Angiogenin maintains gut microbe homeostasis by balancing α-Proteobacteria and Lachnospiraceae
Authors: Yaxin Liu
Liang Luo
Xiaolong Ge
Wei Zhou
Shasha Tang
Zhengrong Yao
Rongpan Bai
Zhengping Xu
Guo-Fu Hu
Chi Luo
Jinghao Sheng
Desen Sun
Journal: Gut (2021)
Discipline: CLINICAL MEDICINE
Keywords: antibacterial peptide; inflammatory bowel disease; intestinal microbiology.
Affiliations: Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China., Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China., Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Bioelectromagnetics Laboratory, Zhejiang University School of Public Health, Hangzhou, Zhejiang, China., Division of Hematology and Oncology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA., Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China  .

Abstract:  Objective: Antimicrobial peptides (AMPs) play essential roles in maintaining gut health and are associated with IBD. This study is to elucidate the effect of angiogenin (ANG), an intestine-secreted AMP, on gut microbiota and its relevance with IBD. Design: The effect of ANG on microbiota and its contribution to colitis were evaluated in different colitis models with co-housing and faecal microbiota transplantation. ANG-regulated bacteria were determined by 16S rDNA sequencing and their functions in colitis were analysed by bacterial colonisation. The species-specific antimicrobial activity of ANG and its underlying mechanism were further investigated with microbiological and biochemical methods. ANG level and the key bacteria were characterised in IBD faecal samples. Results: ANG regulated microbiota composition and inhibited intestinal inflammation. Specifically, Ang1 deficiency in mice led to a decrease in the protective gut commensal strains of Lachnospiraceae but an increase in the colitogenic strains of α-Proteobacteria. Direct binding of ANG to α-Proteobacteria resulted in lethal disruption of bacterial membrane integrity, and consequently promoted the growth of Lachnospiraceae, which otherwise was antagonised by α-Proteobacteria. Oral administration of ANG1 reversed the dysbiosis and attenuated the severity of colitis in Ang1-deficient mice. The correlation among ANG, the identified bacteria and IBD status was established in patients. Conclusion: These findings demonstrate a novel role of ANG in shaping gut microbe composition and thus maintaining gut health, suggesting that the ANG-microbiota axis could be developed as a potential preventive and/or therapeutic approach for dysbiosis-related gut diseases. 

Retracted: No

PubPeer comments:
 Assessment: Figure 2D shows a bacterial profile, which does not at all agree with conventional wisdom about the gut microbiota. It contains many environmental bacteria (Alpha-proteobacteria, Nitrosphaera, Hydrogenophilales, Thiobacillus, Brevundimonas), and Thaumarchaeota are also not known to inhabit the gut. The authors mention that mice with high alphaproteobacterial count lost more weight than others, which probably indicates also a lower amount of stool biomass, and a higher likelihood for contamination. We posit that the bacterial isolates could potentially be isolated from contamination, but this is unclear. We are aware that the authors have done extensive follow-up experiments to show the effect of the 2 alpha-proteobacterial strains, but their intestinal origin is doubtful in my opinion. Supporting analysis: I performed the following analysis to support the claim that the 2 isolated strains are not a member of the normal mouse microbiota. I downloaded 2 genomes of species, to which the isolates belong, Sphingomonas paucimobilis ZJSH1 and Brevundimonas diminuta ATCC 19146. I downloaded 346 metagenomic samples of the mouse microbiome, each 1GB, from 4 different studies, PRJNA397886, PRJEB7759 PRJNA549182 and PRJEB32890 (The integrated mouse gut metagenome catalog). These reads were mapped with bowtie2 to the 2 mentioned genomes. The highest amount of reads mapping in an individual sample was 681 reads, with on average 26 reads mapping per sample. The Murine Microbiome Database furthermore lists these 2 organisms as only being present in 1 and 10 samples out of 762 in their database, see: u2022http: leb.snu.ac.kr mmdb taxon Brevundimonas%20diminuta%20group u2022http: leb.snu.ac.kr mmdb taxon Sphingomonas%20paucimobilis%20group This seems to be insufficient evidence to support that these 2 organisms are present in the healthy mouse gut. ,