Tag Archives: Leucine

Can a disrupted gut microbiota contribute to anorexia nervosa pathogenesis?

if (g_displayableSlots.mobileTopLeaderboard) {
pushDisplayAd(function() { googletag.display(‘div-gpt-mobile-top-leaderboard’); });

In a recent study published in the journal Nature Microbiology, researchers investigated whether intestinal microbial alterations contribute to anorexia nervosa (AN) pathogenesis.

AN, a disorder associated with altered eating, has caused considerable mortality, especially among women. However, therapies based on scientific evidence are scarce. AN pathogenesis likely involves several environmental and genetic factors. Studies have reported intestinal microbial dysbiosis among AN-affected individuals. However, data were obtained from small sample sizes, and genus-level microbial alterations were analyzed by amplicon sequencing.

Study: The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice. Image Credit: Tatiana Shepeleva / ShutterstockStudy: The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice. Image Credit: Tatiana Shepeleva / Shutterstock

About the study

In the present study, researchers assessed the association between the intestinal microbiome and AN.

The team performed metabolomics and shotgun metagenomic analyses on serum and fecal samples, respectively, that were obtained from women with AN (n=77) and age- and sex-matched healthy controls (n=70). Further, the fecal microbiome was transplanted from anorexia nervosa cases to murine animals fed calories-limited diets over three weeks to simulate AN eating behavior for in vivo analysis. In addition, the team explored causal associations in silico by bidirectional mediation analysis. The intestinal microbiome was analyzed at functional, taxonomic, and genetic levels.

The team used the eating disorder inventory-3 (EDI-3) questionnaire to assess eating behaviors and insulin resistance was assessed using the homoeostatic model assessment for insulin resistance (HOMA-IR) tool. The team examined covariations between bacterial abundance at species and genus levels and clinical variables for AN cases and controls. Linear regression modeling was performed, adjusting for confounders such as age, smoking status, medications, and body mass index (BMI).

Further, the team evaluated the growth dynamics of gut bacteria by calculating peak-to-trough ratios (PTR) using the metagenomic dataset. The functional modules of gut bacteria were identified using gut-brain modules (GBMs) and gut metabolic modules (GMMs). Differences in bacterial genomics were explored based on the Canberra distance of bacterial structural variant profiles.

​​​​​​​Graphical abstract of the study workflow and findings.

if (g_displayableSlots.mobileMiddleMrec) {
pushDisplayAd(function() { googletag.display(‘div-gpt-mobile-middle-mrec’); });


Several bacterial organisms (including Clostridium) were altered among individuals with anorexia nervosa and were associated with mental well-being and eating behavior estimates. Bacterial functional-type modules related to neurotransmitter degradation were enriched among those with anorexia nervosa. Further, several structural variants (SVs) in bacterial organisms were associated with the metabolic characteristics of anorexia nervosa.

The findings indicated a probable role of the intestinal microbiome in AN-associated changes concerning satiety and the metabolism of secondary bile acids. The metabolomic analysis indicated an elevation in metabolites linked to lowered food consumption (including taurine-hyodeoxycholic acid, taurine-α-muricholic acid, and indole-3-propionic acid molecules). Causal inference analysis indicated that serological bacterial metabolites probably mediate the effect of gut microbial alterations on anorexia nervosa. At the phylum level, AN microbiome samples showed lowered Actinobacteriota and Bacteroidota counts. Among families of bacteria, Christensenellaceae species, particularly CAG-138, showed the most significant enrichment in AN.

At the genus level, elevated Lactobacillus counts were observed in the AN microbiota. The Ruminococcacea-enterotype was more prevalent in cases of AN. Species-level analysis indicated greater β-diversity among AN-affected women. In AN, Roseburia inulinivorans and Roseburia intestinalis were depleted, whereas those of Erysipelatoclostridium ramosum, Blautia species CAG, and Enterocloster bolteae innocuum (Clostridium) were increased. Clostridium counts correlated positively with eating disorder scores. The abundance of Bifidobacterium and Parasutterella, in absolute terms, showed positive correlations with perfectionism and body dissatisfaction, respectively.

Absolute Brachyspira count showed a positive association with ‘drive for thinness’ markers in anorexia nervosa. Median values for PTR markedly differed between individuals with AN and controls. Women with AN were leaner, had lower fasting serological insulin, glucose, and C-reactive protein (CRP) levels, and were more sensitive to insulin than controls. Bacterial organisms with significant growth retardation, among AN case individuals included Alistipes finegoldii, Akkermansia muciniphila, Eubacterium siraeum, Coprococcus catus, SS3/4, and Odoribacter splanchnicus.

In addition, the intestinal virome was altered among AN-affected individuals, including lowered bacterial-viral interactions, due to attenuated interactions of viruses with short-chain fatty acid (SCFA)-producing bacteria, including Roseburia inulinivorans, Roseburia hominis, and Faecalibacterium prausnitzii. The team observed greater viral richness and Shannon diversity in the fecal samples of AN cases compared to controls. Notably, 25/30 viruses increased in AN were Lactococcus bacteriophages. The abundance of GBMs for serotonin synthesis and degradation of tryptophan, glutamate, and dopamine, were enriched in AN.

