Abstracts & Literature Review 4

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Non-Celiac Gluten Sensitivity Triggers Gut Dysbiosis,
Neuroinflammation, Gut-Brain Axis Dysfunction, and Vulnerability for Dementia

Mak A. Daulatzai
CNS & Neurological Disorders – Drug Targets, 2015, 14, 110-131

Trials 2013 14:18.
JACO Editorial Reviewer: Jeffrey R. Cates, DC, MS, FACO, DABCC


Journal of the Academy of Chiropractic Orthopedists
June 2015, Volume 12, Issue 2

The original article copyright belongs to the original publisher. This review is available from: http://www.dcorthoacademy.org ©2015 O’Dwyer and the Academy of Chiropractic Orthopedists. This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Author’s Abstract:

The non-celiac gluten sensitivity (NCGS) is a chronic functional gastrointestinal disorder which is very common worldwide. The human gut harbors microbiota which has a wide variety of microbial organisms; they are mainly symbiotic and important for wellbeing. However, “dysbiosis” – i.e. an alteration in normal commensal gut microbiome with an increase in pathogenic microbes, impacts homeostasis/health. Dysbiosis in NCGS causes gut inflammation, diarrhea, constipation, visceral hypersensitivity, abdominal pain, dysfunctional metabolic state, and peripheral immune and neuro-immune communication. Thus, immune-mediated gut and extra-gut dysfunctions, due to gluten sensitivity with comorbid diarrhea, may last for decades. A significant proportion of NCGS patients may chronically consume alcohol, nonsteroidal anti-inflammatory drugs, and fatty diet, as well as suffer from various comorbid disorders. The above pathophysiological substrate and dysbiosis are underpinned by dysfunctional bidirectional “Gut-Brain Axis” pathway. Pathogenic gut microbiota is known to upregulate gut- and systemic inflammation (due to lipopolysaccharide from pathogenic bacteria and synthesis of pro-inflammatory cytokines); they enhance energy harvest, cause obesity, insulin resistance, and dysfunctional vago-vagal gut-brain axis. Conceivably, the above cascade of pathology may promote various pathophysiological mechanisms, neuroinflammation, and cognitive dysfunction. Hence, dysbiosis, gut inflammation, and chronic dyshomeostasis are of great clinical relevance. It is argued here that we need to be aware of NCGS and its chronic pathophysiological impact. Therapeutic measures including probiotics, vagus nerve stimulation, antioxidants, alpha 7 nicotinic receptor agonists, and corticotropin-releasing factor receptor 1 antagonist may ameliorate neuroinflammation and oxidative stress in NCGS; they may therefore, prevent cognitive dysfunction and vulnerability to Alzheimer’s disease.

JACO Editorial Summary:

The article is very compelling for the further investigation of the role of gluten sensitivity, in absence of Celiac Disease (CD), and inflammation. This is called Non-Celiac Gluten Sensitivity (NCGS).

