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. 2025 Aug 22;26(17):8121.
doi: 10.3390/ijms26178121.

Abscopal Brain Proteomic Changes Associated with Microbiome Alterations Induced by Gastrointestinal Acute Radiation Syndrome in Swine

Kathleen Hatch  1   2   3 , Timothy S Horseman  4   5 , Babita Parajuli  4   5 , Erin K Murphy  1   2   3 , Robert N Cole  6 , Robert N O'Meally  6 , Daniel P Perl  1   2 , David M Burmeister  4   5 , Diego Iacono  1   2   3   7   8
Affiliations

Abscopal Brain Proteomic Changes Associated with Microbiome Alterations Induced by Gastrointestinal Acute Radiation Syndrome in Swine

Kathleen Hatch et al. Int J Mol Sci. .

Abstract

Emerging research highlights the gut microbiota's critical role in modulating brain activity via the gut-brain axis. This study explores whether targeted gastrointestinal irradiation induces abscopal effects on the brain proteome, revealing microbiota-mediated neurobiological changes. Male Sinclair minipigs were randomized to receive either sham treatment (n = 6) or 8 Gy lower hemibody (gut-targeted) irradiation (n = 5). Over 14 days, rectal swabs were collected to monitor microbiota dynamics, followed by frontal cortex proteomic analysis. Irradiation altered gut microbiota composition, notably reducing Chlamydiae and Firmicutes phyla, while increasing Coriobacteriaceae and Acinetobacter. Proteomic analysis identified 75 differentially abundant proteins in the frontal cortex, including a significant decrease in pannexin-1 (PANX1), suggesting modulation of the NLRP3 inflammasome pathway. Functional enrichment analysis revealed immune and neurotransmission-related changes linked to microbial shifts. These results demonstrate that gut-targeted radiation can remotely affect brain protein expression, emphasizing the microbiota's role in neuroimmune regulation and pointing to novel therapeutic opportunities in gut-brain axis disorders.

Keywords: frontal cortex; gut–brain axis; microbiomics; pelvic irradiation; proteomics.

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Conflict of interest statement

Authors Kathleen Hatch, Erin K. Murphy, and Diego Iacono were employed by the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF) Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Figure 1
Figure 1
Effects of 8 Gy gut irradiation on gut microbiota at the Phyla level taxonomic classification. Phyla consisting of >1% total bacterial composition are shown for 8 Gy, with mean relative abundance changing over time for CONTROL and RAD groups. Log2 (FC) (FC = fold change) of relative abundance for RAD microbiota at d14 compared to baseline is shown. Firmicutes and Chlamydiae were both significantly altered by RAD at d14 vs. CONTROL.
Figure 2
Figure 2
Effects of 8 Gy gut irradiation on common gut microbiome Genera. A panel of common gut microbiota shows how genera change over time after 8 Gy gut irradiation. Genera are color coded to match major Phyla colors in Figure 2.
Figure 3
Figure 3
Significantly altered Genera identified following 8 Gy gut irradiation. This level of irradiation primarily affected microbiota of low relative abundance at d14 compared to CONTROL swine. Change in relative abundance was tracked over time. Log2 (FC) is presented.
Figure 4
Figure 4
FCtx proteomic profiling of RAD vs. CONTROL swine. (A) Volcano plot of log2 (FC) vs. −log10 (p-value) of FCtx proteomic profiles, with up-regulated proteins on the right (red) and down-regulated proteins on the left (green). Significance threshold of p < 0.05 is indicated by shading, with all significantly changed proteins with log2 (FC) ≥ 0.26 included in our analysis shown in the corresponding color shaded boxes (p-value of per group ratio calculated by t-test; fold changes visualized as log2 of abundance ratio). We identified 18 up-regulated (red square) and 57 down-regulated (green square) proteins within these criteria through the proteomic profiling.
Figure 5
Figure 5
Identifying a network of interactions among up- and down-regulated proteins identified as differentially abundant by MS proteomic analysis. STRING interaction network of proteins with increased (red) and decreased (green) abundance following 8 Gy gut irradiation (A). STRING GO analysis results are presented for implicated molecular functions, cellular components and biological processes (B).
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