Preprint Persistent SARS-CoV-2 Spike is Associated with Localized Immune Dysregulation in Long COVID Gut Biopsies, 2026, Abraham Soria et al

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Persistent SARS-CoV-2 Spike is Associated with Localized Immune Dysregulation in Long COVID Gut Biopsies

Abraham Soria, Salim; Peterson, Patrick; VanElzakker, Michael B; Tankelevich, Michael; Mehandru, Saurabh; Proal, Amy; Putrino, David; Freire, Marcelo

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Abstract
SARS-CoV-2 persistence is a proposed driver of Long COVID (LC), but the in-situ relationship between residual viral antigen and immune dysregulation remains poorly defined. To address this critical gap, we employed a high-resolution, multi-modal approach—combining RNAscope, GeoMx Digital Spatial Profiling (DSP), spatial transcriptomics, and multiplex immunofluorescence—on 25 terminal ileum and left colon biopsies from a clinical cohort of 8 LC participants and 5 healthy controls.

We confirmed the persistence of SARS-CoV-2 Spike transcript and protein in the gut tissue of all LC cases and controls tested. Yet, comparison of Spike-positive (Spike+) regions in LC versus healthy control colon tissues revealed a differential, symptomatic state-associated signature, with 57 differentially expressed genes (DEGs) (26 upregulated, 31 downregulated), revealing genes that disrupt the immune response in LC subjects.

LC colon Spike+ regions demonstrated increased expression of AQP8 and other absorptive-related genes (SLC26A3, SLC26A2, and CLCA4) which are involved with Crohn′s disease along with transcripts involved in tumorigenesis (GUCA2A, S100P, TSPAN1). Simultaneous downregulation of key homeostatic chemokines (CXCL13, CCL19, CCL21), and other transcripts reported to exhibit low expression in colorectal cancers (TMEM88B, NIBAN3, DMBT1), suggesting a paradox of epithelial tissue stress yet dysfunctional immune trafficking. Further analysis comparing Spike+ versus Spike- regions within LC colon tissue demonstrated an active, localized, antigen-driven immune microenvironment, identifying 122 DEGs (82 upregulated, 40 downregulated), including tumorigenesis genes.

Cellular deconvolution of Spike+ regions revealed a statistically significant focal enrichment of myeloid-derived cells (macrophages, non-classical/intermediate monocytes), plasma cells, and regulatory T cells, coupled with significant enrichment in T-cell-related pathways, including ″Antigen processing and presentation,″ and ″Th1/Th2/Th17 cell differentiation″. The ileum displayed a similar, though less pronounced, signature, demonstrating these statistically significant findings are specific to the colon of LC subjects.

In contrast, corresponding Spike+ vs. Spike- analysis in healthy control colon tissues showed a more modest transcriptional response with 38 DEGs.

Our data provide robust evidence that persistent SARS-CoV-2 Spike protein detection in the gut is not immunologically inert. Instead, it is actively associated with distinct, immune cell composition shifts and a dysfunctional pro-inflammatory transcriptional profile, supporting the hypothesis that retained viral antigen drives chronic immune dysregulation in tissue of Long COVID subjects.

Web | DOI | PDF | bioRxiv | Preprint
 
Alright, so it confirms other findings that fragments of COVID can hang out in the gut long after infection. I think that’s to be expected. They’ve shown that there are some transcriptomic and protein signatures of immune cells being in proximity to the COVID fragments, and they interpret this to mean that the fragments must be immunologically “stimulatory” rather than inert. I think that’s heavily confounded by the fact that the fragments were likely harbored within phagocytic immune cells to begin with. It seems like they only co-stained with a B cell marker so we can’t confirm or deny that (if I’m missing something please let me know)

The main difference they’ve shown between LC and control is that there’s a little more signal specifically from viral RNA in the colon (but not the ileum, and no differences for actual viral proteins). But the remaining evidence here doesn’t really show what differential effect, if any, this has in LC. For all we know, something about the LC disease state just slightly impairs how fast macrophages break down lingering viral RNA fragments over time.

It seems like an interesting question of whether lingering fragments could explain post-COVID GI issues, but I’m not sure if these tools and methods give much to answer it.
 
@jnmaciuch was wondering if you have access to the paper in this thread, the twitter folks seem to be citing both of these studies as viral persistence(I can’t see the below ):
SNT Gatchaman

Thread 'Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID, 2026, Wang et al.'

Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID
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Long COVID has emerged as a significant public health challenge with no effective treatments currently available, yet the pathophysiological mechanisms underlying its persistent gastrointestinal (GI) symptoms remain poorly understood. Here, integrating clinical data with transgenic animal models, we discover a...
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  • Replies: 3
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ChronicallyOverIt said:
@jnmaciuch was wondering if you have access to the paper in this thread, the twitter folks seem to be citing both of these studies as viral persistence(I can’t see the below ):
SNT Gatchaman

Thread 'Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID, 2026, Wang et al.'

Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID
Man Wang; Yi Chen; Ming Guo; Pengzhi Xie; Xinzhe Zhao; Shulin Chen; Yian Deng; Rui Hu; Qianyi Wan; Juanyu Zhou; Zhuzhen Zhang; Ke Lan; Haiyang Chen; Yuan Liu

Long COVID has emerged as a significant public health challenge with no effective treatments currently available, yet the pathophysiological mechanisms underlying its persistent gastrointestinal (GI) symptoms remain poorly understood. Here, integrating clinical data with transgenic animal models, we discover a...
  • SNT Gatchaman
  • dysbiosis fatty acids fenofibrate gastrointestinal gut gut dysbiosis lipid metabolism lipids peroxisome phenylbutyrate ppar
  • Replies: 3
  • Forum: Long Covid research
Click to expand...
Whatever their findings of spike protein-induced dysregulation, it would only matter if something was differential between LC and healthy controls. That study has one finding showing that nucleocapsid protein fragments were only found in LC. That directly contradicts this study, where all other fragments measured were at pretty close levels between LC and control. So whatever they're finding, it doesn't explain why people with LC have those symptoms and other people with prior COVID infection don't when those fragments are definitely also present in recovered controls.

Maybe nucleocapsid specifically makes the difference, but I can't see how.
 
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