In Crohn's disease and ulcerative colitis, inflammation blocks its own healing

by Susanne Landis, PMI Exzellenzcluster Präzisionsmedizin für chronische Entzündungserkrankungen

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Why does inflammation persist in Crohn's disease and ulcerative colitis, even as the body is trying to bring it under control? Researchers in Kiel and the United States have identified a mechanism that offers a surprising answer: Inflammation itself disrupts a key metabolic pathway needed to supply the intestinal lining with energy.

The findings come from three closely linked studies by a German–U.S. research team involving the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) at Kiel University. Together, the studies reveal how chronic inflammation interferes with the production of a central molecule in cellular energy metabolism, how the body responds to the resulting shortage, and how these insights could point toward new therapeutic strategies.

The research began during a research stay by Dr. Lina Wehkamp at Penn State College of Medicine. Together with colleagues in Kiel and the United States, she set out to answer a fundamental question: Why does the inflamed intestine fail to restore its energy supply?

When the gut runs low on energy

At the center of the research is nicotinamide adenine dinucleotide, or NAD⁺, a molecule essential to virtually every cell in the body. NAD⁺ plays a central role in energy metabolism and helps cells repair damage and renew tissue. The intestinal lining depends particularly heavily on a reliable supply: It is one of the body's most rapidly renewing tissues and must continuously regenerate, especially during inflammation. In chronic intestinal inflammation, however, this process appears to be disrupted.

"During inflammation, the body is actually trying to repair the damaged intestinal lining, and that requires large amounts of energy," says Dr. Lina Wehkamp, first author of the study and a clinician scientist at the Department of Internal Medicine I at University Hospital Schleswig-Holstein (UKSH) in Kiel and the Institute of Clinical Molecular Biology at Kiel University. "Instead, production of this essential metabolic molecule stalls at a critical step."

One way the body normally produces NAD⁺ is from the amino acid tryptophan. In their new study, the researchers show that this pathway is blocked during active intestinal inflammation. At the heart of the bottleneck is an enzyme called quinolinate phosphoribosyltransferase, or QPRT, which catalyzes one of the final steps in NAD⁺ synthesis.

During active inflammation, production of QPRT is reduced. As a result, an intermediate metabolite called quinolinic acid (QA) accumulates, while NAD⁺ production through this pathway falls. The intestinal lining is left facing a metabolic bottleneck.

"What we see is a mechanism by which inflammation itself prevents cellular metabolism from returning to balance," says Professor Konrad Aden of the Institute of Clinical Molecular Biology at Kiel University and the Department of Internal Medicine I at UKSH, one of the study's senior authors. "In this way, inflammation may itself make it harder for the intestinal lining to regenerate."

The researchers confirmed this relationship in several independent patient cohorts as well as in experimental models. The research is published in the Journal of Crohn's and Colitis.

The body looks for another route

The discovery raises another question: What happens when such an important metabolic pathway is blocked? In a second study, published in Cell Reports in mid-August, the team used stable-isotope tracing to follow NAD⁺ precursors through cellular metabolism. They found that the body responds to NAD⁺ depletion by increasingly relying on alternative routes to replenish it.

"The body does not simply accept the energy deficit," says Professor Philip Rosenstiel, director of the Institute of Clinical Molecular Biology at Kiel University. "We see a broad metabolic adaptation. The organism reorganizes its metabolism to compensate, at least in part, for what has been lost."

Nicotinamide (NAM), a form of vitamin B3, appears to play a particularly important role in this response. The experiments show that under inflammatory conditions, cells can use nicotinamide particularly efficiently to produce NAD⁺.

A potential route to new treatments

These findings could have direct implications for the development of new therapies. Because nicotinamide can bypass the blocked section of the metabolic pathway, the study provides a mechanistic rationale for the ongoing ORNATUS clinical trial, which is investigating locally delivered nicotinamide as a therapeutic approach in ulcerative colitis.

"We now understand not only why NAD⁺ production breaks down in the inflamed intestine," says Wehkamp. "We also understand which alternative routes the body uses to compensate. That gives us concrete starting points for developing new therapeutic approaches."

Inflammation, metabolism and the microbiome are interconnected

In a subsequent third experimental study, the researchers found initial evidence that the gut microbiome may also be part of this metabolic network. The findings suggest that intestinal bacteria can influence how tryptophan is metabolized and how efficiently NAD⁺ can be produced. The study was published in the International Journal of Tryptophan Research.

"Chronic inflammatory bowel diseases are not simply disorders of the immune system," says Professor Stefan Schreiber, spokesperson for the Cluster of Excellence PMI and director of the Department of Internal Medicine I at University Hospital Schleswig-Holstein. "Our findings show that metabolic processes also play a central role. Only by understanding these different levels together will we be able to develop new precision therapies."

Taken together, the studies suggest a broader view of inflammatory bowel disease: Persistent inflammation may be driven not only by misdirected immune responses, but also by the failure of inflamed tissue to maintain the metabolism needed for repair. If this metabolic bottleneck can be bypassed, it could open new ways to support regeneration of the intestinal lining and, ultimately, achieve more durable control of inflammation.

Publication details

Lina Wehkamp et al, A metabolic constraint in de novo NAD+ synthesis drives mucosal inflammation in IBD, Journal of Crohn's and Colitis (2026). DOI: 10.1093/ecco-jcc/jjag043

Abrar I. Alsaadi et al, Tracing NAD+ metabolism uncovers adaptive coordination between host and microbiome during colitis, Cell Reports (2026). DOI: 10.1016/j.celrep.2026.117730

Lina Wehkamp et al, Systematic Screening of Tryptophan Metabolism Identifies Site- and Microbiota-Dependent Signatures of Tryptophan Utilization in Experimental Colitis, International Journal of Tryptophan Research (2026). DOI: 10.1177/11786469261472316

Journal information: Cell Reports

Key medical concepts

Ulcerative ColitisCrohn's Disease

Clinical categories

Gastroenterology Provided by PMI Exzellenzcluster Präzisionsmedizin für chronische Entzündungserkrankungen Who's behind this story?

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