Researcher Details Microbiome Mysteries Connecting the Gut, Brain

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Our knowledge of the human microbiome has only been developed over the past decade, according to Elaine Hsaio, PhD, assistant professor of integrative biology and physiology at the University of California, Los Angeles (UCLA), at the 73rd Annual Scientific Convention of the Society of Biological Psychiatry meeting in New York City, May 10 to 12.

Hsaio, a winner of numerous scientific awards who has created a TED talk about the topic, presented about how the microbiome influences brain function, development and behavior.

She started by noting that more than 1000 human microbes exist, compared to the 16 “priority” pathogens declared by the CDC.

An infant inherits its microbiome from its mother, and in humans, this microbiome is mature by 3 years, said Hsaio. The microbiome exhibits structure, stability, and resiliency, and there are differences in infants born via vaginal birth compared to cesarean section births, leading to some conjecture as to whether the rise in chronic disease is linked to the rise in cesarean births, because the microbiome differs between the 2 types.

Microbiobes also produce or modulate several hundred biochemicals in the body, including ones needed for digesting complex polysaccharides that regular human cells do not digest, as well as for processing some drugs used in neurological diseases.

Microbes interact with their host to influence brains and behavior, including social interaction, anxiety-like behavior, learning and memory, appetite and satiety, emotional regulation, aging, locomotion, and communication. But these behaviors can also be altered if microbes are altered by the environment (for example, if the host is raised in a germ-free [GF] environment).

To study this, researchers examine mice raised in GF environments, which will exhibit abnormal behavior compared to those that are not. Gene expressions in those animals will be different, she said.

When Hsaio was at the California Institute of Technology, she published work in 2013 in Cell that first garnered attention, partly because of its implications for autism spectrum disorder (ASD).

The team treated vocally deficient offspring of maternal mice with the human commensal Bacteroides fragilis, and corrected gut permeability, altered their microbial composition, and fixed defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors.¹

The study suggested a gut-microbiome-brain connection in a mouse model of ASD and identified a potential probiotic therapy for GI and particular behavioral symptoms in ASD and other neurodevelopmental disorders.

Colleagues in her UCLA lab, as well as other researchers, are now studying microbes in autism, depression and multiple sclerosis.

And in another study, scientists discovered the absence of gut microbiota in GF mice resulted in decreased immobility time in the forced swimming test relative to healthy control mice.²

The GF mice had been altered with fecal microbiota transplants from human subjects with major depressive disorder (MDD) and showed depressive behaviors.

Clinical samples showed the gut microbiotic compositions of MDD patients and healthy controls were significantly different, with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria, and Bacteroidetes.

Mice with “depression microbiota” primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism.

In another study by another researcher, offspring of maternal mice fed a high-fat diet show problems with social interaction with other mice and also exhibit differences in oxytocin expression.

A similar study was recently done by transplanting mice with fecal transplants from patients with Parkinson disease; the mice then display motor problems.

All in all, many conditions are now traced to microbiome abnormalities, including addiction, allergies, anxiety, autism, depression, epilepsy, multiple sclerosis, Parkinson, schizophrenia, and probably more, but the molecular underpinnings are not well understood.

This effect is also seen in the treatment of children with epilepsy who are resistant to drug therapy but who respond to a ketogenic diet. The diet has been used for about 100 years and is already integrated into clinical practice, she said. Hsaio’s lab wanted to see if the microbiome changes as a result.

The diet, described as a last resort, is difficult to follow, she said.

They replicated the effect with GF mice and showed that the diet seemed to decrease seizures through the action of gamma glutamylated ketogenic amino acids, which influence neurotransmitters. The effect is lost, however, if the mice are treated with antibiotics.

The study is in press.

Reference

1. Hsiao EY, McBride SW, Hsien S, et al; Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451-1463. doi.org/10.1016/j.cell.2013.11.024

2. Zheng P, Zeng B, Zhou C, et al; Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21(6):786-796. doi:10.1038/mp.2016.44