Microbiome May Identify New Types of Hypertension

Caroline Helwick

September 10, 2019

NEW ORLEANS — Hypertension accompanied by depression may be an entirely different disorder from hypertension that develops in persons without depression, an analysis of the gut microbiome suggests.

University of Florida researchers have identified differences in the gut's microbiota — bacterial makeup — that distinguish four groups of people: those who have hypertension and depression, those with hypertension without depression, those with depression without hypertension, and healthy persons who do not have either disorder.

"We believe we have uncovered new forms of high blood pressure," said lead investigator Bruce R. Stevens, PhD, professor of physiology and functional genomics, medicine, and psychiatry at the University of Florida College of Medicine, Gainesville.

"Our hypothesis was based on the fact that humans are 'meta-organisms' engaged in bidirectional interactions with each personal microbiome ecology, coupled with the idea that hypertension is a mosaic of diseases, not a single entity," he said.

"Depressive hypertension may be a completely different disease than nondepressive hypertension, and these are both different from nonhypertensive depression. In the future, health professionals may target your gut in order to prevent, diagnose, and selectively treat different forms of hypertension," Stevens said here at the American Heart Association's Hypertension 2019 Scientific Sessions.

Novel Technique

The investigators collected stool samples from 95 volunteers who had been diagnosed with hypertension and/or a depressive disorder, as well as from healthy persons who did not have either condition. To analyze the stool microbiome, they obtained data via initial 16S rRNA gene amplicon sequence analyses, then conducted extensive whole-genome metagenomic shotgun sequencing analyses.

"We put these analyses together to come up with a new physiological model of hypertension. But we had to invent a novel technical approach," Stevens said.

"We identified amplicon sequence variant [ASV] prevalences at single-nucleotide resolution, then used a machine-learning high-throughput pipeline to pull data out of 'noise.' Our technique transcends many of the inherent errors of the widely used traditional operational taxonomic unit (OTU) relative abundances," he explained. The machine-learning component was devised by Eric Triplett, PhD, and Luiz Roesch, PhD.

Of more than 3000 genes, the researchers identified 86 prevalent ASV sequences that were relevant in distinguishing these four clinical entities.

"With 95% confidence, we were able to identify, from stool samples, whether a person belonged to a cohort with hypertension, depression, or both," Stevens reported.

The analyses revealed four significantly different (P < .05) patterns of taxa and bacterial genes encoding pathways for signature molecules. The molecules are known to be associated with gut barrier leakiness, inflammation of brain centers for blood pressure and mood, metabolism, and the cardiovascular/renal system.

"No matter how we sliced and diced the data, we always came up with discrete populations," he said. "We can identify completely distinct cohorts with different clinical phenotypes identified by their microbiota ecology and metabolic pathways."

Depressive Hypertension

The cohort with depressive hypertension demonstrated a microbiome ecology that contained bacteria previously associated with depression or hypertension. In contrast, the nondepressive hypertension microbiome ecology was different. Both were different from that of healthy reference participants.

"The depressive hypertension phenotype is accompanied by bacteria and metabolic pathways that are consistent with untoward events," he noted.

These metabolic pathways involve, among other things, tyrosine degradation, which down-regulates catecholamine biosynthesis; beta-alanine catabolism, which augments depression and anxiety; short-chain fatty acid degradation, which leads to "leaky gut"; and an enzyme, DapE, which generates inflammation-inducing molecules. Interestingly, the antihypertensive angiotensin-converting enzyme inhibitor captopril exerts potent antibiotic activity by killing gut bacteria via binding to DapE.

Healthy reference taxa were dominated by Blautia obeum and Collinsella aerofaciens. The metabolic pathway for this cohort reflected processes that stabilize the gut barrier, regulate the immune system, are anti-inflammatory, and generate beneficial bioactive amines.

"Our technique identifies hypertension and depression risks based on gut bacterial genes," Stevens concluded. "The take-home message is that the gut microbiome, and the gut itself, should be clinical targets of hypertension and depression management."

Study coauthor Carl Pepine, MD, has launched clinical trials using antibiotics to treat treatment-resistant hypertension, he added.

Intriguing to Hypertension Specialists

Hypertension specialists found the data provocative. Christopher Wilcox, MD, director of the Hypertension Research Center, Georgetown University Medical Center, Washington, DC, called the research "brilliant, highly creative, and novel" and commented, "If this pans out, it's the beginning of something.

"He's identified some important potential pathways that we were not aware of, and some new disease groupings. I will start thinking about these relationships and what they mean," Wilcox told Medscape Medical News.

Willie E. Lawrence Jr, MD, chief of cardiology at Research Medical Center, Kansas City, Missouri, was not surprised to hear that the gut was involved in hypertension.

"We've always thought of sodium handling as it occurs in the kidney, but from the GI literature, we understand a lot of sodium handling also occurs in the GI tract. The gut flora can influence how sodium is handled," he said in an interview.

"We keep focusing on the same mechanisms for dealing with resistant hypertension. It may be that this hypertension is not solely related to what's going on in the kidneys but also the GI tract. The study points to the fact that we don't necessarily need a shotgun approach to managing hypertension. It may be there are new targets through manipulating GI mechanisms.

"It's great to think outside the box and expand our thought process about a disease we have been managing for decades," Lawrence added. "This is an important paper, and it's opened my eyes."

The study was funded by the National Heart, Lung, and Blood Institute, the University of Florida Clinical and Translational Science Institute, and the Department of Physiology and Functional Genomics at the University of Florida. Stevens, Wilcox and Lawrence have disclosed no relevant relationships.

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