Gut InflamX Technical Data

Gut InflamX Technical Data

Herbs and Nutrients that May Assist

Zinc carnosine
Polaprezinc
Vitamin D
Colecalciferol
Andrographis
Andrographis paniculata, herb top
Boswellia
Boswellia serrata, gum oleoresin
Gold thread (Berberine hydrochloride)
Coptis chinensis, rhizome
Ginger
Zingiber officinale, rhizome

Actions

  • Promotes vago-vagal cholinergic anti-inflammatory pathway (CAP)
  • Enhances gastrointestinal-associated immune function
  • Supports healthy gastrointestinal mucosa

Clinical Applications

  • Inflammatory gastrointestinal disorders
    • Mucosal ulcers
    • Ulcerative colitis
  • Systemic inflammatory conditions
    • Osteoarthritis
    • Rheumatoid arthritis

Boswellia serrata and Coptis chinensis for Gut and Systemic Inflammation

The gastrointestinal (GI) barrier is crucial for maintaining health and preventing disease.[1] Imbalances affecting its function can harm health, with GI inflammation being a key aspect of barrier dysfunction. Research shows that impaired vagus nerve activity can worsen chronic GI inflammation and is linked to higher levels of inflammatory cytokines, emphasizing the vagus nerve’s role in maintaining balance.[3]

To support GI and overall health, botanical extracts from Andrographis paniculata (andrographis)[4] and Coptis chinesis (coptis)[5,6] stimulate vagal cholinergic anti-inflammatory pathways (CAP) to reduce inflammation. Additionally, zinc carnosine, vitamin D, berberine, Boswellia serrata (boswellia), and Zingiber officinale (ginger) promote mucosal healing, helping to restore the gut barrier (Figure 1). This unique combination of natural ingredients aims to restore vagal communication, offering a holistic approach to managing GI and systemic inflammation.

Background Information

Anti-inflammatory Effects of the Vagus Nerve

The gastrointestinal (GI) barrier is crucial for immune function and the development of digestive and systemic disorders.[1] Changes in GI barrier function, often due to chronic stress, poor diet, infections, dysbiosis, and pharmaceutical use, can lead to increased intestinal inflammation.[7,8] Severe and chronic tissue damage, such as in inflammatory bowel disease (IBD), also contributes to barrier dysfunction, creating a pro-inflammatory environment that disrupts intestinal microbiota, epithelial mucosal layers, and immune function.[1,7-9]

In response to barrier dysfunction, the enteric nervous system (ENS) activates anti-inflammatory pathways via the gut-brain axis, including the vago-vagal anti-inflammatory reflex (CAP) and the vagal-sympathetic pathway (VSP).[10] These pathways are triggered by inflammatory cytokines like TNF-α and IL-6, detected by afferent vagal nerve fibers, which relay signals to the brain.[1,10] This initiates parasympathetic recruitment of efferent vagal fibers, releasing acetylcholine (ACh) in the ENS. ACh then stimulates α7 nicotinic acetylcholine receptors (α7nAChR) on intestinal macrophages, reducing the release of pro-inflammatory mediators such as TNF-α and NFκB.[2,3,11]

The VSP further promotes ACh activity by engaging the sympathetic nervous system (SNS) to mitigate inflammation.[3] Afferent vagal signaling activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing noradrenaline (NE), which activates β2-adrenergic receptors on choline acetyltransferase (ChAT)-positive T cells in the spleen. This promotes ACh release by these T cells, moderating systemic inflammation. Thus, CAP and VSP activation helps downregulate pro-inflammatory processes throughout the body.[3]

Impaired Vagal Communication and Immune Dysfunction

In healthy individuals, the vagus nerve maintains GI and immune homeostasis.[3] However, imbalances in the autonomic nervous system, such as elevated SNS and low parasympathetic nervous system (PNS) states, are linked to diminished vagal activity.[3] Chronic stress, for example, prolongs SNS activation at the expense of PNS function, reducing both afferent and efferent vagal signaling and impairing CAP and VSP-mediated immune regulation.[3,12] This pattern of raised SNS and reduced PNS activity is observed in many inflammatory conditions, including IBD, rheumatoid arthritis, and irritable bowel syndrome (IBS),[13,14] suggesting that impaired vagal communication may underlie various inflammatory presentations.

Figure 2: CAP modulates the inflammatory response via the release of acetylcholine on immune cells.[15]

Key: CAP: Cholinergic anti-inflammatory pathway; SNS: sympathetic nervous system; PNS: Parasympathetic nervous system.

