Metabolic Disease Linked to Instability of the Gut Microbiome

By Frederik Joelving

November 18, 2020

NEW YORK (Reuters Health) - The gut microbiome appears to be largely stable over time in most people, but metabolic disorders such as fatty liver disease and diabetes are associated with increased microbial instability, according to new research.

"Microbial instability is characterized by larger gut microbiome alterations over time and is accompanied by an increase in the amount of facultative pathogenic bacteria such as Escherichia," said Dr. Fabian Frost of University Medicine Greifswald, in Germany.

"Remarkably, individuals who were healthy at baseline but had developed fatty liver disease (and to a lesser extent diabetes mellitus) at follow-up already displayed significant gut microbiota alterations at baseline before the disease was present," he told Reuters Health by email. "This underlines the potential for possible applications of pre- or probiotics to induce shifts in the gut microbiome towards a more beneficial microbiota composition in order to prevent the incidence of metabolic liver disease."

The gut microbiota is critical for human health, and dysbiosis has been linked to a variety of disorders, Dr. Frost and his colleagues note in Gut. Much of the research has been cross-sectional, however.

To investigate the importance of long-term changes in the microbiome, the researchers compared intestinal microbiota profiles based on 16S rRNA gene sequencing of 2,564 paired fecal samples from 1,282 individuals who had participated in the Study of Health in Pomerania. The samples were collected at two time points five years apart.

Overall, the microbiome remained stable and dominated by Bacteroides, Prevotella and Faecalibacterium. This was confirmed in an analysis of beta diversity, which indicates how microbiota communities or samples differ from each other.

But there were changes in some individuals suggesting specific microbiota shifts. The presence of fatty liver disease or diabetes was associated with significant changes in the fecal microbiome, as was the level of hemoglobin A1c. This instability, in turn, was linked to an increase in facultative pathogens such as Enterobacteriaceae, Escherichia/Shigella and Citrobacter.

The researchers note that "greater microbiota instability with increased abundance of these potential pathogens may have harmful consequences for its human hosts by increasing the risk for localized or systemic infections."

"Moreover," they add, "at follow-up the predicted microbial pathways for LPS (lipopolysaccharides) biosynthesis were increased by 27%. This increase was again pronounced in subjects with less stable fecal microbiota composition, for example, diabetics. LPS triggers the production of proinflammatory cytokines and can contribute to the development of (fatty liver disease) and diabetes mellitus."

They also found that people who developed fatty liver disease during follow-up already had changes in Clostridium XIVa, Clostridium XIVb, Collinsella and Oscillibacter and several plasma metabolite levels before diagnosis.

"Clostridium XIVa, which was increased in these individuals, also associated with an increased expression of those microbial pathways necessary for biosynthesis of saturated and unsaturated fatty acids, some of which have been described to promote hepatic lipogenesis or are correlated to increased hepatic lipogenesis," Dr. Frost and his colleagues write. "Whether Clostridium XIVa could serve as a treatment target for prebiotic or probiotic therapy to reduce the incidence of FLD needs to be determined in future interventional trials."

Meanwhile, factors associated with greater microbiome stability were a high initial microbial diversity, female sex, a high household income and preserved exocrine pancreatic function. And some diseases showed no link to microbiome stability.

"Surprisingly," said Dr. Frost, "phenotypes such as atherosclerosis, cardiac function, thyroid dysfunction or renal impairment, which have been described to associate with gut-microbiota changes in other cross-sectional studies, did not associate with the gut microbiota (in-)stability in the long term."

He concluded, "The pathophysiological mechanisms by which metabolic liver disease or diabetes mellitus cause gut microbiome instability are still unclear. We hypothesize that a lack of human antimicrobial peptides, e. g. secreted by intestinal or pancreatic acinar cells, plays a pivotal role in this process. Identification of these peptides and their role in the homeostasis of the gut microbiome may not only reveal novel insights in the gut microbiome physiology but also offer the opportunity to identify new compounds with antibiotic potential."

SOURCE: https://bit.ly/3lEbMPh Gut, online November 9, 2020.

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