Validation of a Low-Nickel Diet as an microbiome-targeted intervention for Endometriosis

Overview

A low-nickel diet has enormous potential as a microbiome-targeted intervention (MBTI) for endometriosis by targeting nickel-dependent microbial virulence mechanisms. Emerging evidence connects nickel to pathogenic activity in microbes that exacerbate endometriosis like Escherichia coli which is a major microbial association (MMA) with the condition, making nickel restriction a critical therapeutic strategy.

Microbial Modulation

Nickel serves as an essential cofactor for several microbial enzymes linked to virulence, including urease and [NiFe]-hydrogenases. ^[1] These enzymes enable pathogens to survive hostile environments, evade the immune response, and drive inflammation—all key contributors to endometriosis pathology. The microbiome signature of endometriosis consistently identifies elevated levels of nickel-reliant pathogens, including E. coli, Ureaplasma urealyticum, and Pseudomonas aeruginosa. These microbes exacerbate endometriosis through inflammation, oxidative stress, and immune dysregulation, with nickel playing a central role in their pathogenicity. By reducing dietary nickel, the virulence of these pathogens is diminished, directly addressing the dysbiotic patterns seen in endometriosis. This dietary approach not only weakens pathogenic microbes but also allows for the proliferation of non-nickel-dependent beneficial species such as Lactobacillus spp., restoring a healthier microbial balance.

Validation of the Endometriosis Microbiome Signature

The endometriosis microbiome signature consistently includes key nickel-dependent microbial associations, such as Escherichia coli, Ureaplasma urealyticum, and Pseudomonas aeruginosa. These taxa rely on nickel to fuel virulence mechanisms, including urease activity and oxidative stress resistance, which exacerbate inflammation and tissue damage in endometriosis. The ability of a low-nickel diet to specifically disrupt the activity of these pathogens demonstrates the clinical relevance of the microbiome signature. Furthermore, clinical studies and systematic reviews have indicated that a low-nickel diet significantly alleviates gastrointestinal, extra-intestinal, and gynecological symptoms in women with endometriosis. ^[6][7] This reduction in symptoms, paired with the observed microbial shifts, validates the microbiome signature as an accurate representation of endometriosis-associated dysbiosis​​.

Dual Validation of MBTI and Microbiome Signature

A low-nickel diet addresses both the microbial and systemic hallmarks of endometriosis. By targeting nickel-dependent enzymes and virulence factors, it weakens key pathogens, thereby reducing their ability to promote inflammation and oxidative stress. Simultaneously, the low-nickel dietary intervention improves microbial balance and alleviates clinical symptoms, such as chronic pelvic pain and dysmenorrhea. These outcomes not only validate the effectiveness of the diet as a microbiome-targeted intervention (MBTI) but also reinforce the microbiome signature’s accuracy in characterizing the microbial underpinnings of endometriosis. This dual validation underscores the interconnectedness of microbial dysbiosis and disease progression, supporting the diet’s role as a viable therapeutic strategy​​.

Conclusion

A low-nickel diet exemplifies the potential of microbiome-targeted interventions to address both dysbiosis and systemic inflammation in endometriosis. By disrupting nickel-dependent microbial virulence mechanisms, this intervention validates the clinical relevance of the endometriosis microbiome signature and provides meaningful symptom relief. These findings highlight the critical role of dietary strategies in advancing the management of endometriosis and emphasize the value of precision-targeted microbiome approaches in clinical practice.

References

1. Inhibition of urease activity by different compounds provides insight into the modulation and association of bacterial nickel import and ureolysis. Svane, S., Sigurdarson, J.J., Finkenwirth, F. et al.. (Sci Rep 10, 8503 (2020))
2. Mechanisms of nickel toxicity in microorganisms. Macomber L, Hausinger RP.. (Metallomics. 2011)
3. Inhibition of urease activity by different compounds provides insight into the modulation and association of bacterial nickel import and ureolysis. Svane, S., Sigurdarson, J.J., Finkenwirth, F. et al.. (Sci Rep 10, 8503 (2020))
4. Inhibition of urease activity by different compounds provides insight into the modulation and association of bacterial nickel import and ureolysis. Svane, S., Sigurdarson, J.J., Finkenwirth, F. et al.. (Sci Rep 10, 8503 (2020))
5. High-affinity metal binding by the Escherichia coli [NiFe]-hydrogenase accessory protein HypB is selectively modulated by SlyD.. Khorasani-Motlagh M, Lacasse MJ, Zamble DB.. (Metallomics. 2017)
6. Ureaplasma Urealyticum Infection Contributes to the Development of Pelvic Endometriosis Through Toll-Like Receptor 2.. Noh EJ, Kim DJ, Lee JY, Park JH, Kim JS, Han JW, Kim BC, Kim CJ, Lee SK.. (Front Immunol. 2019)
7. Inhibition of urease activity by different compounds provides insight into the modulation and association of bacterial nickel import and ureolysis. Svane, S., Sigurdarson, J.J., Finkenwirth, F. et al.. (Sci Rep 10, 8503 (2020))
8. Mechanisms of nickel toxicity in microorganisms. Macomber L, Hausinger RP.. (Metallomics. 2011)
9. Inhibition of urease activity by different compounds provides insight into the modulation and association of bacterial nickel import and ureolysis. Svane, S., Sigurdarson, J.J., Finkenwirth, F. et al.. (Sci Rep 10, 8503 (2020))
10. Irritable Bowel Syndrome-Like Disorders in Endometriosis: Prevalence of Nickel Sensitivity and Effects of a Low-Nickel Diet. An Open-Label Pilot Study.. Borghini R, Porpora MG, Casale R, Marino M, Palmieri E, Greco N, Donato G, Picarelli A.. (Nutrients. 2020)
11. Impact of diet on pain perception in women with endometriosis: A systematic review.. Sverrisdóttir UÁ, Hansen S, Rudnicki M.. (Eur J Obstet Gynecol Reprod Biol. 2022)