Microscopic view of a healthy gut lining with R-spondin 3.

Gut Health Revolution: How R-Spondin 3 Could Change Your Life

Kai Mendoza in Health & Wellness August 2025 • 3 min read.

"Discover the groundbreaking research on R-spondin 3 and its vital role in maintaining a healthy gut, potentially preventing serious conditions."

The human gut is a complex ecosystem, crucial for overall health and well-being. Maintaining its delicate balance is essential, and recent research has shed light on a key player in this process: R-spondin 3. A new study published in Nature identifies R-spondin 3 as a critical protein that regulates gastric epithelial stem cells and the homeostasis of antral glands—essential components of your stomach.

This discovery isn't just for scientists; it has significant implications for understanding how conditions like Helicobacter pylori infection can lead to gastric cancer. By understanding the role of R-spondin 3, we can explore new ways to prevent and treat common yet serious digestive issues.

Think of your gut lining as a constantly renewing surface. Stem cells within the gastric glands are responsible for this renewal. However, the signals that control these stem cells and their turnover have been unclear—until now. Researchers have begun to unravel these mysteries, clarifying the direct impact of certain factors on stem cell behavior.

R-Spondin 3: The Gut's Unsung Hero

Microscopic view of a healthy gut lining with R-spondin 3.

R-spondin 3 is a protein released by gastric myofibroblasts, which are specialized cells in the connective tissue of the stomach. These myofibroblasts are strategically located beneath the glands, allowing R-spondin 3 to directly influence the stem cells within.

To understand how R-spondin 3 works, researchers traced the lineage of cells expressing AXIN2, a Wnt target gene. Wnt signaling is crucial for stem cell maintenance and tissue regeneration. By identifying cells with active Wnt signaling in gastric gland stem cell niches, they pinpointed two distinct stem cell populations in the antrum (the lower part of the stomach):

AXIN2+LGR5+ cells: Located at the base of the glands.
AXIN2+LGR5- cells: Found in the lower isthmus.
AXIN2+LGR5+ cells were unable to repopulate glands within 7 days.
AXIN2+LGR5- cells were more proliferative, entirely repopulating glands in the same timeframe.

The study revealed that AXIN2+LGR5- cells could replenish AXIN2+LGR5+ cells, especially when the LRG5+ population was depleted. This indicates a dynamic interplay between these cell types, highlighting the plasticity and resilience of the gut lining. Furthermore, in situ hybridization pinpointed that R-spondin 3’s distribution pattern was uniquely restricted to the stem cell niche at the bottom of the gland, underscoring its specific role in stem cell regulation.

What This Means for You

The discovery of R-spondin 3’s role in gut health opens new avenues for therapeutic interventions. Understanding how this protein influences stem cell behavior can lead to targeted strategies for preventing and treating gastric diseases. For instance, maintaining optimal levels of R-spondin 3 could potentially reduce the risk of H. pylori-induced gastric hyperplasia and, consequently, gastric cancer. While more research is needed, these findings offer hope for developing novel approaches to support gut health and prevent serious digestive conditions. Future studies are likely to explore how diet and lifestyle factors influence R-spondin 3 levels and activity, providing even more insights into maintaining a healthy gut.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1038/nrgastro.2017.128, Alternate LINK

Title: R-Spondin 3 Is A Critical Regulator Of Gastric Antral Stem Cell Homeostasis

Subject: Gastroenterology

Journal: Nature Reviews Gastroenterology & Hepatology

Publisher: Springer Science and Business Media LLC

Authors: Hugh Thomas

Published: 2017-09-06

Everything You Need To Know

What is R-spondin 3 and what role does it play in gut health?

R-spondin 3, released by gastric myofibroblasts, is a crucial protein that regulates gastric epithelial stem cells and the homeostasis of antral glands. Its specific location allows it to directly influence stem cells, promoting the renewal of the gut lining. Understanding R-spondin 3's function is vital for developing strategies to prevent and treat gastric diseases.

What are the different stem cell populations identified in the study, and how do they interact with each other?

The study identified two distinct stem cell populations in the antrum: AXIN2+LGR5+ cells located at the base of the glands, and AXIN2+LGR5- cells found in the lower isthmus. Interestingly, AXIN2+LGR5- cells demonstrated a greater ability to repopulate glands compared to AXIN2+LGR5+ cells, showcasing a dynamic interplay where AXIN2+LGR5- cells can replenish the AXIN2+LGR5+ population, particularly when the latter is depleted. This suggests a resilient and adaptable gut lining.

How could understanding R-spondin 3's role in gut health lead to new therapeutic interventions?

By understanding how R-spondin 3 influences stem cell behavior, targeted strategies can be developed for preventing and treating gastric diseases. For instance, maintaining optimal levels of R-spondin 3 could potentially reduce the risk of *H. pylori*-induced gastric hyperplasia and, consequently, gastric cancer. This could involve dietary or lifestyle interventions aimed at promoting R-spondin 3 production or activity.

How does R-spondin 3 relate to the Wnt signaling pathway, and why is this significant for gut health?

The Wnt signaling pathway is crucial for stem cell maintenance and tissue regeneration in the gut. R-spondin 3 influences this pathway, as evidenced by tracing cells expressing AXIN2, a Wnt target gene. AXIN2+LGR5+ and AXIN2+LGR5- populations show that R-spondin 3 helps maintain the stem cell niche necessary for gut health.

What are the future directions of research regarding R-spondin 3, and how might they impact the prevention of gastric diseases?

Future research will likely focus on how diet and lifestyle influence R-spondin 3 levels and activity. Further studies may also investigate how to therapeutically target R-spondin 3 to prevent *H. pylori*-induced gastric hyperplasia, and consequently, gastric cancer. The goal is to find ways to optimize R-spondin 3's function to promote gut health and prevent serious digestive conditions.