy is a chronic disease of the central nervous system affecting more than 70 million people globally. About 30-40% of epilepsy patients are resistant to minimum two or more types of antiepileptic medications. This condition is known as drug-resistant epilepsy and it causes a great socio-economic burden to the families and society. Although many new drugs have been discovered, treatments are still limited as the specific mechanisms behind this condition remain unknown.

• What this research adds
  Researchers analyzed the microbiome composition of patients affected by drug-resistant epilepsy and noted that dysbiosis might be playing a vital role in the pathogenesis of this condition.

• Conclusions
  Researchers reported the association between dysbiosis and drug-resistant epilepsy. The gut flora in patients with this condition was characterized by a significant richness of rare bacteria and a decrease in the normal commensal bacteria. Bifidobacteria and Lactobacilli could be considered as a protective factor in epilepsy, and they also help to restore the gut microbial community, which may be considered as a novel therapeutic approach for drug-resistant epilepsy.

Dysbiosis may be involved in the mechanism of drug-resistant epilepsy and that the restoration of the gut microbial community may be a novel therapeutic method for drug-resistant epilepsy. It is the conclusion of a study carried out by Anjiao Peng and colleagues at the Sichuan University, Chengdu, in China, and published in the journal Epilepsy Research.

Gut Microbiome and Central Nervous System disorders

Multiple studies have reported that the gut microbiome is closely connected with the central nervous system, and dysbiosis has been reported in many central nervous system (CNS) disorders such as epilepsy, Parkinson’s disease, multiple sclerosis and Alzheimer disease.

The microbiome regulates the CNS through multiple metabolites, neurotransmitters and inflammatory factors. The CNS, in turn, regulates the gut microbiome through the vagus nerve or the hormonal axis. The interaction between the gut microbiome and the CNS is called the Gut-microbial-brain axis.

Whether the gut microbiome plays a role in the pathogenesis of drug-resistant epilepsy is still not clear. In previously conducted studies, researchers found that ABC (ATP-Binding Cassette) transporters were significantly active in patients with drug-resistant epilepsy. ABC transporters (e.g., P glycoprotein and multidrug resistance associated proteins) constantly pump the drug out of the cell relying on the ATP decomposition, thereby resisting the concentration gradient of the drug.

Since the metabolic pathways of ABC transporters are strongly associated with Ruminococcus and other rare bacteria, it was speculated that the altered microbial community may also play a vital role in the pathogenesis of drug-resistant epilepsy by impairing the synthesis and further metabolism of transporters.

Antiepileptic medications and the disruption of gut microflora

Studies have demonstrated that drugs targeting the nervous system, especially antipsychotics and calcium-channel blockers, exhibit significant anti-commensal activity.

When the normal flora is repressed, it results in abnormal overgrowth of Ruminococcus and other rare bacteria with a high level of ABC transporter metabolism. Conversely, the disruption of gut microflora further leads to a decrease in the absorption of drugs, which weakens the antiepileptic effect of the drug. Therefore, in this case, anti-commensal activity should be considered as one of the side effects of antiepileptic medications, the alleviation of which should be helpful for the therapeutic management of the disease.

Bifidobacteria and Lactobacilli were found to be significantly higher in patients with 4 or fewer seizures per year than those who had more than 4 seizures. These floras were found to be responsible in further promoting the synthesis of gamma aminobutyric acid which is a major inhibitory neurotransmitter. These results demonstrated that Bifidobacteria and Lactobacilli might play significantly protective roles in patients with epilepsy.

In this study, a total of 42 patients with drug-resistant epilepsy (DR), 49 patients with drug-sensitive epilepsy (DS) and 65 healthy controls (HC) were enrolled. To further minimize the dietary impact on the gut flora, all healthy controls were selected from the patients’ families. Oxcarbazepine was the most frequently used drug in both groups, followed by levetiracetam and valproate.

Researchers analyzed the microbiome composition by high-throughput sequencing of the bacterial DNA and reported that dysbiosis might be involved in the pathogenesis of drug-resistant epilepsy.

The results showed that the α-diversity of patients with 4 seizures or fewer per year was similar to that of HC while patients with more than 4 seizures reported significantly higher α-diversity.

The β-diversity analyses showed that the microbiome community of the samples in the DR group was different from that of the DS group.

Drug-resistant epilepsy and altered bacterial gut microbiota

The overall gut microbiome composition was found to be similar between the HC and DS groups at the phylum level with Bacteroidetes being the largest phylum and Firmicutes being the second largest.

In the DR group the abundance of Bacteroidetes was comparatively lower. That of Firmicutes was higher and it was reported as the largest phylum. In contrast, many other rare phyla showed an increased tendency in the DR group. For example, Verrucomicrobia was also more abundant in the DR group than in the DS group and HC group.

The differences in bacterial community structure were further confirmed with the help of a linear discriminant effect size (LEfSe) analysis. Bacteroidetes along with its two genera, Bacteroides and Barnesiell, were considerably present in the DS group, while the flora of the DR group seemed to be characterized by an increased abundance of numerous rare bacteria, including Clostridium XVIII,  Atopobium, Holdemania, Dorea, Saccharibacteria, Delftia, Coprobacillus, Araprevotella, Ruminococcus, Gemmiger, Akkermansia, Neisseria, Coprococcus, Fusobacterium,Methanobrevibacter, Phascolarctobacterium and Roseburia…etc.

A condition where rare bacteria are dominant

Glucose- and lipid-associated metabolic pathways were all down-regulated. The analysis of the relationship between different species and metabolic pathways showed that these pathways were associated with Ruminococcus and other rare bacteria.

These results suggest that the dysbiosis may be involved in the mechanism of drug-resistant epilepsy and that the restoration of the gut microbial community may be a novel therapeutic method for drug-resistant epilepsy.

This study also demonstrates that patients with drug-resistant epilepsy harbor an altered composition of the gut microbiome characterized by a significantly increased abundance of numerous rare bacteria.

The gut microbiota in patients with drug-sensitive epilepsy was found to be similar to that of healthy controls. The microbial community richness in patients with drug-resistant epilepsy was significantly increased as compared to that of patients with drug-sensitive epilepsy and the healthy controls. This may result from an abnormal increase in numerous rare bacteria mainly belonging to the phylum Firmicutes.

Future studies should assess the microbial metabolites and the resulting host response to further shed light on the composition of the gut microbiome in patients with drug-resistant epilepsy.