Chronic Inflammatory Response Syndrome (CIRS) Naturopathic Protocol

Chronic Inflammatory Response Syndrome (CIRS) Naturopathic Protocol

This Chronic Inflammatory Response Syndrome (CIRS) Naturopathic Protocol is provided as information for patients of HealthMasters Naturopath Kevin Tresize ND as part of a treatment plan to assist patients with understanding of their treatment plan and should not be substituted for medical advice, diagnosis or treatment. It is important to note that this is a summary only and is intended to assist discussion between practitioner and patient as part of consultations. This Chronic Inflammatory Response Syndrome (CIRS) Naturopathic Protocol may be changed to suit the individual requirements of the patient and should not be substituted for medical advice, diagnosis or treatment.

HealthMasters Naturopath Kevin Tresize ND




Consultation Overview

Key Drivers

Treatment Priorities

Red Flags

Treatment Recommendations

Supportive Programs

Diet and Lifestyle Recommendations

Clinical Investigation and Pathology

Pharmaceutical Treatments




Content for Definition



  • Chronic inflammatory response syndrome (CIRS) is a progressive, multisystem, multi-symptom illness caused by an aberrant immune response to certain biotoxins.[1]
  • The most common source of exposure is from water-damaged buildings,[2] causing moulds and spores to develop in damp, decaying timber framing, in addition to biotoxins produced by some cyanobacteria, dinoflagellates, tick-borne microbes and fungi.[3]
  • CIRS biotoxins create ion channels within cell membranes, giving them the ability to move between cells and through cytoplasm.[4] Several complex, inflammatory pathways underlie CIRS pathogenesis (Figure 1):

Stage 1 - Biotoxin effects: Ineffective biotoxin removal (due to genetic variants within the human leukocyte antigen [HLA] gene complex) allows the biotoxin to circulate throughout the body, binding to surface receptors in cells, such as toll-like receptors. This binding causes up-regulation of multiple proinflammatory cytokines.[5],[6]

Stage 2 - Cytokine effects: Inflammatory activation stimulates cytokine release, causing generation of tissue-degrading matrix metalloproteinase 9 (MMP-9), as well as increased production of transforming growth factor beta 1 (TGF-β1); a cytokine associated with heightened T regulatory (Treg) cell activity. The complement pathway also generates antibody production. Influenza-like symptoms including fatigue, headaches, chills and rigors, muscles aches, and impaired cognition are common during this stage.[7],[8]

Stage 3 - Reduced vascular endothelial growth factor (VEGF): Elevated cytokine levels in the capillaries (particularly TGF-β1) attract white blood cells, supressing VEGF production (essential to the growth of vascular endothelial cells) and restricting blood flow/oxygenation to the tissues (capillary hypoperfusion). Reduced VEGF impairs mitochondrial function, resulting in symptoms of fatigue, muscle cramps and shortness of breath.[9],[10]

Stage 4 - Immune system effects: Treg cell activity is disrupted, causing these cells to transform into proinflammatory effector cells. The complement system becomes chronically activated, resulting in high levels of complement component 4a (C4a) and complement component C3a (C3a) that perpetuate the inflammatory cycle. Immune dysregulation triggers inappropriate antibody production to gliadin and self-tissue, thereby increasing predisposition to gluten intolerance and autoimmune development.[11],[12]

Stage 5 - Leptin resistance and low melanocyte stimulating hormone (MSH): Elevated cytokines bind to leptin receptors, interfering with leptin signalling and creating leptin resistance and subsequent weight gain. Additionally, this mechanism blocks hypothalamic production of MSH, which is involved in immune regulation in numerous hormone pathways. This leads to dysregulation of immune and inflammatory pathways, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, chronic pain, circadian rhythm disruption, and poor control of appetite and energy expenditure. Low MSH is also associated with increased gastrointestinal permeability, leading to gut dysfunction and further immune dysregulation.[13]

Stage 6 - Multiple antibiotic resistant coagulase negative staphylococci (MARCoNS): Reduced MSH allows MARCoNS colonies to survive in biofilm within mucous membranes of the nasal passage.[14] MARCoNS produce exotoxins that cleave MSH,[15] further decreasing MSH levels and perpetuating the inflammatory cycle.

