N-acetyl-D-glucosamine (NAG or GlcNAC) is an amino sugar derived from glucosamine, which is naturally produced by the body to maintain optimal health in various ways. First and foremost, NAG plays a pivotal role in promoting balanced immune function through the process of O-GlcNAcylation, a type of post-translational modification. This complex mechanism supports the development, proliferation, and activation of T and B cells, regulates macrophage responses, and promotes the function of activated neutrophils – all critical players in the immune system.

NAG has been described as a triple modulator of inflammatory responses, myelination, and neurodegeneration. It promotes the biosynthesis of N-linked glycans, which enhance N-glycan branching — a process critical for the proper function of immune cells, including T cells, natural killer cells, and dendritic cells. Through this mechanism, NAG supports the activity of anti-inflammatory T regulatory (Treg) cells and mitigates excessive activation of Th1 and Th17 responses, which are associated with autoimmune conditions. 

Furthermore, NAG helps to promote healthy inflammatory and immune responses in ways that may go unrecognized. NAG is essential for the formation of glycoproteins, proteoglycans, and glycosaminoglycans (GAGs), all of which are integral components of connective tissues, cell surfaces, and cell walls. These GAGs and glycoproteins serve as materials for tissue repair and healthy inflammatory responses. Additionally, NAG is needed for the production of mucin – a gel-like substance that coats the intestinal lining. Mucin is vital for maintaining optimal gut barrier function, immune system balance, and healthy inflammatory responses in the gut.

What Research Shows

Emerging human, animal, and in vitro studies highlight the potential clinical relevance of NAG to support gut conditions like inflammatory bowel disease, certain autoimmune diseases, and possibly respiratory conditions. Common denominators of these conditions are heightened inflammatory and unbalanced immune responses. 

• A mechanistic trial showed that high administrations of NAG at 6 g/day (n = 18) and 12 g/day (n = 16) of NAG for four weeks may inhibit markers of neuroinflammation and neurodegeneration in patients with multiple sclerosis, although more research is needed. 
• In a rheumatoid arthritis mouse model, the group receiving 0.5% NAG-containing food for 56 days exhibited lower arthritis scores and improved histopathology compared to controls. The NAG experimental group displayed significantly decreased serum levels of interleukin (IL)-10, IL-2, and transforming growth factor β-1, demonstrating healthy inflammatory responses.
• A lipopolysaccharide-induced inflammatory mouse model demonstrated that the administration of NAG and its two derivatives, BNAG1 and BNAG2, all significantly decreased serum levels of IL-6 and tumor necrosis factor-α (TNF-α). This further supports NAG’s role in helping promote healthy inflammatory responses.
• In a pilot study, among 12 children with severe treatment-resistant IBD (10 with Crohn’s disease, two ulcerative colitis) who were given 3 to 6 g/day of NAC, eight of the children showed clear improvement, while four required resection.
• In an open-label clinical trial, 34 adults with IBD received 6 g/day (2 g three times per day) of NAG for four weeks, with symptom scores assessed at baseline and the study's conclusion. Notably, 30 out of 34 patients (88.1%) who were administered NAG supplementation reported reduced IBD symptoms, with 58.8% noting improvements in abdominal pain and a 49% reduction in symptom scores (P = 0.00022). Additionally, 64.7% of patients experienced improvements in diarrhea, accompanied by a 47% reduction in symptom scores (P = 0.0003), with significant decreases also observed for nausea, mucus discharge, and rectal bleeding.
• Lastly, a laboratory study revealed that NAG could reduce biofilm formation by pathogenic Escherichia coli.

Conclusion 

NAG is a key player in promoting immune health and healthy inflammatory responses. It plays a multifaceted role in maintaining healthy connective tissues, supporting mucosal barrier function in the gastrointestinal tract, and promoting the balanced production of immune cells. Ongoing research continues to explore NAG’s potential benefits for individuals with heightened inflammatory or immune challenges.

Learn more about NAG: 

N-Acetylglucosamine and Immunometabolism

The Hidden Effects: Medications and Their Impact on Your GI Tract

By Danielle C. Male, MS, CNS, LDN