  • Most primary care givers and conventional medicine practioners unfortunately do not know the symptoms of NCGS.
  • Gastrointestinal (GIT) microflora is colonized from birth. The symbiotic gut microflora is greatly increased as the small intestine travels into the large intestine and finally the rectum. This leads to increased immunity and absorption of nutrients.
  • Symbiotic microflora include many different types of microflora. One important flora is Heliobacter hepaticus which under normal circumstances is commensal. It is generally kept in check by another commensal bacterium, Bacillus fragilis. B fragilus expresses a polysaccharide called PSA. PSA is a chief promoter of inflammatory interleukin-10. This symbiotic relationship keeps the intestinal immune system in check. When it is out of balance, the author describes it as a cycle of “changes in gut flora -> dysbiosis -> gut inflammation and dysfunction -> systemic inflammation -> neuroinflammation and pathophysiologic changes”. This includes behavioral changes.
  • When this symbiosis is disrupted, inflammation increases predisposing the host to a variety of diseases whose symptoms are as varied and disconnected as: psychiatric disorders, chronic fatigue, indigestion, reflux, whole bowel symptoms, malabsorption syndrome, rashes of unknown origin, anemia, cephalgia, cystitis, depression, ataxia, chronic obstructive sleep apnea, neurologic dyfunction, hypotension, via vagus nerve and solitary nucleus stimulation causing brainstem inflammation and decreased immunity.
  • Of those patients who have NCGS and ataxia, 70% also possess the HLA DQB1*0201 haplotype. This is significant as it (HLA DQB1*0201) is also normally present in approximately 40% of all Caucasians. Interesting that celiac disease is also linked to this haplotype. As a result of this relationship, CD and NCGS patients with ataxia are considered in the same disease spectrum.
  • As stated previously, NCGS is often expressed in very vague symptoms. The neurologic compromise and the irritable bowel syndrome often goes undiagnosed. As a result, NCGS patients often suffer needlessly with symptoms that most probably could be resolved within months with a gluten free diet.
  • Inflammation from the reaction of the immune system to the gliadin of gluten (the protein covering of the endosperm of the grain) causes an interleukin inspired reaction of the immune system.
  • More recently, the relationship between Alzheimer-like dementia has been investigated for links correlating inflammation due to immune response of NCGS and mental decline. It seems reasonable that when the sensitive neurology is inflamed due to the reaction to gluten and its respective gliadins, the transmission of signal, and neurotransmitter function would also be impaired.
  • The gut microbiome is disrupted, almost daily, with chemicals, as well as with the increase of antibiotic and prescription medication use. The body is unable to effectively detoxify the various chemicals it is assaulted with, leading to chronic inflammation and further dysbiosis. Levels of lipopoysaccharide (LPS) also play a major role in the inflammatory cycle. More recent research has revealed that increasing the LPS causes an increase in the inflammatory cascade response which compounds the inflammatory process. The increase in LPS causes an increase in pro-inflammatory cytikines such as TNF-a and IL-1B. These cause gut permeability and metabolic endotoxemia to both increase, thus causing a chronic inflammatory state in the host.
  • In both CD and NCGS, levels of IgA (the immunoglobulin found in the gut) is chronically disrupted. In CD, but not NCGS, this leads to blunting of the microvilli. In NCGS as the cellular connections break down, intestinal materials are allowed to leak into the abdominal cavity (leaky gut). It is similar to the mortar between the bricks starting to crumble. As a result, inflammation increases. This leads to a cyclic pattern of inflammation and ramped up immune response. As you might expect, this chronic inflammatory pattern eventually wreaks havoc on all systems due to the disruption in homeostasis.
  • Co inflammaging”, fatty-food obesity, alcohol abuse, fatty liver, NSAID’s, serum amyloid A (acute phase protein which increases during infections, inflammation, tissue injury and stress response) and hypoxia from chronic obstructive sleep apnea (OSA). This OSA is often compounded with obesity causing a vicious cycle.mplicating factors of NCGS inflammation range from increased age, aka ”
  • Neuroinflammation causes cognitive impairment in patients of all ages due to the interaction of the vagus nerve (CN X) and the gut. The vagus nerve has a cholinergic antiinflammatory pathway via the efferent pathways (recall that efferent pathways are motor and travel from the brain area to the target organ; afferent pathways are sensory and travel from the end organ to the brain). When ACh (vagal neurotransmitter) is released from the synaptic terminals of the vagus nerve onto the receptors of the gastrointestinal tract, spleen and liver, the effect is immune activation and suppressed pro-inflammatory cytokine release. Afferent vagal stimulation signals to the brain help effect appetite modulation, glucose homeostasis, energy balance regulation and possibly more critically inflammation. Generally, the immune system and the nervous system regulate homeostasis in the body. Systemic inflammation can affect cognitive function through inflammed brainstem vessels. This inflammation increases vascular resistance which will then cause inadequate perfusion. It may also affect neuronal excitability. There is a strong correlation that LPS and gut inflammation cause neuroinflammation and cognitive impairment via systemic inflammation, possibly leading to myelin and axonal degeneration. This inflammation of the CNS can cause responses such as ataxia caused by lymphocytic infiltration of the cerebellum , Alzheimers-like dementia or delerium. This correlate is poorly understood, often dismissed warranting further investigation of inflammatory mediators is needed.
  • Environmental factors may also exert inflammatory stress on our systems. It is hypothesized that with the overzealous use of cleansers and sanitizers, childhood antibiotic use, psychological stress, environmental pollutants and poor diet may cause an imbalance in the gut microflora.
  • Editorial comment:

    With the increase in geneticallymodified organisms (GMO – introduced in 1996), excessive plant hybridization, and “Round- Up” ready glyphosphate (resistent to pesticide/herbicide) and Bacillus thuringeniensis) crops; the grains that are conventionally produced and consumed are not the ancient grains of our forefathers. There is evidence suggesting that in particular, GMO gluten, glyphosphate and bT toxin, cause the bonds between the intestinal wall to leak. Excessive hybridization has caused the gluten content of the wheat, barley or rye to increase. The barrage of gluten on our oftimes unbalanced and fragile immune system may be the cause of increase sensitivities to gluten. While I am a strong proponent of gluten free, free range and organics, I realize that more research may be warranted, as “gluten allergy” is often maligned as the “diagnosis of the day”. Fortunately, research is often correlated to antecdotal evidence. As more information is discovered, there is a very compelling argument that when we manipulate our food sources we are damaging our health. Evidence suggests that increasing our pre-biotics (essentially nondigestible carbohydrates which act as food for the gut microbiota), probiotics (found in fermented foods or added into foods) and non-processed/non-manipulated food sources can help to stimulate the innate healing power of our systems. If we consciously eat as our ancestors before us, it may be possible to support our immune systems successfully fend off the environmental toxins that accost us daily. This is important to remember for the Doctor of Chiropractic with whom some patients have vague, yet pervasive symptoms which do not completely resolve or fail to respond with chiropractic treatment.