Stage 7 - Pituitary effects: Chronically low MSH levels decrease pituitary output of anti-diuretic hormone (ADH), leading to frequent urination, thirst and neurally-mediated hypotension. The resulting low blood volume and high osmolality[*] causes symptoms of dizziness, headache and increased shocks from static electricity. Androgen-based sex hormone production also diminishes due to upregulation of aromatase activity, resulting in excess conversion of testosterone to oestradiol. Despite adrenocorticotropic hormone (ACTH) and cortisol levels increasing during early stages of CIRS, this phase of the biotoxin pathway is characteristic of excessively low levels.[16]

Chronic Inflammatory Response Syndrome (CIRS) Figure 1 | HealthMasters

Figure 1: The CIRS biotoxin pathway in genetically susceptible people.[17]

Key: TLR: Toll-like receptors; MMP-9: matrix metalloproteinase 9; MSH: melanocyte stimulating hormone; VEGF: vascular endothelial growth factor; TGF-β1: transforming growth factor beta 1; T regs: T regulatory cells; ROR: RAR-related orphan receptor.


Consultation Overview:


Identify Risk Factors

In Clinic Investigations- Refer to Key Drivers and the Clinical Investigation and Pathology sections below for further guidelines:

  • Have patient complete the CIRS and Biotoxin Questionnaire.
  • If indicated, have the patient complete a visual contrast sensitivity (VCS) test to screen for nerve damage and capillary hypoperfusion, which are associated with CIRS.
  • Assess patient’s exposure to mould or other potential sources of biotoxins.
  • Assess patient’s infectious history including chronic bacterial and/or viral infections, and tick-borne illnesses. Have patient complete the Horowitz Lyme-MSIDS Questionnaire where indicated.
  • Assess patient’s stress levels.
  • Screen for additional comorbidities and/or differentials including tick-borne illnesses (Lyme/Lyme-like disease), fibromyalgia or chronic fatigue syndrome.
  • Consider evaluating omega-3 status via the OmegaQuant®Omega-3 Index, which may be low in inflammatory states.

Pathology Investigations- Refer to Key Drivers and the Clinical Investigation and Pathology sections below for guidelines:

  • If the patient’s VCS test is positive, determine genetic susceptibility to CIRS via HLA DR/DQ gene testing.
  • If genetic susceptibility is verified, confirm CIRS by testing for biomarkers commonly impacted by this condition, including leptin, TGF-β1, vasoactive intestinal polypeptide (VIP), MSH, ADH, and osmolality. Additional pathology tests to consider include MARCoNS swab (culture of nasal bacteria), anti-gliadin antibodies (AGA), VEGF, cortisol-awakening response (CAR) profile, ACTH, MMP-9, C4a, and C3a.
  • Exposure must be determined by testing the patient’s home and/or workplace/school for mould, using the Environmental Relative Mouldiness Index (ERMI).


Identify Signs of CIRS

In a susceptible individual, the biotoxin pathway results in a complex presentation of symptoms affecting multiple organ systems, seen in Table 1:

Table 1: The complex, multisystem presentation of CIRS.[18]

Organ System Symptom % of CIRS Patients Impacted Organ System Symptom % of CIRS Patients Impacted






Abdominal pain




Multi-factorial; unique


Skin sensitivity




Night sweats

Mood swings

Poor temperature regulation

Appetite swings








Unusual pain

Ice pick pain

Lightning bolt pain

Joint pain

Morning stiffness









Poor memory

Poor focus/concentration


Decreased assimilation of new knowledge

Decreased word finding ability








Antidiuretic hormone

Excessive thirst

Frequent urination

Static shocks







Shortness of breath







Metallic taste







Light sensitivity

Red eyes

Blurred vision






Key Drivers:

Genetic susceptibility: In healthy individuals, biotoxins are effectively recognised and presented to the adaptive immune system for elimination. However, genetically susceptible individuals fail to mount an appropriate immune response to these biotoxins, allowing them to recirculate and trigger an aberrant inflammatory process driven by the innate immune system. This susceptibility is caused by variants in HLA genes, specifically HLA DR/DQ haplotypes. HLA DR/DQ haplotypes occur in approximately 24% of the population[19] and in 90% of patients with CIRS.[20]

Chronic infections: Exposure and recirculation of biotoxins produced by Borrelia species and other common tick-borne coinfections are associated with prolonged symptoms in Lyme and Lyme-like disease patients, known as post-Lyme syndrome.[21],[22] Biotoxins produced by these pathogens can continue to circulate throughout the body, causing dysfunction and biotoxin illness long after the infection has cleared.[23]

Immune exhaustion: Chronic infection, whereby the immune system is incapable of mounting an effective adaptive immune response against pathogenic infection, causes alterations in the T cell phenotype, resulting in diminished cytotoxic capacity.[24] ‘Exhausted’ T cells display increased levels of inhibitory receptors, including programmed cell death protein 1 (PD-1), leading to apoptosis and subsequent reduction in T cell numbers,[25] creating immune dysfunction that increases susceptibility and severity of infection, contributing to CIRS severity.

