Pam Harrison

July 09, 2015

ATHENS, Greece — The composition of the oropharyngeal virome in patients with schizophrenia differs from that of healthy persons, and understanding the pathologic consequences of these differences may open up new avenues for therapeutic intervention, new research suggests.

Robert Yolken, MD, Johns Hopkins School of Medicine, Baltimore, Maryland, and colleagues found that a single bacteriophage — Lactobacillus phage phi-adh — was more likely to be present and to be present in higher concentrations in the oropharyngeal virome of patients with schizophrenia compared with control individuals.

Bacteriophages are viruses that infect bacteria and alter their metabolism and replication.

When present in patients with schizophrenia, levels of Lactobacillus phage phi-adh correlated with a higher prevalence of immunologic disorders as well.

Intriguingly, none of the patients with schizophrenia in the study who were taking valproate had evidence of this particular bacteriophage, in contrast with about half of those who were not taking valproate.

In animal models, valproate acid has been shown to alter the microbiome, although its mechanism of action in patients with schizophrenia has not been fully elucidated.

"We don't yet know if this particular bacteriophage is altering the microbiome in any way," Dr Yolken told Medscape Medical News.

"But we can say that patients presenting to our study with a diagnosis of schizophrenia had certain changes in their microbiome, and one of the changes was the presence of this particular bacteriophage," he added.

"And the biological consequences of this difference and the potential effect of altering bacteriophage levels through therapeutic interventions are worthy of further investigation."

The study was presented here at the 12th World Congress of Biological Psychiatry.

Probiotics a Potential Treatment?

According to Dr Yolken, studies have clearly demonstrated that alterations in the microbiome can profoundly affect both cognition and behavior in rodents.

Changes in the bacterial and viral composition of the intestinal tract also alter the ability of molecules to cross the blood-brain barrier, which has clear implications in a range of neurologic and psychiatric disorders.

However, most studies to date have focused on the bacterial components of the microbiome, and focusing only on bacteria misses out on the possible contribution that viruses ― including viruses that infect bacteria ― fungi, and protozoa could make to different pathologic processes, said Dr Yolken.

Using metagenomic analysis, the investigators set out to characterize bacteriophage genomes in the oral pharynx of 41 patients with schizophrenia and 33 control participants who had no psychiatric diagnosis.

Of more than 100,000,000 sequence reads generated from each sample, investigators identified 79 distinct bacteriophage sequences in the oropharyngeal samples.

Of these, one bacteriophage genome, Lactobacillus phage phi-adh, was present in 17 of 41 (41.5%) patients with schizophrenia compared with just 1 of 33 (3.3%) control individuals (P < .001).

The differential levels of this single bacteriophage remained significant when controlling for age, sex, race, socioeconomic status, and cigarette smoking (P < .006).

As Dr Yolken observed, patients with schizophrenia in general have a higher rate of comorbid immunologic diseases.

In patients with schizophrenia in his own study, 9 of 17, or almost half of the cohort who had evidence of Lactobacillus phage phi-adh, also had a comorbid immunologic disorder.

Immunologic disorders included type 1 and type 2 diabetes and Crohn's disease.

Furthermore, none of the six patients with schizophrenia being treated with valproate had evidence of Lactobacillus phage phi-adh in their oral pharynx.

In contrast, 17 of 35 patients with schizophrenia who were not receiving valproate had evidence of the bacteriophage (P = .026).

"Valproate is clearly an effective medication in some patients with schizophrenia, even though the mode of action is not really well known," Dr Yolken noted.

"So the possibility that medications that are changing the virome or the microbiome and altering behavior or having their effects based on these changes is an intriguing idea, because if we could figure out how they are affecting the microbiome, we could develop better drugs with lower degrees of toxicity than valproate."

The primary host bacteria for Lactobacillus phage phi-adh is Lactobacillus gasseri.

Lactobacillus gasseri is a common component of the oral and gastrointestinal mucosa and is capable of binding to intestinal epithelium.

It is also a common component of foods and probiotic preparations.

Interventions directed at decreasing the carriage rate of Lactobacillus phage phi-adh and its host bacteria in patients with schizophrenia may include probiotic or prebiotic preparations or narrow-spectrum antibiotics, all of which can alter the microbiome, said Dr Yolken.

Intriguing Findings

Asked by Medscape Medical News to comment on the study, session chair James Kennedy, MD, director of molecular brain science, Centre for Addiction and Mental Health, Toronto, Ontario, called the findings "very intriguing" in that they suggest there is a balance between bacteria and viruses in the gastrointestinal tract in healthy individuals but an apparent imbalance in patients with schizophrenia, in light of the fact that a significant proportion of the study group harbored the Lactobacillus phage compared with very few control persons.

"What needs to be looked at now is the relationship of this Lactobacillus phage to the life course of schizophrenia, because young people show no symptoms of the disorder until they reach their high school years," Dr Kennedy suggested.

The strongest risk factor for schizophrenia is still genetics, he emphasized.

However, a working hypothesis for how an altered microbiome might affect the development of schizophrenia is that the bacteriophage sets up an inflammatory response in its bacterial host, and inflammatory molecules that arise from this interaction eventually cross the blood-brain barrier, as they have been shown to do in rodents.

If that process takes place in a genetically vulnerable adolescent, inflammatory molecules could interact with a person's genetic susceptibility to foster the disorder.

"What we do know from human brain development is that just after puberty, the brain undergoes a pretty large-scale pruning of neurons that are not being used," Dr Kennedy said.

"So the adolescent brain starts to refine itself and take on its adult format, and if that process, which is rather delicate, is upset by changes in the microbiome that hit the brain with cytokines and other kinds of inflammatory molecules during adolescence, that could be one of the mechanisms by which the microbiome contributes to or, in the most extreme case, causes schizophrenia."

The study was funded by the Stanley Research Medical Institute. Dr Yolken and Dr Kennedy report no relevant financial relationships.

12th World Congress of Biological Psychiatry. Abstract S-37:004. Presented June 17, 2015.

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