Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

Leaky gut: inflammation, chronic fatigue and depression

Neuroendocrinology Letters--leaky gut and chronic fatigueLeaky gut‘ is abnormal intestinal permeability that occurs when the epithelial tissues that comprise the gut barrier have been damaged. When intact the gut barrier prohibits antigenic contents of the intestines from access to the gut-associated lymphoid tissue (GALT) right on the other side of the intestinal wall. Gut barrier integrity (absence of leaky gut) is crucial to prevent loss of immune tolerance (autoimmunity) since the GALT comprises 60-80% of all immune tissue in the body.

Normalization of leaky gut improves chronic fatigue

LPS (lipopolysaccharide from bacterial cell walls) is so highly antigenic that it’s used as an adjuvant in vaccines. Translocation of LPS across a damaged gut barrier elicits systemic inflammation, accompanied by oxidative and nitrosative stress. A study published in Neuroendocrinology Letters demonstrates how normalization of the antibody responses to LPS not only ameliorates but can predict the clinical outcome in chronic fatigue syndrome (CFS). The authors state:

“There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).”

They investigated this by measuring serum concentrations of IgA and IgM to LPS of several gram-negative enterobacteria CFS patients, both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, while consuming a leaky gut diet during 10-14 months. They also measured corresponding result with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and after 10-14 months on the NAIOSs.

Good clinical response to lowered IgA and IgM

The improvement in CFS scores that they documented was very gratifying:

Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).”

The authors’ comments on their data can hardly be overemphasized for clinicians participating in case management of chronic fatigue and fibromyalgia:

“The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.”

High IgA response to normal gut bacteria fires up inflammation in CFS

Journal of Affective DisordersAn interesting study published in the Journal of Affective Disorders documents how LPS from commensal gut bacteria that translocates into the GALT provokes inflammation that drives CFS. The authors note:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin.”

These authors investigated the IgA/IgM responses to the LPS of 6 different enterobacteria by measuring serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). When they correlated with biomarkers for inflammation, CMI and the symptoms of ME/CFS the results were noteworthy:

“Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.”

This is extremely important in clinical practice due to the great functional significance of both systemic inflammation and autonomic nervous system regulation. The authors conclude:

“The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.”

Autoimmune attack on serotonin production

Another fascinating paper also published in the Journal of Affective Disorders reveals that bacterial translocation through the gut barrier into immune lymphoid tissue can provoke antibodies that attack 5-HT, the precursor of serotonin, contributing to chronic fatigue and depression. The authors state:

“Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.”

The examined 117 patients with ME/CFS for autoimmune activity against 5-HT, measuring plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria. This was correlated with the fibromyalgia and chronic fatigue syndrome rating scale. Their data show a strong association:

“The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.”

This is very significant for clinicians involved in case management of fatigue, depression, chronic pain and autonomic dysregulation. The authors sum it up:

“The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions…These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.”

Leaky gut, LPS and depression

Yet another study in the same journal investigated increased IgA and IgM antibodies aimed at gut commensal bacteria specifically in depression. The authors measured antibodies directed against Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in depressed patients and normal controls, and found a very significant correlation to symptoms of depression and fatigue:

“The prevalences and median values of serum IgM and IgA against LPS of these commensals were significantly higher in depressed patients than in controls. The IgM levels directed against the LPS of these commensal bacteria were significantly higher in patients with chronic depression than in those without. The immune responses directed against LPS were not associated with melancholia or recurrent depression. There was a significant correlation between the IgA response directed against LPS and gastro-intestinal symptoms.”

Clinical note

The treatment of chronic fatigue and depression demands a holistic, multidisciplinary approach. A core feature with a number of potential contributing causes that can vary in each case is up-regulation of immune pathways driving inflammation in the brain and against elements in neurotransmitter production. The authors highlight these considerations in their discussion:

“The results indicate that increased bacterial translocation with immune responses to the LPS of commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression…The findings suggest that “translocated” gut commensal bacteria activate immune cells to elicit IgA and IgM responses and that this phenomenon may play a role in the pathophysiology of (chronic) depression by causing progressive amplifications of immune pathways.”

Compounds that modulate neuroinflammation induced by LPS

Neurochemistry InternationalA wide range of therapeutic resources are available to the functional practitioner to employ, depending on the individual case, that can ameliorate autoimmune inflammation triggered by reactions to the LPS of bacteria translocated through a leaky gut. By way of one example among many, a paper published in Neurochemistry International shows that anthocyanins (polyphenolic compounds imparting a blue color, found in vegetation such as blueberries) can ameliorate inflammation triggered by reactions to LPS.

“Several studies provide evidence that reactive oxygen species (ROS) are key mediators of various neurological disorders. Anthocyanins are polyphenolic compounds and are well known for their anti-oxidant and neuroprotective effects. In this study, we investigated the neuroprotective effects of anthocyanins (extracted from black soybean) against lipopolysaccharide (LPS)-induced ROS-mediated neuroinflammation and neurodegeneration in the adult mouse cortex.”