Chronic stress: Chronic stress alters the HPA axis response to promote excessive release of proinflammatory cytokines, therefore altering the immune response and increasing the susceptibility to immune dysfunction and infectious development. Chronic secretion of catecholamines, noradrenaline, adrenaline and dopamine enhance the growth of pathogens,[26] while also lowering natural killer (NK) cell activity, which increases vulnerability to infectious disease and associated symptoms.[27]

Inflammation: Chronic inflammation, characterised by prolonged and maladaptive production of inflammatory mediators, can cause oxidative stress and damage to the mitochondria, leading to progressive dysregulated structure and function.[28] Mitochondrial dysfunction further exacerbates inflammation via production of mitochondrial reactive oxygen species (ROS), with levels increasing upon disruption of mitochondrial respiratory chain function, promoting inflammation.[29]


Treatment Priorities:

  • Test for the presence of mould in the home, workplace, school or other frequented buildings using Environmental Relative Moldiness Index (ERMI), to identify and remove the biotoxin source.
  • Use a binding agent to eliminate endogenous biotoxins and encourage down-regulation of the inflammatory pathways that perpetuate CIRS.
  • Eradicate MARCoNS contained within biofilms by enhancing mucosal immune function, thereby reducing inflammatory load.
  • Modulate innate and adaptive immune function to encourage regulatory adjustment of the immune response and reduce proinflammatory cytokine levels that potentiate hyper-inflammation and immune dysregulation.
  • Provide anti-inflammatory support to minimise production of MMP-9, TGF-β1 and other cytokines, reducing their detrimental effects on VEGF, the complement system and hormone production (MSH, ACTH and sex hormones).
  • Increase testosterone production by reducing aromatase activity, preventing its conversion to oestradiol, to correct sex hormone imbalances associated with underlying overstimulation of the innate immune system.
  • Minimise drivers of inflammation including chronic stress, toxicity and intestinal permeability, to attenuate immune dysregulation.
  • Provide symptomatic relief as required, including mitochondrial support for cellular energy production, as well as pain management, to improve quality of life.


Red Flags:

Tick-borne illnesses: CIRS is associated with other chronic illnesses including post-Lyme syndrome.[30] Borrelia species can cause both Lyme and other tick-borne illnesses. In the acute stage, Borrelia infection and Lyme disease cause fatigue, fever, sweats, rash, swollen glands, headaches and joint pain. Chronic Lyme disease patients can present with fatigue, neurological symptoms, musculoskeletal pain or stiffness, and/or nerve pain, tingling and/or numbness - symptom pictures that mimic a range of autoimmune conditions.[31] Coinfections, such as Bartonella, are often contracted together with Borrelia from the offending tick.[32] Coinfections can contribute to or exacerbate Lyme disease symptoms,[33] and make the infection more resistant to treatment.[34] Additional tick-borne infections such as Candidatus Neoehrlichia mikurensis, Rickettsia, Coxiella burnetii and Babesia can also cause Lyme-like illness, with overlapping symptoms including muscular pains, nervous system involvement and rashes.[35] Examine patient’s history of travel to high-risk areas overseas, history of tick bite and history of bulls-eye shaped erythema migrans (EM) rash. If Lyme or Lyme-like disease is suspected, use the Horowitz Lyme-MSIDS Questionnaire to assess the presence and severity of signs and symptoms and refer to a General Practitioner for further testing.

Fibromyalgia (FM): Due similar symptom pictures, CIRS patients are often misdiagnosed with FM[36]; a chronic illness characterised by widespread musculoskeletal pain and tenderness, with varying degrees of additional symptoms including fatigue, sleep disturbances, musculoskeletal stiffness, cognitive dysfunction and high levels of distress.[37] Patients with FM experience heightened pain perception including widespread hyperalgesia, in particular to deep-pressure stimuli, enhanced temporal summation (a clinical measure of central sensitisation) and inhibition of heterotopic noxious stimulation (which produces analgesia).[38] On physical examination, patients with FM may have tenderness in particular soft tissue locations called tender points. If FM is suspected, have the patient complete the Fibromyalgia Impact Questionnaire to assess patient functionality and the intensity of FM symptoms, and refer to the Fibromyalgia protocol for treatment recommendations.

