GDF11 Mitigates Severe Acute Pancreatitis-Associated Intestinal Injury by Enhancing CD25 ⁺ FOXP3 ⁺ Regulatory T Cell Function

Background: Intestinal injury represents a key driver of multiple organ dysfunction syndrome (MODS) in patients with severe acute pancreatitis (SAP). Regulatory T cells (Treg cells) are crucial in maintaining normal physiological function of the intestine, and growth differentiation factor 11 (GDF11) exerts anti-inflammatory effects across diverse disease models. Nevertheless, the impact of GDF11 on SAP-associated intestinal injury and its role in modulating Treg cells' function remain incompletely elucidated. Therefore, this study aimed to investigate whether GDF11 mitigates SAP-induced intestinal damage by enhancing Treg cells' function. Methods: A mouse model of SAP was induced using cerulein combined with lipopolysaccharide (LPS). Serum amylase and lipase levels, and hematoxylin-eosin (HE) staining, were used to assess pancreatic and intestinal tissue injury. The levels of inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were assessed using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Moreover, flow cytometry was used to analyze the proportion of splenic CD4⁺CD25⁺FOXP3⁺ cells to evaluate Treg cells. To evaluate Treg differentiation, naïve CD4⁺ T cells were cultured, Treg-related markers (CD134 and CD357) were measured by flow cytometry, and the proportion of CD25⁺FOXP3⁺ cells was determined. Results: <i>In vivo</i>, GDF11 treatment substantially reduced serum amylase and lipase levels in SAP mice. Furthermore, the treatment alleviated histological injury in both the pancreatic and intestinal tissues (<i>p</i> < 0.01), decreased intestinal inflammation by reducing IL-6, IL-1β, and TNF-α (<i>p</i> < 0.05) levels, and increased the proportion of CD25⁺FOXP3⁺ regulatory T cells in the spleen of SAP mice (<i>p</i> < 0.05). Moreover, GDF11 induced the differentiation of mouse naïve CD4⁺ T cells into CD25⁺FOXP3⁺ Treg cells (<i>p</i> < 0.01), and GDF11-induced naïve CD4⁺ T cells exhibited the potential to enhance the expression of key suppressive molecules in Treg cells (<i>p</i> < 0.01). Conclusion: The effect of GDF11 to promote CD25⁺FOXP3⁺ Treg cells' function represents a significant mechanism by which GDF11 safeguards intestinal tissue in the context of SAP.