Restoring Vagal Communication and Barrier Function

Research shows that vagal activation can significantly reduce pro-inflammatory activity in various disorders via CAP and VSP, down-regulating chronic immune activation.[2,3] Ingredients that repair mucosal damage can also aid barrier dysfunction. Zinc carnosine, vitamin D, andrographis, boswellia, berberine, and ginger work synergistically to stimulate afferent signaling,[16-18] promote ACh activity,[4,5,19] repair barrier damage,[20,23] and lower systemic inflammation.[24,25] Combined, these therapeutics may help restore healthy vagal communication, improving GI and immune function.

Actions

Promotes Vago-vagal Cholinergic Anti-inflammatory Pathways (CAP)

CAP stimulation has anti-inflammatory effects in disorders like arthritis, ulcerative colitis, and pancreatitis.[5] Ingredients that promote vagal activation can enhance these mechanisms. For example, zinc increases gut peptides (e.g., neuropeptide Y, orexin)[26] that activate vagal receptors in animal models.[27] Bitter herbal extracts like andrographis and coptis[28,29] stimulate GI tract taste receptors,[30,31] triggering gut hormones (e.g., cholecystokinin) that activate vagal receptors.[31,32], These effects promote signaling to autonomic centers mediating CAP.[27]

Herbal medicines also increase CAP by promoting α7nAchR activity. Compounds like 3-dehydroandrographolide (3-DA) from andrographis[33] and berberine[34] from coptis[5] stimulate α7nAchR, reducing inflammatory cytokines (e.g., IL-6, TNF-α, NFκB).[5,33] Berberine also boosts ACh levels[5,35] by inhibiting acetylcholinesterase (AChE), a mechanism shared with ginger extracts. These ingredients support CAP and exert anti-inflammatory benefits.[36]

Modulates Gastrointestinal-Associated Immune Function

Sub-epithelial gut-associated lymphoid tissue (GALT) maintains healthy immune function[37] by coordinating inflammatory responses.[38] T-regulatory (Treg) cells influence various innate and adaptive cells:

  • Macrophages: Tregs inhibit pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) and promote anti-inflammatory phenotypes.[39,40]
  • Mast cells: Tregs suppress mast cell degranulation.[41]
  • T cells: Tregs coordinate CD4+ T helper cells (Th1, Th2, Th17) for adaptive immunity.[38,42]

Reduced Treg levels lead to excessive mast cell activation,[41] overactive Th1,[42] and Th17-driven autoimmune inflammation.[43] CAP activation increases Tregs and decreases Th1 and Th17, reducing pro-inflammatory cytokines.[44,45] Andrographis and berberine enhance CAP by downregulating IL-6, TNF-α, and NFκB in macrophages.[3,5]

Nutrient availability also affects Treg activity. Zinc deficiency impairs Tregs, while supplementation strengthens them.[46] Vitamin D regulates Tregs, Th1, Th17, and mast cells, with deficiency linked to increased mast cell activation. Ensuring adequate zinc and vitamin D levels supports immune function.[47-50]

Boswellia[51] and andrographis-derived andrographolide[52] increase Treg cells. Berberine increases Tregs, reduces Th1 and Th17, and mitigates tissue damage in autoimmune disease models.[53] These extracts also stabilize mast cells, suppressing inflammatory cytokines (e.g., histamine, TNF-α, NF-κB). These activities promote GALT-mediated immune homeostasis.[5,54,55]

Supports Healthy Gastrointestinal Mucosa

Zinc carnosine supports GI mucosa by maintaining tight junction proteins (TJ) in the intestinal barrier.[56] Zinc depletion elevates TNF-α and alters TJ, compromising barrier integrity.[57,58] Zinc deficiency is common in gastrointestinal diseases like IBD, affecting 15-40% of cases.[59] Vitamin D deficiency also compromises intestinal barrier function,[60] while adequate levels reduce inflammation and barrier dysfunction.[61,62]

Boswellia, berberine, and ginger protect epithelial morphology and mitigate cytokine activity (e.g., NFκB, TNF-α) under inflammatory conditions.[63-65] These herbs and nutrients support healthy GI mucosa and barrier function.

Clinical applications

Stimulating vagal communication can improve the management of various conditions, both within the GI tract and beyond. Research on mechanical vagal nerve stimulation shows improvements in IBS, IBD, and fibromyalgia symptoms.[2,66,67] Nutritional and herbal interventions for CAP stimulation are evolving, suggesting potential for natural therapies to address a range of disorders.

