Commensal gut bacteria and virus are a contributing cause of anorexia nervosa

Marked changes of the intestinal ecosystem of bacteria and virus may contribute to some stages of the progression and retention of anorexia nervosa.
Commensal gut bacteria and virus are a contributing cause of anorexia nervosa
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In individuals who develop a disorder within the spectrum of anorexia nervosa, the award system of the brain is changing to first prioritize weight loss causing extreme changes of behavior. 

Nine of 10 cases are females, and in girls anorexia characteristically debuts around puberty where a natural reshaping of the female body occurs. In cases, who in this transition between childhood and adulthood develop anorexia, the person perceives herself as overweight or 'odd-shaped' even though this is not necessarily true. Thoughts related to food, physical exercise, appearance, body weight and shape take over in an obsessive way and the affected eats less and less and starts intensifying daily exercise. When the body weight reaches a level that is 15% below normal weight for age and sex, the case fulfill the criterion for the diagnosis of anorexia nervosa.

During undernutrition and higher energy combustion, major changes occur in whole body metabolism and related hormonal systems. In addition, parts of brain activities controlling social behavior, personality and appetite are altered and the affected person suffers to an increasing extent of various obsessions, anxiety, fatigue, sleep problems, and in girls of menstrual disorders.

The heritability of anorexia is about 50%, and the etiology involves a complex interplay between multiple susceptibility genomic variants and environment including trendsetting impulses from cultural and social phenomena like skinny models and general attitudes in the population to what is considered overweight or an attractive body image.

At a global level, an average of about 1% of teenagers and women suffer from anorexia and about 20% turns into a chronic and not seldom a life-threatening disease course. The incidence of anorexia nervosa is too upward.

In most parts of the world, a multidisciplinary team of medical specialists, psychologists, dietitians and family counselors offers conventional care to the affected. No specific medical treatment is available.

Disruption of the gut microbiome and blood bacterial metabolites in anorexia nervosa are associated with personality traits

In the present study, we show that a severe dysbiosis of the gut microbiome may constitute an 'environmental' factor at some stages of the pathogenesis of cases within the spectrum of anorexia nervosa disorders.

We undertook shotgun metagenomics and metabolomics on stool and serum samples, respectively, from 77 females with anorexia and 70 healthy females from Denmark. Abundance of multiple bacterial taxa (for example, Clostridium species) were altered in affected individuals and correlated with estimates of eating behavior and mental health and bacterial functional modules that were associated with degradation of microbiome-produced neurotransmitters were enriched in anorexia cases.

In in silico inference analyses, we observed that changes in serum levels of secondary bile acids and tryptophan metabolites mediate impact of changed abundance of specific bacterial species in anorexia cases on psychometric scores and estimates of eating behavior. 

Analyses of thousands of deletions and variable structural variants in genomes of gut bacterial species indicated that bacterial genetics might influence anorexia-relevant behavioral traits and pathophysiology. Of special interest was a 10-kbp deletion in the Bacteroides uniformis genome that was associated with estimates of bulimia and self-denial. We predicted that this deletion results in the loss of a thiamine-monophosphate kinase-encoding gene, which may result in a relative deficiency of microbiota-produced thiamine.

In addition, the gut virome was altered in anorexia including a reduction in viral–bacterial interactions and a higher viral richness and diversity. Of major interest, 23 of 27 increased viral species in anorexia cases were Lactococcocus phages with known Lactococcus lactis hosts. 

Mechanistic studies in mice

To investigate potential causal relationships between a disrupted gut microbiota and anorexia, we did fecal microbiota transplantation (FMT) from anorexic cases and matched controls to germ-free mice. Ad libitum chow diet feeding did not generate any phenotypic alterations in mice; an observation consistent with a previous report on kwashiorkor. However, when fed a 30% calorie restricted diet for three weeks to mimic reduced food intake in human anorexia nervosa, mice transplanted with stools from anorexic cases showed a larger initial decline in body weight and a slower weight gain over time compared with mice that received  stools from healthy controls. 

Hypothalamic gene expression analysis following FMT showed that anorexia-transplanted and control-transplanted recipients differed in expression of several hypothalamic genes involved in the control of eating behavior and energy expenditure. This included increased expression of the appetite suppressors Bdnf and Cartpt, and the receptor for serotonin, Htr1b (involved in the downstream regulation of serotonin) in anorexia-FMT recipients. In addition, expression of Snca, which encodes the neuronal protein alpha-synuclein associated with several neurodegenerative diseases, was higher in anorexia-transplanted mice.

Further, analyzing mRNA levels of genes encoding proteins regulating adipose tissues thermogenesis we found that abundance of Ucp1, Elovl3 and Pgc1α mRNA was increased in inguinal fat of anorexia-transplanted mice, suggesting enhanced adipose tissue thermogenesis.

Taken together, the present multi-omics study uncovers profound and complex disruptions of the gut microbiota in individuals with anorexia nervosa with functional implications and altered serum metabolites. The bacterial compounds may act via the blood circulation or via gut-microbiota-brain neuronal signaling pathways affecting brain regulation of appetite, emotions and behavior. FMT from human anorexic donors to germ-free mice under energy-restricted feeding resulted in lower body weight gain and a number of changes in expression of hypothalamic and adipose tissue genes involved in controlling behavior and energy homoeostasis. The combination of multi-omics and in vivo experiments complement the in silico causal inference analyses to allow the identification of some of the specific bacterial metabolites that potentially mediate human host anorexia nervosa traits. The findings lend support to the hypothesis that a severely disrupted intestinal microbiota contributes to some of the stages of progression and retention of anorexia nervosa.

Translational perspective

In a translational perspective, the outcome of the present study may add to the rationale to initiate clinically controlled interventions in anorexia nervosa. Such trials might explore the efficacy of FMT from young healthy females administered as a colon installation, an intra-duodenal infusion or freeze-dried tablets once weekly for several months together with oral supplements of thiamine (B1 vitamin) and multi-strain lactic acid bacteria probiotics as adjunctive therapeutics on top of conventional multidisciplinary intervention.

Oluf Pedersen, MD, Doctor of Medical Science, Professor

Yong Fan, PhD, Assistant Professor

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Denmark

Link to original paper: https://www.nature.com/articles/s41564-023-01355-5

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