Dual role for microbial short-chain fatty acids in modifying SIV disease trajectory following anti-α4β7 antibody administration

Abstract

Background

Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection is associated with significant gut damage, similar to that observed in patients with inflammatory bowel disease (IBD). This pathology includes loss of epithelial integrity, microbial translocation, dysbiosis, and resultant chronic immune activation. Additionally, the levels of all-trans-retinoic acid (atRA) are dramatically attenuated. Data on the therapeutic use of anti-α4β7 antibodies has shown promise in patients with ulcerative colitis and Crohn’s disease. Recent evidence has suggested that the microbiome and short-chain fatty acid (SCFA) metabolites it generates may be critical for anti-α4β7 efficacy and maintaining intestinal homeostasis.

Materials and Methods

To determine whether the microbiome contributes to gut homeostasis after anti-α4β7 antibody administered to SIV-infected rhesus macaques, faecal SCFA concentrations were determined, 16S rRNA sequencing was performed, plasma viral loads were determined, plasma retinoids were measured longitudinally, and gut retinoid synthesis/response gene expression was quantified.

Results

Our results suggest that anti-α4β7 antibody facilitates the return of retinoid metabolism to baseline levels after SIV infection. Furthermore, faecal SCFAs were shown to be associated with retinoid synthesis gene expression and rebound viral loads after therapy interruption.

Conclusions

Taken together, these data demonstrate the therapeutic advantages of anti-α4β7 antibody administration during HIV/SIV infection and that the efficacy of anti-α4β7 antibody may depend on microbiome composition and SCFA generation.

Keywords:

• Anti-α4β7 antibodies
• SIV
• short-chain fatty acid (SCFA)
• 16S rRNA
• retinoic acid
• gut

Acknowledgments

This study was partially supported by the National Institutes of Health grants R21MH113455 and R01 AI129745 to SNB). Additional support was provided by the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014). We thank the UNMC Comparative Medicine Veterinary Staff and SB’s previous and current lab members for contributing to the animal experiments. We also thank the NIH Nonhuman Primate Reagent Resource and NIAID Simian Vaccine Evaluation Unit for providing the abovementioned reagents. We also thank Dr. Aftab Ansari for his critical reading and suggestions for editing the manuscript. Figures 1a and 6 were created using Biorender.com.

Author contributions

SB designed the study. SJ and LK performed animal experiments. NP, JY, and MK determined the retinoid and SCFA concentrations. SJ designed the primers and quantified gene expression. LK determined the plasma VLs. LK and SJ performed microbiome assays. SJ performed additional data analysis, generated the figures, and wrote the manuscript. SB acquired the funding, supervised the study, and edited the manuscript. All authors contributed to the final manuscript editing and approved the final submission.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

16S rRNA sequencing FASTQ files are available in the previously uploaded BioProject in the NCBI Sequence Read Archive under the accession number PRJNA870961. The software and reagents used in this study are included in the Materials and Methods section.