A new paper on the blood microbiome of HCV patients might close a gap in our recent work

Our paper on bacterial lipoxygenases has been cited by the group working on a problem of HCV-related cirrhosis. The context of this citation might provide the solution of a long-lasting problem of our project and valuable insights in the role of lipoxygenases in Sphingomonadales bacteria.
A new paper on the blood microbiome of HCV patients might close a gap in our recent work
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medRxiv
medRxiv medRxiv

Altered blood microbiome in patients with HCV-related decompensated cirrhosis

Background Altered bacterial translocation is associated with transitioning from compensated to decompensated cirrhosis. Thus, we aimed to study differences in the blood microbiome of HCV-infected patients with and without hepatic decompensation. Methods We conducted a cross-sectional study in patients with advanced HCV-related cirrhosis with or without human immunodeficiency virus (HIV) infection (n=88). MiSeq Illumina technology for bacterial 16S rRNA sequencing was used. Non-targeted metabolomics was performed by GC-MS and LC-MS ESI+ and ESI-. Results Patients with decompensated cirrhosis had lower levels of richness (Chao1), and alpha diversity (Shannon and Simpson indexes) at phylum level, than patients without decompensation. Likewise, we observed significant differences in beta diversity between groups at phylum, class and order levels, being lower in decompensated cirrhotic patients. Higher relative abundance of Proteobacteria (Fold Change (FC)=1.54, p=0.012), Alphaproteobacteria (FC=1.57, p=0.016) and Sphingomonadales (FC=1.61, p=0.050) were significantly associated with hepatic decompensation. The phylum Proteobacteria was positively correlated with ethanolamine and oleic acid (p=0.005 and p=0.004, respectively) and negatively with p-cresol (p=0.006). In addition, the order Sphingomonadales was also negatively correlated with p-cresol (p=0.001). Conclusions Blood microbial diversity was significantly decreased in patients with decompensated cirrhosis, who presented an enrichment of Proteobacteria, Alphaproteobacteria, and Sphingomonadales, compared to patients with compensated cirrhosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant numbers CP17CIII/00007, PI18CIII/00028 and PI21CIII/00033 to MAJS, PI17/00657 and PI20/00474 to JB, PI17/00903 and PI20/00507 to JGG, and PI17CIII/00003 and PI20CIII/00004 to SR) and Ministerio de Ciencia e Innovacion (PID2021-126781OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” to AFR). The study was also funded by CIBER - Consorcio Centro de Investigacion Biomedica en Red - (CB 2021; CB21/13/00044), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion and Union Europea - NextGenerationEU. CB and DR acknowledge funding from the Ministerio de Ciencia, Innovacion y Universidades (RTI2018-095166-B-I00). MAJS and MR are Miguel Servet researchers supported and funded by ISCIII (grant numbers: CP17CIII/00007 to MAJS and CP19CIII/00002 to MR). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received the approval of the Research Ethics Committee of the Instituto de Salud Carlos III (CEI42\_2020, CEI41\_2014) and was carried out following the Declaration of Helsinki. All participants of the study gave their written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. The raw sequences are publicly available at the European Nucleotide Archive repository (ENA; <https://www.ebi.ac.uk/>) under the accession number PRJEB65371 <https://www.ebi.ac.uk/> * aAMR : Adjusted arithmetic mean ratio AMR : Arithmetic mean ratio ART : Antiretroviral therapy CTP : Child-Turcotte-Pugh ESI : Electrospray ionization FC : Fold Change FDR : False discovery ratio GC-MS : Gas chromatography-mass spectrometry GLM : Generalized linear model HCC : Hepatocellular carcinoma HCV : Hepatitis C virus HIV : Human immunodeficiency virus HVPG : Hepatic venous pressure gradient INR : International normalized ratio LC-MS : Liquid chromatography-mass spectrometry MANOVA : Multivariate analysis of variance OTU : Operative taxonomic Unit PCoA : Principal coordinates analysis PCR : Polymerase chain reaction

That's when a citation of your work suggests a way to close a "blind spot" — a problem in the data that you couldn't solve yourself.

The working group of ESCORIAL study, a Spanish study of HIV-infected patients with HCV-related cirrhosis published a medRxiv preprint [1] citing our paper on bacterial lipoxygenases from 2020 [2]. Earlier, this group successfully published other articles on the same project [3, 4]

The context of the citation is interesting primarily because lipoxygenases are not the focus of the paper at all. The authors studied differences in the blood microbiome in hepatitis C patients having compensated and decompensated cirrhosis. In addition to a depleted microbiome composition and a predominance of Proteobacteria, patients with cirrhosis showed an increased DNA content of bacteria of the order Sphingomonadales in the blood [1].

