A loss of crAssphage stability in the human gut virome is associated with obesity and metabolic syndrome

Abstract

Viral metagenomics studies of the human gut microbiota unravel differences in phage populations between healthy and disease, stimulating interest in the role that phages play in bacterial ecosystem regulation. CrAssphages are not only the most abundant viruses but also are a common component of the gut phageome across human populations. However, the role of crAssphages in obesity (O) and obesity with metabolic syndrome (OMS) remains largely unknown. Therefore, we explored the role that crAssphages have on both diseases in a children's cohort. We found decreased crAssphage abundance, prevalence, richness, and diversity in O and OMS compared to normal-weight (NW), suggesting a loss of crAssphages stability in the human phageome associated with the disease. Interestingly, when we analyzed the abundance of host crAssphages bacteria, we found that Bacteroidetes, Bacteroidia, and Bacteroidales were significantly decreased in O and OMS, suggesting a possible relation with the loss of crAssphages stability. Regarding crAssphage taxonomy, a significantly decreased abundance of the crAssphage Alpha subfamily and the Alpha_1 and Alpha_4 genus and a significant overabundance of the Delta_8 was found in OMS. A strong taxonomical signature of obesity is the over-abundance of Bacilli, which also were significantly increased in O and OMS. Notably, we found a significant negative correlation between crAssphages and Bacilli abundances, suggesting an association between the decreased abundance of crAssphage and the over-abundance of Bacilli in OMS. Furthermore, we found a loss of crAssphage stability in the human virome associated with the presence of obesity, having a more significant impact on obesity with metabolic syndrome, suggesting that these bacteriophages could play an essential role in inhibiting metabolic syndrome in obese individuals. Our results open a promising treatment for these diseases through fecal crAssphage transplantation.

Improvement of crAssphage detection/quantification method and its extensive application for food safety

“…According to previous studies, the intestinal microbiome, especially the abundance of Bacteroides, is affected by intestinal diseases, such as IBS, Crohn's disease, and CRC (Wang et al, 2021;Zafar and Saier, 2021). Moreover, a recent study reported that crAssphage subfamilies showed different stability in the human phageome dependent on the abundance of Bacteroidales in the gut of people suffering from obesity and metabolic syndrome (Cervantes-Echeverria et al, 2022), suggesting that the association between human diseases and crAssphage prevalence may be dependent on the abudance of host species of each crAssphage subfamily. However, those crAssphage-targeting primer/probe combinations cannot discriminate its subfamilies for detection and monitoring at this time.…”

Bacteriophages of the Order Crassvirales: What Do We Currently Know about This Keystone Component of the Human Gut Virome?

“…Indeed, whole-virome analysis of inflammatory bowel disease (IBD) and ulcerative colitis (UC) datasets shows IBD-specific alterations in the gut virome, specifically a loss of crAss-like phages and Microviridae , identifying crAss-like phages as critical components of the core virome in healthy individuals [ 16 ]. Another study reporting loss of phageome stability in disease found reduced abundance and diversity in children with obesity and obesity-related metabolic syndrome [ 15 ]. The fact that a virulent crAssphage core represents a healthy microbiome at equilibrium and that virome dysbiosis can be overcome by FMT highlights the importance of considering the viral portion of a patient’s metagenome when considering FMT therapy [ 38 ].…”

“…As no detrimental associations between human health and the presence of crAssphage have yet been found, it has been deemed a benign entity in the gut microbiome [ 11 , 12 ]. A beneficial role in the human gut has been suggested by observations of depleted crAss-like phage populations in patients with inflammatory bowel disease, and a destabilisation of p-crAssphage is linked to obesity and metabolic syndrome [ 15 , 16 ].…”