Inflammatory Gastrointestinal Disorders

Mucosal Ulcers: Zinc carnosine enhances recovery in small bowel inflammation. In a randomized controlled trial, 10 patients with aspirin-induced mucosal ulcers took 150 mg/day of zinc carnosine for four weeks, significantly reducing ulcerative lesions and mucosal damage (p<0.05).[21] Another study with 109 patients showed zinc carnosine, combined with a proton pump inhibitor (PPI), was as effective as the gastroprotective medication rebamipide in reducing ulcer lesions.[20]

Ulcerative Colitis: Vitamin D benefits patients with autoimmune ulcerative colitis (UC). In a randomized, double-blind trial with 22 individuals, 1,000 IU/day of vitamin D for 12 weeks significantly improved quality-of-life scores (p<0.05).[23] Andrographis also enhances UC outcomes. In a study with 53 patients, 1.2 g/day of andrographis extract showed comparable symptom reduction to mesalazine (56% vs. 59%; p<0.001) and improved mucosal healing (53% vs. 40%; p<0.001).[22]

Systemic Inflammatory Conditions

Osteoarthritis: Clinical trials support ginger’s benefits for inflammatory joint disorders. In one study, 40 patients taking 30 mg/day of ginger extract experienced similar pain relief to 1,200 mg/day ibuprofen, reducing osteoarthritis (OA) pain from 72% to 30% (p<0.0001).[68] Two studies with 500 mg/day ginger powder for 12 weeks showed significant reductions in inflammatory markers (TNF-α, IL-1β, nitric oxide, C-reactive protein).[24,25] Another study with 1,000 mg/day ginger for 48 weeks showed significant improvements in pain and handicap scores (p<0.001).[69]

Rheumatoid Arthritis: Ginger also benefits autoimmune rheumatoid arthritis (RA). In a randomized double-blind trial with 35 individuals, 1,500 mg/day ginger powder for 12 weeks reduced disease activity scores, swelling, and tenderness (p<0.003). These outcomes were linked to increased gene markers for Treg cells (p<0.02), supporting ginger’s immune modulatory effects.[69]

Summary of evidence

Population Study Details Outcome

Small bowel mucosal injury[21]

150 mg/d zinc carnosine

4 weeks; randomised controlled clinical trial

Zinc carnosine treatment significantly reduced the average number of endoscopic ulcerative lesions and erosive mucosal damage compared to placebo (p<0.05).

Submucosal ulcers[20]

150 mg/d zinc carnosine alongside proton pump inhibitor (PPI) vs. PPI and rebamipide

4 weeks; randomised placebo-controlled clinical trial

Gastroprotective effects of zinc carnosine were comparable to rebamipide in minimising diameter and total area of sub mucosal ulcer lesions.

Ulcerative colitis[23]

1,000 IU/d vitamin D

12 weeks; randomised, double-blind clinical trial

Vitamin D supplementation was associated with statistically significant increase in quality of life scores (p<0.05).

Ulcerative colitis[22]

1.2 g/d of andrographis extract containing 96 mg-120 mg of andrographolides vs. mesalazine

8 weeks; randomised, double-blind parallel group trial

UC symptom reduction was comparable (56% symptom reduction in the andrographis group vs. 59% reduction in mesalazine group; p<0.001). Mucosal healing observed via colonoscopy noted a 25% improvement in intestinal damage in 53% of the andrographis group vs. 40% in the mesalazine group (p<0.001).

Osteoarthritis[25]

500 mg/d ginger powder vs. placebo

12 weeks; randomised double-blind placebo-controlled clinical trial

Ginger supplementation reduced inflammatory markers in OA, including nitric oxide (reducing from 29.02 ± 0.82 down to 26.02 ± 1.82; p<0.001), and C-reactive protein (lowering from 11.06 ± 1.43 down to 8.47 ± 1.62; p<0.001).

Knee osteoarthritis[69]

1,000 mg/d ginger vs. placebo 48 weeks; randomised double-blind placebo-controlled crossover trial

Overall, ginger led to a significant difference between pain on movement and handicap scores. In group 1 patients received ginger from week 1 to week 12, pain scores fell 76% to 41% and handicap scores reduced from 75% to 39% (p<0.001). These individuals resumed ginger treatment again (following placebo crossover completion) between weeks 24 to 48 where pain scores dropped from 82% to 9% (p<0.001). In group 2, patients received ginger from week 12 to week 48, pain scores lowered from 50% to 15%, whilst handicap scores reduced from 46% to 15% (p<0.001).

Rheumatoid arthritis[70]

1,500 mg/d ginger powder vs. placebo

12 weeks; randomised double-blind placebo-controlled clinical trial

Treatments led to a reduction in disease activity scores within joint tissues, decreasing rheumatic swelling and tenderness from 4.73 ± 0.27 to 3.44 ± 0.30 (p<0.003).

Safety Information

Disclaimer: In the interest of supporting Healthcare Practitioners, all safety information provided at the time of publishing is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects.

For further information on specific interactions with medications, please contact Clinical Support on 1800 777 648, or via email, anz_clinicalsupport@metagenics.com

Pregnancy and Lactation

  • Likely unsafe; avoid using.[71]

Contraindications

  • Contraindicated with cyclosporine; berberine may inhibit cytochome CYP P450 3A4 which metabolises this drug.[71]

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