The team detected 2,423 and 5,056 variable SVs and deletion SVs, respectively, across 56 species of bacteria, including Bacteroides uniformis, Faecalibacterium prausnitzii, Parabacteroides distasonis, Methanobrevibacter smithii. Individuals with AN lacking the genomic region of B. uniformis had greater scores for self-denial and bulimia. The genetic deletion in B. uniformis could result in the deficiency of thiamine, a vitamin associated with intestinal and mental health. The serotonin synthesis module causally affected BMI through glycoursodeoxycholic acid, which is upregulated by serotonin.

Serum leucine mediated the influence of B. vulgatus counts on glucose homeostasis. Mice receiving AN individuals’ fecal transplants initially lost more weight with a slower gain of weight with time than those receiving fecal transplants of control individuals. The finding was related to greater levels of hypothalamic appetite-suppressing genes and thermogenesis-associated genes in the adipose tissues of mice receiving fecal transplants from individuals with AN.

Based on the study findings, gut microbial disruptions may contribute to the pathogenesis of AN.

if (g_displayableSlots.mobileBottomLeaderboard) {
pushDisplayAd(function() { googletag.display(‘div-gpt-mobile-bottom-leaderboard’); });

Journal reference:

Simple blood tests for telomeric protein could provide a valuable screen for certain cancers

Once thought incapable of encoding proteins due to their simple monotonous repetitions of DNA, tiny telomeres at the tips of our chromosomes seem to hold a potent biological function that’s potentially relevant to our understanding of cancer and aging.

Reporting in the Proceedings of the National Academy of Science, UNC School of Medicine researchers Taghreed Al-Turki, PhD, and Jack Griffith, PhD, made the stunning discovery that telomeres contain genetic information to produce two small proteins, one of which they found is elevated in some human cancer cells, as well as cells from patients suffering from telomere-related defects.

Based on our research, we think simple blood tests for these proteins could provide a valuable screen for certain cancers and other human diseases. These tests also could provide a measure of ‘telomere health,’ because we know telomeres shorten with age.”

Jack Griffith, PhD, the Kenan Distinguished Professor of Microbiology and Immunology and Member of the UNC Lineberger Comprehensive Cancer Center

Telomeres contain a unique DNA sequence consisting of endless repeats of TTAGGG bases that somehow inhibit chromosomes from sticking to each other. Two decades ago, the Griffith laboratory showed that the end of a telomere’s DNA loops back on itself to form a tiny circle, thus hiding the end and blocking chromosome-to-chromosome fusions. When cells divide, telomeres shorten, eventually becoming so short that the cell can no longer divide properly, leading to cell death.

Scientist first identified telomeres about 80 years ago, and because of their monotonous sequence, the established dogma in the field held that telomeres could not encode for any proteins, let alone ones with potent biological function.

In 2011 a group in Florida working on an inherited form of ALS reported that the culprit was an RNA molecule containing a six-base repeat which by a novel mechanism could generate a series of toxic proteins consisting of two amino acids repeating one after the other. Al-Turki and Griffith note in their paper a striking similarity of this RNA to the RNA generated from human telomeres, and they hypothesized that the same novel mechanism might be in play.

They conducted experiments – as described in the PNAS paper – to show how telomeric DNA can instruct the cell to produce signaling proteins they termed VR (valine-arginine) and GL (glycine-leucine). Signaling proteins are essentially chemicals that trigger a chain reaction of other proteins inside cells that then lead to a biological function important for health or disease.

Al-Turki and Griffith then chemically synthesized VR and GL to examine their properties using powerful electron and confocal microscopes along with state-of-the-art biological methods, revealing that the VR protein is present in elevated amounts in some human cancer cells, as well as cells from patients suffering from diseases resulting from defective telomeres.

“We think it’s possible that as we age, the amount of VR and GL in our blood will steadily rise, potentially providing a new biomarker for biological age as contrasted to chronological age,” said Al-Turki, a postdoctoral researcher in the Griffith lab. “We think inflammation may also trigger the production of these proteins.”

Griffith noted, “When you go against current thinking, you are usually wrong because you are bucking many people who’ve worked so diligently in their fields. But occasionally scientists have failed to put observations from two very distant fields together and that’s what we did. Discovering that telomeres encode two novel signaling proteins will change our understanding of cancer, aging, and how cells communicate with other cells.

“Many questions remain to be answered, but our biggest priority now is developing a simple blood test for these proteins. This could inform us of our biological age and also provide warnings of issues, such as cancer or inflammation.”

Journal reference:

Al-Turki, T., et al. (2023) Mammalian Telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins. PNAS. doi.org/10.1073/pnas.2221529120.