A New Player in Gut Inflammation: How a New Bacterial Polyamine Disrupts Mitochondria and Why Spermidine May Help

The human gut microbiome is a bustling ecosystem, home to trillions of microorganisms that shape everything from digestion to immunity. Inflammatory Bowel Disease (IBD) arises when this delicate dialogue between gut microbes and the immune system breaks down, an imbalance influenced by genetics, environment, and increasingly, microbial metabolites. A groundbreaking study, hot off the press in Nature Communications has now identified one such microbial molecule: a previously unknown atypical polyamine called N¹-aminopropylagmatine (N¹-APA), produced by certain gut bacteria such as Bacillus subtilis. This metabolite appears capable of disrupting mitochondrial function and altering immune responses, potentially contributing to IBD pathology. Even more compelling, the findings raise the possibility that dietary spermidine may help counteract N¹-APA’s harmful effects. Let’s break down what this discovery means and how spermidine could play a protective role.

How N¹-APA fuels gut inflammation and how spermidine helps protect against it. Based on findings from Nauta et al., 2025. © Melissa Cano, 2025. 

What Is Inflammatory Bowel Disease (IBD)?

Inflammatory Bowel Disease is a chronic, relapsing condition marked by persistent inflammation of the gastrointestinal tract. It primarily includes:

1. Crohn’s Disease
   - Can affect any part of the digestive tract
   - Involves deeper, transmural inflammation
   - Common symptoms: abdominal pain, diarrhea, weight loss, fatigue, malnutrition
2. Ulcerative Colitis
   - Limited to the colon and rectum
   - Causes superficial inflammation and ulceration (open sores in the gut lining).
   - Common symptoms: bloody diarrhea, urgency, abdominal pain

IBD arises from an imbalance between the immune system and the gut environment. Microbial factors, including bacteria and the molecules they produce, are increasingly recognized as major contributors to inflammation.

A Surprising Discovery: A New Bacterial Polyamine Called N¹-APA

Polyamines like spermidine, putrescine, and spermine are essential for cell growth, RNA translation, and mitochondrial health. Traditionally, gut microbes help supply these polyamines, supporting host health. But the new study reveals that under certain conditions, bacteria such as Bacillus subtilis and Escherichia coli produce a different polyamine: N¹-aminopropylagmatine (N¹-APA).

Understanding N¹-APA Buildup in IBD: Diet, Microbiome, and Inflammation

In IBD, gut bacteria can produce N1-APA, a harmful polyamine, when their normal metabolic pathways are disrupted. Key factors driving its accumulation include:

1. Loss of agmatinase activity: Mutations or loss of the bacterial enzyme SpeB or agmatinase, which converts agmatine to putrescine and into other useful compounds like spermidine, can lead to N1-APA buildup.
2. High dietary agmatine: Elevated dietary agmatine (usually found in high amounts in fermented or protein-rich foods) fuels N¹-APA production when agmatinase is absent or impaired.
3. Gut microbiome dysbiosis: Altered microbial communities in IBD shift polyamine metabolism toward noncanonical compounds like N¹-APA.
4. Inflammatory environment: IBD-associated inflammation changes nutrient availability and bacterial gene expression, favoring N¹-APA synthesis.
5. Medication effects: Drugs like metformin may inhibit bacterial agmatinase, indirectly promoting N¹-APA accumulation.

In short, when bacteria’s normal spermidine-producing pathways are disrupted, they accumulate this atypical polyamine. And N¹-APA doesn’t just stay in the gut: it enters host cells and causes trouble.

How N¹-APA Disrupts Gut Cell Function and Drives Inflammation

After being produced, N¹-APA enters intestinal cells via a conserved polyamine transporter called CATP-5, where it interferes with several critical biological systems.

1. It disrupts mitochondrial function
   N¹-APA triggers the mitochondrial unfolded protein response (UPRmt), signaling cellular stress. Because mitochondria are essential for energy production and immune regulation, their dysfunction can directly contribute to inflammation.
2. It blocks hypusination of eIF5A
   Hypusination is a rare but essential protein modification that requires spermidine. This modification activates the translation factor eIF5A, which is critical for producing proteins needed for mitochondrial function. By preventing hypusination, N¹-APA disrupts eIF5A activation and reduces mitochondrial protein synthesis, directly impairing cellular energy production and overall cell survival.

Note: While the paper does not directly study autophagy, external research suggests that hypusinated eIF5A is essential for translating proteins involved in the autophagy process, the cell’s cleanup and recycling system. Therefore, by blocking hypusination, N¹-APA could theoretically impair autophagy, further compromising cell health.

3. It interferes with immune regulation
   In mouse macrophages (immune cells that fight infections and help calm inflammation), N¹-APA reduces mitochondrial activity and blocks the development of anti-inflammatory macrophages, weakening the immune system’s ability to control gut inflammation and promoting a pro-inflammatory environment, a hallmark of IBD.
4. It disrupts development in tiny model worms
   Experiments in Caenorhabditis elegans and Pristionchus pacificus, small lab-friendly worms used to study basic biology, showed that exposure to N¹-APA halted normal development and reduced fertility. While these worms are very different from humans, they provide valuable insights because many cellular processes are surprisingly similar.

Connecting N¹-APA to Inflammatory Bowel Disease

Several lines of evidence link N¹-APA to IBD:

• E. coli strains lacking SpeB have been associated with colitis in mice.
• These strains accumulate N¹-APA.
• N¹-APA disrupts mitochondrial function and mitochondrial stress is increasingly recognized as a driver of IBD.
• N¹-APA inhibits anti-inflammatory macrophage activation, favoring gut inflammation.
  

Together, these findings suggest that N¹-APA may be a microbial metabolite contributing to the onset or worsening of IBD.

How Spermidine Counters N¹-APA and Protects Gut Health

Here’s the exciting part: spermidine supplementation reversed many of N¹-APA’s harmful effects in the study’s models.

Spermidine helps by:

• Restoring polyamine balance in cells
• Reducing mitochondrial stress
• Rescuing developmental issues caused by N¹-APA
• Competing with or counteracting N¹-APA at the cellular level

In essence, supplying the “right” polyamine may neutralize the effects of the “wrong” polyamine. While human clinical trials are still needed, the mechanistic evidence is compelling.

This raises an important possibility: spermidine supplementation could help mitigate certain forms of microbial-driven gut inflammation, including IBD. While human clinical studies are needed, the mechanistic data are compelling.

Conclusion: A New Link Between Microbes, Mitochondria, and Inflammation, With Spermidine as a Potential Ally

This study reveals a fascinating interaction between gut bacteria and host health. The identification of N¹-APA as a mitochondrial disruptor highlights how microbial metabolites can profoundly influence inflammation and disease.

Equally encouraging is the finding that spermidine supplementation can counteract these harmful effects, restoring mitochondrial function and preventing developmental and immune dysregulation.

As research progresses, spermidine may prove to be a valuable tool in supporting gut health, reducing inflammation, and potentially contributing to future IBD therapies.