Leaky gut: inflammation, chronic fatigue and depression

'Leaky 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

An 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

A 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."