Interferon-Linked Lipid and Bile Acid Imbalance Uncovered in Ankylosing Spondylitis in a Sibling-Controlled Multi-Omics Study, 2025, Wang et al.

[SNT Gatchaman]

Interferon-Linked Lipid and Bile Acid Imbalance Uncovered in Ankylosing Spondylitis in a Sibling-Controlled Multi-Omics Study

Spoiler: Authors

Wang, Ze; Huang, Yi; Guo, Ziyu; Sun, Jianhua; Zheng, Guoquan

Ankylosing spondylitis (AS) displays wide inter-patient variability that is not accounted for by HLA-B27 alone, suggesting that additional immune and metabolic modifiers contribute to disease severity.

Using a genetically matched design, we profiled peripheral blood mononuclear cells from two brother pairs discordant for AS severity and one healthy brother pair. Strand-specific RNA-seq was analyzed with a family-blocked DESeq2 model, while untargeted metabolites were quantified using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS). Differential features were defined as follows: differentially expressed genes (DEGs) (|log2FC| ≥ 1 and FDR < 0.05) and metabolites (VIP > 1, FC ≥ 1.2, and BH-adjusted p < 0.05). Pathway enrichment was performed with KEGG and Gene Ontology (GO). A total of 325 genes were differentially expressed.

Type I interferon and neutrophil granule transcripts (e.g., IFI44L, ISG15, S100A8/A9) were markedly up-regulated, whereas mitochondrial β-oxidation genes (ACADM, CPT1A, ACOT12) were repressed. Metabolomics revealed 110 discriminant features, including 25 MS/MS-annotated metabolites. Primary bile acid intermediates were depleted, whereas oxidized fatty acid derivatives such as 12-Z-octadecadienal and palmitic amide accumulated. Spearman correlation identified two antagonistic modules (i) interferon/neutrophil genes linked to pro-oxidative lipids and (ii) lipid catabolism genes linked to bile acid species that persisted when severe and mild siblings were compared directly. Enrichment mapping associated these modules with viral defense, neutrophil degranulation, fatty acid β-oxidation, and bile acid biosynthesis pathways.

This sibling-paired peripheral blood mononuclear cell (PBMC) dual-omics study delineates an interferon-driven lipid–bile acid axis that tracks AS severity, supporting composite PBMC-based biomarkers for future prospective validation and highlighting mitochondrial lipid clearance and bile acid homeostasis as potential therapeutic targets.

Web | PDF | International Journal of Molecular Sciences | Open Access

 

[SNT Gatchaman]

Summary quotes —

Although carriage of the class I allele HLA-B27 represents the single strongest genetic risk factor, it explains less than half of the estimated heritability, and its penetrance is highly variable across ethnicities. Genome-wide association studies have extended the risk landscape to dozens of non-HLA loci—chiefly genes involved in antigen presentation, innate immunity and amino-acid metabolism—but how these variants translate into the complex serological and radiographic phenotypes of AS remains incompletely understood.

At the molecular level, circulating cytokine profiles indicate a chronic, mixed innateadaptive inflammatory state typified by TNF-α, IL-17/IL-23, and type I interferon activity. Parallel metabolomic surveys have reported altered lipid β -oxidation, tryptophankynurenine catabolism, and bile acid turnover in the serum or [faeces] of AS patients.

Up-regulated genes were dominated by interferon stimulated genes (IFI44L, ISG15, OAS1) and neutrophil granule markers (S100A8, S100A9, LTF), while key components of mitochondrial energy metabolism (ACADM, CPT1A) were down-regulated.

KEGG pathway enrichment analysis showed that primary bile acid biosynthesis and fatty acid β-oxidation were the most significantly perturbed routes (q < 0.05), followed by linoleic and arachidonic acid metabolism. These metabolomic findings dovetail with the transcriptomic repression of β-oxidation genes and reinforce a model in which chronic inflammation in AS is accompanied by impaired bile acid homeostasis and the accumulation of lipid peroxidation products.

associations suggest that vascular signaling genes interface with inflammatory lipid mediators and that impaired ACOT12 parallels bile acid depletion.