Chronic fatigue syndrome (CFS): CIRS has a significant clinical overlap with symptoms of CFS/myalgic encephalopathy (ME) including muscle pain, polyarthralgia and impaired memory and concentration.[39] Biotoxin exposure has also been shown to trigger CFS/ME symptoms in genetically susceptible people.[40] CFS/ME has a strong association with viral and bacterial infections and is often accompanied by signs of infection including fever, sore throat and tender lymph nodes[41]; more than 40% of Australians suffering from CFS report that an infectious event preceded symptom onset.[42] Refer to Chronic Fatigue Syndrome protocol if CFS is suspected.


Treatment Recommendations

Core Recommendations


Stage 1 - Remove Biotoxin Exposure

The VCS test is an objective measurement to track the effect of binders, which may be decreased once the VCS is passed and patient is in a safe environment

Determine whether the presence of water damage in frequented buildings (home, workplace, school etc.) has caused mould amplification using ERMI.

Bind biotoxins for removal using zeolite, charcoal, bentonite clay, modified citrus pectin, or chitosan*.

*Adhere to recommended dosage guidelines on product label.


If MARCoNS and biofilms are present, the Gut Pathogen Elimination Detoxification Program is indicated:

See Metagenics Clinical Detoxification Program under Supportive Programs


Antimicrobial Sinus Spray

Dosage: 2 sprays in each nostril, every two hours.

Direct the nozzle into your right nostril and spray twice, sniffing between each spray. Repeat in the left nostril.

Antimicrobial essential oils to eradicate biofilm-producing MARCoNS that colonise within mucous membranes of the nasal passage.

Mechanism of Action/Clinical Research:

Thymol, found in thyme, has been shown to disrupt cell wall membranes.[43] Additionally, thyme penetrates the extracellular matrix, cell membrane and/or cell wall of bacterial biofilms, facilitating pathogenic eradication.[44]

Eucalyptus, lavender, peppermint and thyme essential oils provide antiseptic actions that reduce nasal and sinus congestion.

Nasal irrigation with isotonic sodium chloride solution assists clearance of upper airway inflammatory secretions, which provide an ideal growth medium for major pathogens including Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pneumonia.[45]

Xylitol enhances the innate antibacterial defence systems when applied nasally.

A double-blind, randomised, cross-over study involving 21 participants who were prescribed either 5% xylitol solution or a 0.9% saline solution into the nasal cavity for four days demonstrated reductions in coagulase-negative Staphylococcus numbers, determined by nasal swab cultures.[46]


Repeat the MARCoNS swab (culture of nasal bacteria) after four weeks of treatment, to confirm MARCoNS eradication.


Stage 2A – Address Inflammation and Immune Dysregulation

Continue with this treatment phase until MMP-9 and VEGF levels are within normal limits


Specialised Pro-Resolving Mediators[†]

Dosage: 1 capsule twice daily.

Specialised Pro-resolving Mediators (SPMs) to manage underlying systemic inflammation and support immune regulation, which is associated with delayed pathogenic clearance and unresolved inflammation.

Mechanism of Action/Clinical Research:

SPMs encourage resolution by regulating macrophage polarisation. SPMs trigger the switch from proinflammatory M1 macrophages to anti-inflammatory M2 macrophages, reducing inflammation and tissue damage, promoting resolution. Additionally, M2 macrophages have been shown to inhibit polymorphonuclear neutrophils (PMNs) and promote efferocytosis and tissue repair.[47]


BCM-95™ Turmeric & Devil's Claw to Treat Chronic Inflammation

Dosage: Acute dose: 3 capsules twice daily, reducing to the maintenance dose of 1 capsule in the morning and two capsules in the evening, once symptoms have improved.

A combination of herbs to reduce production of inflammatory mediators at multiple points of the inflammatory cascade, including tissue-degrading MMP-9.

Mechanism of Action/Clinical Research:

Curcumin has broad anti-inflammatory effects, decreasing many inflammatory mediators including phospholipase, lipoxygenase (LOX), cyclooxygenase–2 (COX-2), leukotrienes (LTs), thromboxane, prostaglandins (PGs), nitric oxide (NO), collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1, interferon-inducible protein, TNF-α, and IL-12.[48],[49]

Curcumin has been shown to inhibit the production of MMP-3, MMP-9[50] and MMP-13 while also restoring type-2 collagen and glycosaminoglycan synthesis in human chondrocytes, thereby reducing tissue damage.[51]

Boswelliac acid, acetyl-11-keto-beta-boswellic acid (AKBA), demonstrates anti-inflammatory actions via allosteric regulation of 5-LOX, resulting in LT inhibition.[52] Additionally, boswellia exerts anti-inflammatory activity further up the inflammatory cascade, inhibiting the activation of proinflammatory signalling pathway, nuclear factor kappa B (NFĸB).[53]

Devil’s claw provides significant analgesic effects by reducing pain sensations in the brain via increasing gamma-aminobutyric acid (GABA) levels and opioid activity, while also reducing glutamate signalling.[54]


Mental and Physical Energy Powder

Dosage: Add 2 level scoops (9.5 g) to 200 mL of water, twice daily.

