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Anorexia Nervosa Linked to Altered Gut Microbes, Blood Metabolites

NEW YORK – An international team led by investigators at the University of Copenhagen and other centers in Denmark has uncovered ties between anorexia nervosa, the community of bacteria and viruses found in the gut, and the presence of microbe-related metabolite changes in the blood.

"Our 'omics' and mechanistic studies imply that a disruptive gut microbiome may contribute to [anorexia nervosa] pathogenesis," senior and corresponding author Oluf Pedersen, a researcher at the University of Copenhagen and Herlev-Gentofte University Hospital, and his colleagues wrote in Nature Microbiology on Monday.

For the study, the researchers turned to shotgun metagenomics and bioinformatic approaches to profile bacterial and viral representatives in fecal samples from 77 female participants with anorexia nervosa and 70 age- and sex-matched control individuals. In addition, they used gas chromatography time-of-flight mass spectrometry to profile metabolites in blood serum samples and looked for connections with gut microbiome community features.

"[T]he present multiomics study uncovers profound and complex disruptions of the gut microbiota in individuals with [anorexia nervosa], with functional implications and altered serum metabolites," the authors wrote. "These compounds may act via the blood circulation or via gut-microbiota-brain neuronal signaling pathways affecting brain regulation of appetite, emotions, and behavior."

The team's analyses highlighted gut microbiome changes that coincided with anorexia nervosa symptoms and behavior, for example, including changes in genetic variants in gut bacteria, altered representation of bugs in the Clostridium genus, lower-than-usual levels of vitamin B1-producing gut bacteria, and enhanced representation of bacteria from neurotransmitter degradation functional groups. They also observed shifts in Lactococcus phage viruses impacting the intestinal representation of lactic acid-producing bacteria.

"Deficiency of B1 may lead to loss of appetite, various intestinal symptoms, anxiety, and isolating social behavior," co-first author Yong Fan, a researcher at the University of Copenhagen's Novo Nordisk Foundation Center for Basic Metabolic Research, said in a statement, adding that the vitamin B1 and viral particle results "may form the basis of future clinically controlled trials with B1 vitamin supplements and fermented food or probiotics containing various types of lactic acid bacteria."

After delving into in silico interactions between metabolites, microbes, and host traits, meanwhile, the researchers suggested that gut bacteria associated with food intake and psychometric scores are influenced by metabolites such as tryptophan or secondary bile acids that are themselves altered in anorexia nervosa cases.

In a statement, Pedersen suggested that these findings provide a rationale for clinical studies. "In such trials, clinical investigators will likely test the potential effects of an initial antibiotics intervention to reset the aberrant gut microbiome followed by weekly fecal microbiota transplantation (FMT) from young healthy donors for months," he explained, noting that FMT approaches "might be supplemented with B1 vitamin and multi-strain probiotics."

In their own FMT experiments in germ-free mice receiving a calorie-restricted diet or free chow access, the investigators found that stool transplants from patients with anorexia nervosa prompted dramatic physical changes under calorie restriction conditions that were not found in mice transplanted with samples from anorexia-free individuals — changes that were accompanied by gene expression differences detected in hypothalamic, adipose, and brain tissues by RNA sequencing.

"The mice receiving stools from individuals with anorexia nervosa had trouble gaining weight, and analyses of gene activities in certain parts of their brain revealed changes in various genes regulating appetite," Pedersen said in a statement, noting that "mice that had been given stools from individuals affected with anorexia nervosa showed increased activity of genes regulating fat combustion likely contributing to their lower body weight."