Taken together, the integrative analysis indicates that chronic interferon/neutrophil activation in AS is metabolically coupled to accumulated lipid peroxidation products and attenuated bile acid biosynthesis, providing a mechanistic bridge between the transcriptomic and metabolomic layers.

Elevated IFI44L, ISG15, and OAS1 mirror transcriptomic patterns reported in psoriatic arthritis and severe COVID-19, suggesting convergent antiviral-like activation. Simultaneously, strong induction of S100A8/S100A9 and LTF underscores the contribution of primed neutrophils, which have been linked to radiographic progression in AS. The GSEA enrichment of “type-I interferon signaling pathway” and “neutrophil degranulation” therefore positions antiviral defense and granulocyte activation as central, interconnected drivers of systemic inflammation in our subjects.

Down-regulation of mitochondrial lipid catabolism genes (ACADM, CPT1A, ACOT12) coincided with negative GSEA enrichment of “fatty acid β -oxidation” and elevated circulating aldehydes, oxylipins, and long-chain fatty acid amides.

Oxidized lipids correlated positively with neutrophil/interferon genes and negatively with β-oxidation transcripts, whereas primary bile acids showed the opposing pattern. Collectively, the data suggest that inefficient mitochondrial β-oxidation might favor peroxisomal or non-enzymatic oxidation, thereby expanding an inflammatory lipid pool that feeds back into innate immune activation.

Primary bile-acid species […] were uniformly reduced in AS PBMCs and inversely correlated with neutrophil granule transcripts. Beyond fat absorption, bile acids act as immunomodulators through FXR and TGR5 receptors, suppressing NLRP3 inflammasome activity and IL-17 production.

Reduced bile-acid availability could therefore remove a brake on pathologic innate immunity. Whether this depletion reflects hepatic synthesis defects, microbial dysbiosis, or altered enterohepatic circulation in AS remains to be established, but it offers a mechanistic bridge between gut involvement and systemic inflammation that characterizes the spondylarthritis spectrum.

Together, these results define an interferon-linked lipid–bile acid axis that mechanistically joins immune activation to metabolic stress in AS

 

[Hoopoe]

Interesting because my ACADM enzyme activity is about half that of a normal person due to an unambiguously pathogenic variant on one allele. Allegedly this does not cause significant problems but I was never fully convinced the effect was zero in my case.

 

[SNT Gatchaman]

Posting due to previous discussions relating to Ank Spond and the potential for broadly similar mechanistic explanations that might be seen in ME. Eg

My hope is that with genetic data we will not only have a key to understanding exactly why things are going wrong in ME/CFS but that will have major knock on effects on understanding of diseases like lupus, ankylosing spondylitis and narcolepsy/cataplexy.

 

[SNT Gatchaman]

In Multi-omic insights from a multi-ancestry genome-wide meta-analysis of ankylosing spondylitis reveal novel pathways of disease susceptibility (2025) —

rs4848370 (nearby ACOXL) OR = 0.92, p 8x10-12

ACOXL (Acyl-CoA Oxidase Like) is a Protein Coding gene. […] Among its related pathways are Metabolism and Peroxisomal protein import. Gene Ontology (GO) annotations related to this gene include flavin adenine dinucleotide binding and acyl-CoA dehydrogenase activity. An important paralog of this gene is ACOX3.

 

[Yann04]

Posting due to previous discussions relating to Ank Spond and the potential for broadly similar mechanistic explanations that might be seen in ME.

Is there a way we can compare genetic similarity using the DecodeME data? Not just by looking at top hits, but an average maybe?

I like the idea Ank Spond is related to ME, because in my case it kinda fits the story, both grandma and uncle have it.