A magnesium formula to attenuate excessive MMP-9 production, while also providing cofactors required for energy production and oxidative phosphorylation, reducing the effects of physical and mental fatigue associated with CIRS.

Mechanism of Action/Clinical Research:

Magnesium regulates matrix metalloproteinase activity, with higher magnesium levels inversely correlating with MMP-9 concentrations.[55]

Magnesium is a critical cofactor for ATP (adenosine triphosphate) manufacture within the electron transport chain, which generates phosphorylation reactions. Magnesium ions support cellular bioenergetics through interactions with phosphorylated molecules and by influencing the kinetics of ion transport across plasma membranes.[56]

Phosphate (-PO43-) is required for the generation of ATP, providing high-energy phosphate bonds that, when hydrolysed, release energy required for cellular processes.[57]

Carnitine assists in the transport of fatty acids across cell membranes, particularly in muscle tissues, for use as an energy source. It is essential for mitochondrial fatty acid oxidation, the primary fuel source for the heart and skeletal muscle.[58]

4 g/d of carnitine has been shown to reduce both physical and mental fatigue in a randomised, double-blind, clinical trial involving 96 subjects prescribed acetyl-L-carnitine for 180 days.[59]

Nicotinamide (vitamin B3) is essential for many biosynthetic pathways including oxidative phosphorylation.[60]

Pantothenic acid (vitamin B5), as part of coenzyme A, participates in the metabolism of carbohydrates, lipids and protein. It also plays a role in cellular respiration, the oxidation of fatty acids and acetylation of other molecules.[61]

Mecobalamin (vitamin B12) has several key roles, including cell growth and replication; metabolism of carbohydrates, lipids and proteins; nucleic acid synthesis and red blood cell production.[62]


High Purity, Low Reflux, Concentrated Fish Oil Liquid or Capsules

Dosage: 4.2 mL (1 tsp) daily or 2 capsules twice daily.

Omega-3 essential fatty acids (EFAs) to reduce the production of inflammatory cytokines and MMP-9, and normalise VEGF levels, thereby improving mitochondrial function and CIRS-associated symptoms (fatigue, muscle cramps and shortness of breath).

Mechanism of Action/Clinical Research:

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulate the production of eicosanoids, cytokines and other factors such as peroxisome proliferator-activated receptors (PPARs), which regulate the inflammatory response.[63],[64],[65]

EPA and DHA can inhibit cytokine-induced endothelial activation and reduce endothelial migration and proliferation, essential to vascular endothelial cell wound repair. This action occurs via regulation of VEGF.[66]

EPA and DHA decreases proinflammatory MMP-9, a protease that regulates pathological remodelling of the extracellular matrix, basement membrane, and other tissues in the body by digesting collagen components in these tissues, causing inflammation and fibrosis.[67]


If MMP-9 >332 ng/mL:

Adhere to a low amylose diet, such as the Metagenics Shake It Practitioner Weight Management Program


Stage 2B – Address Inflammation and Immune Dysregulation

Continue with this treatment phase until TGF-β1 and VIP levels are within normal limits


Alpha Lipoic Acid for Antioxidant Support

Dosage: 1 tablet daily with food.

Alpha-lipoic acid (ALA) is an intracellular antioxidant that protects mitochondrial membranes from free radical damage, facilitating cellular bioenergetics, as well as reducing excess TGF-β1 levels that suppress VEGF production associated with CIRS.

Mechanism of Action/Clinical Research:

The antioxidant and anti-inflammatory actions of lipoic acid have been shown to reduce TGF-β1 levels, which may help to reduce immune dysregulation characteristic of CIRS.[68]

Lipoic acid (LA) is a cofactor for citric acid cycle enzymes, including mitochondrial pyruvate dehydrogenase (PDH), alpha-ketoglutarate dehydrogenase (KGDH) and branched-chain alpha ketoacid dehydrogenase. These enzymes play a key role in both anaerobic and aerobic cellular energy metabolism,[69] facilitating the production of mitochondrial ATP.