The catch is that there is not much “compromising material” on sphingomonads from a medical point of view. They have been believed to be just hanging around, not bothering anyone and decomposing oil. Their role in pathogenesis and symbiosis is still poorly elucidated with the exception of one species, Sphingomonas paucimobilis [5]. In search of the explanation of the higher abundance of Sphingomonadales, the authors of the new medRxiv preprint found our article, where we had written about the role of lipoxygenases in the ‘’host-microbe‘’ relationship and drew attention to a whole bunch of lipoxygenases of sphingomonads with unclear functional attribution [2]. The authors have referred to these considerations of ours.

It should be noted that there is no assurance that our sample and that of our colleagues included the same sphingomonads. According to our in-house “lipoxygenase occurrence index” we have implemented in the cited work, sphingomonadales were not among the leaders. This fact  keeps the matter open: a lot of sphingomonads could stay lipoxygenase-negative in our analysis. On the other hand, metagenomic studies usually allow us to explore the microbial composition down to the order or a family level, and the exact listing of species might be impossible. Thus, we cannot be sure that the lipoxygenase-positive set of sphingomonads in our research and the blood-recovered set in the new ESCORIAL paper are the same or even intersect. This suspected link needs careful verification. 

However, in our trees and networks, sphingomonads’ lipoxygenases form a suspiciously large cluster which is located close to the clusters pathogen-related and symbiont-related lipoxygenases. I have elaborated the symbiont-related and pathogen-related clusters in my recent bioRxiv preprint [6] and found additional evidence that these bacteria lipoxygenases could play a role in multiple medical conditions, but we still could not find any explanation of presence of lipoxygenases in sphingomonads.    

With the new preprint of the ESCORIAL study group, the puzzle seems to start fitting together. It shows the possible explanation and the direction of further scientific search in the field of sphingomonadal lipoxygenases. Moreover, this discussion of our findings in a medicine-related paper stresses the importance of my recent preprint [6] where our conclusions regarding lipoxygenases in pathogenic bacteria are corrected and refined. Soon, I will post an additional explainer regarding this research.

Stay tuned! 

I am keeping track of the publishing history of the paper by the ESCORIAL group study and will update this post when it is published formally.

References

  1. Brochado Kith, Ó., Rava, M., Berenguer, J., González García, J., Rojo, D., Diez, C., ... & Jiménez Sousa, M. Á. (2024). Altered blood microbiome in patients with HCV-related decompensated cirrhosis. medRxiv, 2024-05. https://doi.org/10.1101/2024.05.06.24306779
  2. Kurakin, G. F., Samoukina, A. M., & Potapova, N. A. (2020). Bacterial and protozoan lipoxygenases could be involved in cell-to-cell signaling and immune response suppression. Biochemistry (Moscow)85, 1048-1063. https://doi.org/10.1134/S0006297920090059
  3. Salgüero, S., Brochado-Kith, Ó., Verdices, A. V., Berenguer, J., González-García, J., Martínez, I., ... & Resino, S. (2023). PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients: A cross-control study. Biomedicine & Pharmacotherapy159, 114220. https://doi.org/10.1016/j.biopha.2023.114220
  4. Medrano, L. M., Berenguer, J., Salgüero, S., González-García, J., Díez, C., Hontañón, V., ... & Resino, S. (2021). Successful HCV therapy reduces liver disease severity and inflammation biomarkers in HIV/HCV-coinfected patients with advanced cirrhosis: a cohort study. Frontiers in Medicine8, 615342. https://doi.org/10.3389/fmed.2021.615342
  5. Rohilla, R., Raina, D., Singh, M., Pandita, A. K., & Patwal, S. (2021). Evaluation of Sphingomonas paucimobilis as an emerging nosocomial pathogen in a teaching hospital in Uttarakhand. Iranian Journal of Microbiology13(5), 617. https://doi.org/10.18502/ijm.v13i5.7425
  6. Kurakin, G. (2022). Bacterial lipoxygenases are associated with host-microbe interactions and may provide cross-kingdom host jumps. bioRxiv, 2022-06. https://doi.org/10.1101/2022.06.21.497025

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