Microbiome-Derived Metabolites and Gut Repair After Stem Cell Transplantation

Nature Communications (October 2025) | Leibniz Institute for Immunotherapy (LIT), University Hospital Regensburg & Technical University of Munich

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many blood cancers. However, it places extreme stress on the body. One of the most vulnerable organs is the intestine. Chemotherapy, radiation, antibiotics, and immune reactions often damage the gut lining, leading to infections, inflammation, and graft-versus-host disease (GvHD).

Over recent years, research has shown that patients with a healthier gut microbiome tend to recover better after transplantation. What has been less clear is why. Is it the bacteria themselves, or the substances they produce, that support recovery? This study focuses on the latter.

The Core Discovery

The researchers identify a microbiome-derived molecule called desaminotyrosine (DAT) as a key driver of intestinal repair after stem cell transplantation.

DAT directly supports the activity of intestinal stem cells, the cells responsible for rebuilding the gut lining after injury. At the same time, its effects are tightly regulated by the cell’s own stress-control systems. This balance allows regeneration without uncontrolled growth or excessive inflammation.

In simple terms: DAT helps the gut heal, but only when the body’s internal “safety checks” are intact.

How the Study Was Conducted

The study combined animal experiments with advanced human tissue models.

Mice undergoing stem cell transplantation were given DAT orally. Researchers then measured how well the intestinal lining regenerated using stem-cell markers, tissue analysis, and organoid recovery tests.

To translate these findings to humans, the team used human intestinal organoids, including organoids derived from patients who had already undergone allo-HSCT. These miniature gut models allowed direct testing of DAT on human tissue.

In parallel, immune cells were studied to understand how DAT affects T-cell activation and inflammation. Molecular analyses helped identify the signaling pathways responsible for DAT’s effects.

Key Findings

DAT consistently improved intestinal regeneration after transplant-like injury in both mice and human organoids. It increased the number and activity of intestinal stem cells that are essential for repairing the gut barrier.

The regenerative effect depended on a balance between growth signals (mTORC1) and stress-control pathways (STING-mediated autophagy). When this balance was disrupted, DAT lost its benefit, showing that regeneration is tightly linked to metabolic control.

Unlike some other microbial metabolites, DAT also stimulated immune cells, especially at higher doses. This means it may support tissue repair while still allowing immune responses to remain effective.

Limitations of the Study

Most of the evidence comes from preclinical models. While human organoids are highly informative, they do not fully reflect the complexity of real patients.

The doses of DAT used in animals are relatively high, and the safest and most effective dose for humans is still unknown. Long-term effects, especially on immune balance and cancer relapse risk, were not assessed.

Finally, transplant patients differ widely in microbiome composition, antibiotic exposure, and immune status. DAT may not work equally well for everyone.

Relevance for Switzerland

This research is particularly relevant for Switzerland for several reasons.

Switzerland has highly specialized transplant centers in Zurich, Basel, Bern, and Lausanne, performing complex allo-HSCT procedures with excellent survival rates, but at very high cost. Intestinal complications and GvHD are among the most expensive and difficult problems to manage after transplantation.

A defined metabolite therapy like DAT could offer a safer and more controllable alternative to approaches such as fecal microbiota transplantation. From a regulatory perspective, this fits well with Swissmedic’s preference for well-characterized substances over live biological mixtures.

For Swiss health insurers, even a modest reduction in post-transplant complications could translate into shorter hospital stays, fewer ICU admissions, and lower long-term care costs. For patients, it could mean faster recovery and better quality of life.

Finally, Switzerland’s strong biotech and translational research ecosystem makes it an ideal setting for early clinical trials of such therapies.

Potential Impacts of a Successful Therapy

If DAT proves safe and effective in humans, it could become a supportive therapy to protect the gut after stem cell transplantation. This may reduce infection risk, improve tolerance of intensive treatments, and possibly lower transplant-related mortality.

Beyond transplantation, the same mechanisms could be relevant for other conditions involving intestinal damage, such as chemotherapy-induced mucositis or inflammatory bowel disease.

Risks

DAT is not purely anti-inflammatory. At higher doses, it enhances immune cell activity, which could worsen GvHD if not carefully controlled.

There is also a theoretical risk that prolonged stimulation of growth pathways could have unintended effects. This makes careful dosing, timing, and patient selection essential.

Overall Assessment

This study provides strong evidence that specific microbiome-derived molecules (not just bacteria as a whole) can actively support intestinal regeneration after severe medical treatments.

DAT stands out as a promising candidate because it combines regenerative effects with built-in biological control mechanisms. The findings move the field closer to precise, mechanism-based microbiome therapies.

What Comes Next

The next step is early-phase clinical testing to assess safety and dosing in transplant patients. Researchers will also need biomarkers to identify patients most likely to benefit.

In the long term, this work supports a shift toward targeted microbiome-based medicines, designed with the same rigor as conventional drugs.

Reference

Göttert, S., Thiele Orberg, E., Fan, K. et al. The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration. Nat Commun 16, 9282 (2025). Link