ALA features two thiol groups, which facilitate its redox activity in the body. From its oxidised state, ALA cycles into its reduced form, dihydrolipoic acid (DHLA) via nicotinamide adenine dinucleotide phosphate (NADP+) enzymes. Together, LA and DHLA assist in the regeneration of endogenous antioxidants, which are essential in stabilising oxidative stress in the body.[70]

LA has been shown to induce nuclear factor erythroid 2-related factor 2 proteins (Nrf2), which are involved in up-regulating genetic expression of endogenous antioxidants and detoxification enzymes in the body.[71]


Vitamin D3

Dosage: Take 1 capsule daily with food.

Vitamin D to modulate the innate and adaptive immune responses, supporting immune function during infection.

Mechanism of Action/Clinical Research:

Vitamin D levels are inversely proportional to TGF-β1, with vitamin D deficiency correlating with elevated TGF-β1.[72] Additionally, vitamin D supplementation has been shown to lower TGF-β1 levels.[73]

Vitamin D receptors are expressed on a wide variety of cell types and are involved in the modulation of activated T and B lymphocytes.[74]

Vitamin D has been shown to regulate T helper (Th) cell and dendritic cell function, as well as induce Tregs.[75]


Continue to attenuate excessive MMP-9 production and reduce the effects of physical and mental fatigue associated with CIRS:

Mental and Physical Energy Powder

Dosage: Add 2 level scoops (9.5 g) to 200 mL of water, twice daily.


If presenting with imbalance in sex hormones:

For low testosterone in men:

Tribulus Reproductive Support

Dosage: Take 2 tablets twice daily.

A blend of herbs combined with zinc to support male sexual health and function by increasing declining testosterone levels caused by low MSH and diminished pituitary output.

Mechanism of Action/Clinical Research:

Tribulus has been shown to increases testosterone, dihydrotestosterone (DHT) and dihydroepiandosterone sulphate (DHEAS).[76] This may be via stimulation of androgen production or from direct activity from steroidal components of tribulus, such as protodioscin.[77]

Zinc is highly concentrated in male genital organs. A cofactor for more than 80 metalloenzymes, zinc is involved in DNA transcription and protein synthesis, and in DNA transcription for germ cell development. Additionally, zinc has a role in testicular development, sperm maturation and release and testosterone synthesis, as well as providing antioxidant protection to counteract ROS that impact fertility.[78]


OR, if with elevated oestradiol:

Soy, Methylating Nutrients and BCM-95™ Turmeric to Clear Oestrogen

Dosage: Take 1 tablet twice daily with food.

Herbs and nutrients that modulate oestrogen metabolism and reduce aromatase activity, to enhance oestrogen clearance and attenuate increased conversion of testosterone to oestradiol, and subsequent androgen deficiency associated with CIRS.

Mechanism of Action/Clinical Research:

Soy has been shown to preferentially bind to oestrogen receptor β (ERβ),[79] down-regulating oestrogen signalling and supporting healthy phase I and II oestrogen metabolism.[80]

Turmeric selectively enhances ERβ,[81],[82] and reduces tissue oestrogen synthesis by down-regulating inflammatory mediators, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α).[83] As inflammation up-regulates synthesising enzymes, aromatase, oestrone sulphatase and 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), turmeric’s anti-inflammatory activity may reduce excessive local oestrogen synthesis.[84],[85]

Milk thistle supports healthy oestrogen signalling,[86] and promotes phase II oestrogen metabolism[87] alongside vitamins B6 and B12.


Re-test sex hormones at three monthly intervals until hormone levels return to within normal range.


Additional Considerations


Improve Treg cell function and support immunity:

Lactobacillus paracasei LP-33®and Lactobacillus rhamnosus (LGG®) for Immune Control

Dosage: 1 capsule daily.

Clinically trialled probiotic strains to restore immune control and moderate over-active immune responses, associated with CIRS pathogenesis.