This benign intervention produced a gratifying result:

“The immunoblotting and morphological results showed that anthocyanins treatment significantly reduced LPS-induced-ROS-mediated neuroinflammation through inhibition of various inflammatory mediators, such as IL-1β, TNF-α and the transcription factor NF-kB…Anthocyanins also prevent overexpression of various apoptotic markers, i.e., Bax, cytosolic cytochrome C, cleaved caspase-3 and PARP-1. Immunohistochemical fluoro-jade B (FJB) and Nissl staining indicated that anthocyanins prevent LPS-induced neurodegeneration in the mouse cortex.”

Of particular note to the clinician:

“Our results suggest that dietary flavonoids, such as anthocyanins, have antioxidant and neuroprotective activities that could be beneficial to various neurological disorders.”

Vitamin C modulates gene expression to control inflammation

Genes and NutritionVitamin C supplementation is controversial because, as with most any other micronutrient, taking it is only going to help when it is needed due to deficiency or increased demand (a fact often overlooked in flawed studies). A fascinating study just published in the journal Genes and Nutrition reveals that vitamin C supplementation in a non-deficient, normal physiologic state has no significant effect. But in the presence of an inflammatory trigger vitamin C modulates gene expression to control inflammation. The authors state:

“In order to study the effects of vitamin C supplementation on gene expression and compare its action between physiological and inflammatory conditions, a pilot study was set up utilizing microarray and qPCR technologies.”

They supplemented healthy volunteers with 1 gram of vitamin C per day for five consecutive days and examined peripheral blood mononuclear cells (PBMNC) before and just after the last supplementation for RNA expression. They also treated the PBMNC with lipopolysaccharide (LPS, a stimulator of inflammation), and again quantified gene expression. Their observations are revealing:

Only a very moderate effect on the baseline gene expression modulation was associated with vitamin C supplementation. However, in spite of the limited number of subjects analyzed, vitamin C supplementation resulted in a markedly different modulation of gene expression upon the inflammatory stimulus, specifically at the level of the MyD88-dependent pathway and of the anti-inflammatory cytokine IL-10 synthesis.”

The authors articulate the significance of their findings:

“This study suggests that vitamin C supplementation in healthy subjects, not selected according to a specific genetic profile, consuming an adequate amount of vitamin C, and having a satisfactory vitamin C plasma concentration at the baseline, does not result in a significant modification of gene expression profile. Under this satisfactory micronutrient status, supplementation of vitamin C is “buffered” within a homeostatic physiological equilibrium. Differently, following a second “hit” constituted of an inflammatory stimulus such as LPS, able to trigger a critical burst to the normal physiological state, the higher availability of ascorbic acid emerges, and results in a significant modulation of cell response.”

Bottom line: vitamin C supplementation may do nothing in a replete individual free of inflammation, but in the presence of an inflammatory response to an immune trigger it can modulate gene expression in a favorable way to help regulate inflammation. This is an action model to consider for other micronutrients in case management.

Quercetin may protect against LPS-induced inflammation

Thrombosis ResearchQuercetin, a flavonoid compound known for its anti-inflammatory and anti-histamine properties, may help to prevent inflammation induced by reactions to lipopolysaccharides (LPS). LPS are potent stimulators of immune reactions, so much so that they are used as adjuvants in vaccines. Do you manage patients with autoimmune disorders and impaired gut barrier function who have a bacterial or fungal gut infection? Then you’re familiar with the clinical plight of needing to clear the infection but avoid amplifying the autoimmune inflammatory response by exposure to LPS and the cell walls of pathogenic organisms break down.

This is certainly a complex matter of timing in case management, yet a paper recently published in the journal Thrombosis Research offers evidence that quercetin may help protect patients from autoimmune flare-ups while treating associated gut infections. The authors examined the effects of quercitin on LPS-induced disseminated intravascular coagulation (DIC), a condition that includes the activation of coagulation pathways by pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), ‘players’ in autoimmunity. The authors state:

“Quercetin is widely distributed in plants and has been reported to have effects of anti-inflammation and anti-thrombosis. In this study, we evaluated the protective effect of quercetin on LPS-induced experimental DIC in rabbits, and tried to clarify its mechanism against DIC.”

They induced DIC in their study animals by LPS and observed quercetin-treated groups of several dosages, the LPS control group, a heparin control group and a saline control group for APTT, PT, and plasma levels of FIB, ALT, BUN, along with the activity of Protein C and ATIII. Quercetin had a marked protective effect:

“A continuous injection of LPS induced a gradual impairment of hemostatic parameters, a rise in plasma level of TNF-α, and damage in renal and hepatic function. The intravenous administration of quercetin significantly attenuated the increase of APTT, PT, ALT, BUN, and TNF-α, and the decrease of plasma FIB level and activity of Protein C and ATIII.”

Clinical note: Caution should still be observed when treating chronic infections complicating autoimmune disorders and careful thought given to timing and the recovery of tolerance, but quercetin can be considered as part of the treatment plan when risking exposure to LPS as a consequence of antimicrobial therapy.

The authors conclude:

Quercetin may have a protective effect against LPS-induced DIC in rabbits through anti-inflammation and anticoagulation.”