Mechanism of Action/Clinical Research:

Lactobacillus paracasei LP-33® and Lactobacillus rhamnosus (LGG®) have been shown to induce Treg cell production, which provides immunoregulatory support (Th1 and Th2 cytokine balance) and dampens inflammation in immune disorders.[88],[89]

Lactobacillus rhamnosus (LGG®) has the capacity to induce IL-10, a key anti-inflammatory and immunoregulatory cytokine that is expressed by Tregs and Th2 cells.[90]


High Bioavailability Zinc with Vitamin C

Dosage: Children 4 to 8 years: Acute: Add ¼ metric teaspoon (0.95 g) to 100 mL water once daily with food; Children 9 to 13 years: Acute: Add ¼ metric teaspoon (0.95 g) to 100 mL water twice daily with food; Children 9 to 13 years: Maintenance: Add ¼ metric teaspoon (0.95 g) to 100 mL water once daily with food. Adults and children over 14 years: Acute: Add ½ metric teaspoon (1.9 g) to 200 mL water twice daily with food; Adults and children over 14 years: Maintenance: Add ½ metric teaspoon (1.9 g) to 200 mL water once daily with food.

Zinc and vitamin C to support the development, function and mediation of immune cells required for pathogenic defence.

Mechanism of Action/Clinical Research:

Vitamin C supplementation has been shown to reduce the duration and severity of infections[91] and is increasingly efficacious when combined with zinc, with deficiencies of vitamin C and zinc both severely suppressing immune responses.[92]

Vitamin C stimulates white blood cell production and function, enhances NK cell activity and chemotaxis, supports clearance of spent neutrophils from sites of infection, increases serum levels of antibodies, and augments lymphocyte differentiation and proliferation, facilitating innate and adaptive immune responses.[93]

Zinc is involved in several aspects of immunological function, including the development, function and mediation of immune cells, such as neutrophils, monocytes and NK cells. Zinc also affects the development of acquired immunity and T lymphocyte function.[94]


If presenting with symptoms of gastrointestinal permeability:

Glutamine & Boswellia (Bospure® Boswellia) for Intestinal Integrity

Dosage: Add 2 level scoops (7.7 g) to 200 mL water twice daily with food, or as directed by your healthcare professional.

Anti-inflammatory herbs combined with nutrients to support and maintain healthy intestinal integrity, protect the gastrointestinal mucosa and assist overall gut health and function.

Mechanism of Action/Clinical Research:

Aloe has been shown to promote the rapid repair of damaged membranes in the gastrointestinal tract.[95]

Boswellic acid compound, AKBA, acts as a potent antibacterial against gram-positive pathogens, with an ability to disrupt the permeability barrier of microbial membrane structures. AKBA has also demonstrated an inhibitory effect against the growth of microbial biofilms, particularly the growth of staphylococcus-containing biofilms.[96]

Glutamine serves as a precursor for nucleotide synthesis in rapidly dividing cells such as intestinal cells, therefore supporting healthy cellular reproduction and decreasing intestinal permeability.[97]

Larch arabinogalactans act as a prebiotic, enhancing beneficial gut microflora such as bifidobacteria and lactobacilli. Arabinogalactans are fermented by intestinal bacteria to create short chain fatty acids, particularly butyrate, which acts as a fuel source for epithelial cells, thereby aiding their replication and integrity and supporting intestinal health and barrier function.[98]

Zinc is involved in the initial step of epithelial wound healing, a process called epithelial cell restitution.[99]

A primary function of vitamin A includes its role in cellular differentiation, where it acts as a transcription factor, supporting mucosal immunity via induction of Tregs and increased secretory immunoglobulin A (sIgA), which protect the mucosal barrier.[100]


If presenting with nerve pain:

High Strength, Enhanced Absorption PEA for Nerve Pain

Dosage: Take 1 capsule twice daily.

Highly bioavailable palmitoylethanolamide (PEA), providing endocannabinoid-like actions to support pain relief, including nerve pain, neuroprotection and anti-inflammatory assistance to CIRS patients.

Mechanism of Action/Clinical Research:

PEA is an endocannabinoid-like lipid mediator influencing a variety of receptors and immune cells to provide antineuroinflammatory, analgesic and neuroprotective actions. PEA is endogenously produced in the body, with levels declining during chronic disease, tissue damage, inflammation, pain syndromes and ageing.[101]

PEA has an association with the endocannabinoid system (ECS) and key bioactive endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG).[102] The ECS regulates an array of physiological functions in the body,[103] with imbalances contributing to the development of several psychological and neurodegenerative disorders.[104],[105],[106]  PEA supports the ECS via directly modulating endocannabinoid signalling (via receptor expression of PPAR-α or orphan G protein-coupled receptor [GPR55] or G protein-coupled receptors [GPCR]) and indirectly activating transient receptor potential vanilloid receptor type 1 (TRPV1) and cannabinoid receptors (CB1, CB2).[107],[108],[109]


Supportive Programs

The Metagenics Clinical Detoxification Program is designed to reduce toxic burden, increase toxin resilience and improve the efficiency of waste elimination. In particular, the Gut Pathogen Elimination Detoxification stream may be used to address biofilm-producing MARCoNS that exacerbate CIRS inflammation.

The Metagenics Shake It Practitioner Weight Management Program is designed to help patients comfortably transition from a hypercaloric diet to a hypocaloric diet, facilitating sustainable weight loss while also improving insulin sensitivity and optimising metabolic function. Additionally, a low amylose diet may be used to attenuate elevated MMP-9 levels observed in CIRS.


Diet and Lifestyle Recommendations


A gluten-free diet is recommended for CIRS patients who test positive for anti-gliadin antibodies.

A low amylose diet, such as the Metagenics Shake It Practitioner Weight Management Program is recommended for patients whose MMP-9 levels exceed 332 ng/mL.

Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fibre from fruits, vegetables, and wholegrains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines.[110]

Current evidence suggests that the Mediterranean diet provides protection against several diseases associated with inflammation and immune activation.[111]

The Mediterranean diet has also been found to improve disease-related fatigue by lowering the inflammatory load and simultaneously balancing gut microbiota.[112]

The Mediterranean diet is inclusive of a high intake of fruits and vegetables, lean protein, quality essential fatty acids, and wholegrains (limiting starchy grains and vegetables).

The Metagenics Wellness Diet reflects the wholefood principles of the Mediterranean diet and also provides a simple guide to moderate portion size and the overall balance of macronutrients.

Maintaining muscle mass and strength through adequate protein intake may enhance energy by preserving functional capacities. In particular, whey protein, which is rapidly digestible and high in leucine, has been shown to stimulate muscle protein synthesis.[113]

Avoid low kilojoule diets or high-energy foods that are nutritionally poor. Energy-dense foods, such as chocolate bars or caffeinated drinks, only offer a temporary energy boost that may worsen CIRS-associated fatigue.

Consuming protein and low glycaemic index carbohydrates, while also avoiding refined carbohydrates, may assist with blood glucose stabilisation.


Infrared light therapy has been shown to increase ATP production and reduce fatigue. Specifically, the mitochondrial electron transport chain has been shown to be photosensitive to red and near-infrared (NIR) light.[114],[115]

Ensure adequate sleep, achieving approximately eight hours of sleep each night.[116]

Avoid alcohol, illicit drugs or additional stimulant substances (caffeine, nicotine), as these may negatively impact HPA axis activity and nervous system function, contributing to daytime fatigue and/or disturbing normal sleep patterns.[117]

Engage in regular physical activity to improve fitness, health and wellbeing, and reduce stress.[118] The type and amount of exercise may depend on symptom severity and patients may require a graded exercise program to prevent post-exertional fatigue.


Clinical Investigation and Pathology


Clinical Screening


Visual Contrast Sensitivity (VCS)

The VCS is a validated test used to screen for toxin exposure, including biotoxins.[119],[120]The inflammatory response produced by biotoxin exposure has been shown to cause nerve dysfunction, leading to a variety of neurological symptoms including diminished VCS.

CIRS and Biotoxins Questionnaire

The CIRS and Biotoxins Questionnaire is a convenient tool that uses symptom clusters to provide Practitioners with a sensitive and accurate assessment of whether a patient has been affected by biotoxins.

Horowitz Lyme-MSIDS Questionnaire

The Horowitz Lyme-MSIDS questionnaire helps determine the probability of having multiple systemic infectious diseases syndrome (MSIDS), Lyme disease and/or other tick borne illnesses. MSIDS is a symptom complex of Lyme disease and multiple associated tick borne coinfections that encompasses Borrelia burgdorferi infection, as well as other bacterial, viral, parasitic and fungal infections.

Fibromyalgia Impact Questionnaire

A patient questionnaire that allows Practitioners to assess and monitor patient functionality and the intensity of FM symptoms.

Omega-3 Index Test

A validated test that measures red blood cell (RBC) EPA and DHA status. An Omega-3 Index in the desirable range of 8% to12% is an indicator of better overall health.


Alphabetical Reference of Nutritional Support: 

Formula Catch Phrase

Key Benefits

77 58 54 50


Supportive Lifestyle Programs: 

Supportive Lifestyle Program Description


Diet, Lifestyle and Specific Natural Treatments: 



In-Clinic Point-of-Care Pathology Tests: 

Test Description


Pathology Tests: 

Pathology Test Interpretation Guidlines


Pharmaceutical Treatments: 

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