Impact of intestinal disorders on central and peripheral nervous system diseases

El-Hakim, Yumna; Bake, Shameena; Mani, Kathiresh Kumar; Sohrabji, Farida

doi:10.1016/j.nbd.2022.105627

Cited by 30 publications

(24 citation statements)

References 157 publications

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“…It is well known how the gut microbiota can influence the immune system, influencing its possible response to ICI therapy ( 53 ). At same time, the mutual relationship between gut microbiota and neurologic disorders is widely recognized, since gut microbiota can interact with the CNS through the so-called microbiota–gut–brain axis ( 54 , 55 ). Probably, a genetic predisposition and microbiome alterations can play a role in the development of immune-related adverse events, including neurological complications ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data

et al. 2022

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Immune checkpoint inhibitors (ICIs) are widely used improving clinical outcomes in many cancer patients. However, they can induce serious consequences, like neurological immune-related adverse drug reactions (NirADRs). Although these are rare complications, they can be serious with important impact on patients’ quality of life. Our purpose is to describe these adverse events observed in the European clinical practice context. We carried out a descriptive analysis of individual case safety reports (ICSRs) related to ICIs collected until February 7, 2020, in the European spontaneous reporting database, EudraVigilance, and reported nervous disorders as suspect adverse drug reactions (ADRs). NirADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA). In order to identify a hypothetical different reporting probability of the NirADR types between the ICI classes, we carried out a disproportionality analysis. The reporting odds ratio (ROR) with 95% CI was computed comparing the different ICI classes to each other based on their pharmacological target [the cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1)]. Finally, we researched in the literature the hypothesized mechanisms, which could explain the onset of these ICI-related neurological complications. Overall, we found 4,875 cases describing 6,429 ICI-related suspected NirADRs. ICI-related neurotoxicities include a wide range of central and peripheral events. These were mainly related to anti-PD-1 agents and occurred in male patients (59%). Our analysis confirmed a gender difference of NirADRs. Twenty-three percent of the events (comprising myasthenia gravis, neuropathy peripheral, and cerebral infarction) had unfavorable fallouts, including fatal outcome (7%). Majority of the NirADRs were categorized as “Neurological disorders NEC” HLGTs MedDRA (2,076; 32%). In 1,094 cases (22%), more NirADRs overlapped with other neurologic complications. An interesting overlapping of myasthenia gravis with myositis or myocarditis emerged. From our disproportionality analysis, an increased reporting probability of peripheral neuropathies and headaches emerged with ipilimumab when compared to anti-PD-1 and anti-PD-L1 agents. However, neuromuscular disorders were more probably reported with anti-PD-1. Several pathogenic mechanisms, including neuronal damage by T cells and autoantibodies and/or cytokine-mediated inflammation processes, have been hypothesized. However, the pathogenesis of these ICI-related complications is not completely understood. Considering the recent marketing authorizations of ICIs, further studies are strongly needed to monitor their neurologic safety profile.

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Section: Discussionmentioning

confidence: 99%

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data

et al. 2022

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“…The inflamed GI structures can be accompanied by strong disruption of the tight junctions present among enterocytes and the development of leaky gut [ 19 ]. Low grade inflammation is the common result in these conditions, with patients reporting gastritis, reflux, colitis, diarrhea, constipation or simply low back pain [ 16 ]. Cytokines and/or toxins can then circulate and directly and/or indirectly affect the CNS, pain pathways in particular.…”

Section: Discussionmentioning

confidence: 99%

“…This competition occurs every minute in our body and is a natural part of homeostatic processes. A chronic, low-grade inflammatory state [ 16 ] can be present in patients with food hypersensitivity and/or intolerance.…”

Section: Introductionmentioning

confidence: 99%

Food-Specific IgG4 Antibody-Guided Exclusion Diet Improves Conditions of Patients with Chronic Pain

Casini

Fatighenti²,

Giannantoni³

et al. 2022

Pain Ther

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Introduction Chronic pain is related to gastrointestinal (GI) functions because food components affect inflammation and pain through their action on the GI immune and/or neural system and because many analgesics interact with the gut to alter its structure and function. Immunoglobulin G4 (IgG4) are food-specific antibodies resulting from exposure of the gut immune system to nutrients. High IgG4 levels have been found to be associated with inflammation. Methods IgG4 were determined (both with the rapid test and enzyme-linked immunosorbent assay, ELISA) in men and women outpatients with chronic pain. All subjects were asked to exclude for 4 weeks all foods to which they had high blood levels of IgG4 antibodies. Pain and quality of life questionnaires were administered before (visit 1) and after (visit 2) the personalized exclusion diet period. Visual analogue scale (VAS), Italian Pain Questionnaire (QUID) and Margolis (MA) questionnaires were administered to determine pain intensity, pain features and pain extent, while Short Form Health Survey (SF-36) and Profile of Mood States (POMS) were used to test the quality of life and mood state. The nutritional status was evaluated in all subjects. Subject groups were women of reproductive age (pre-MW), women in menopause for at least 1 year (MW) and men. Results Fifty-four subjects with chronic pain ( n = 12 neuropathic, n = 14 diffuse pain, n = 11 headache, n = 17 low back pain) completed the two visits and the 1-month exclusion diet. At visit 1, 47 (87%) subjects showed medium/high levels of IgG4 to at least one food. The foods showing the highest IgG4 values were eggs, dairy products, cereals and dried fruit. At visit 2, IgG4 levels were decreased, increased or unchanged. In all groups, the 4-week exclusion diet resulted in a significant reduction in all pain measures and an improvement of quality of life parameters. In particular, at visit 2, the VAS score determined in the morning decreased by more than 50%. Conclusions A food elimination diet based on IgG4 antibody levels may be effective in reducing pain and improving quality of life in patients with chronic pain. Supplementary Information The online version contains supplementary material available at 10.1007/s40122-022-00391-z.

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“…As it might be expected, the resident microorganisms of the intestinal epithelium in the deeper and more anaerobic regions of the small intestine are the most enriched in anaerobic and obligate anaerobic microbial species, and these deeper GI-tract regions are heavily populated by the phylum Bacteriodetes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. In these deeper regions of the human GI-tract microbiome, B. fragilis can be about ~100-fold more abundant than the phylum Proteobacteria and the genus-species Escherichia coli [ 1 , 2 , 3 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. In fact, Bacteroides attain extremely high densities in the most anaerobic regions of the human gut at about 10 10 to 10 11 cells per cubic millimeter of intestinal content and represent the major single source of Gram-negative-bacterium-derived lipopolysaccharides (LPSs) anywhere in the human body ([ 7 , 11 , 13 , 14 ]; see below).…”

Section: The Human Gastrointestinal (Gi)-tract Microbiomementioning

confidence: 99%

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

Zhao

Jaber

Pogue³

et al. 2022

IJMS

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Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In Homo sapiens, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including Bacteroides fragilis and Escherichia coli. LPSs have been abundantly detected in aged human brain by multiple independent research investigators, and an increased abundance of LPSs around and within Alzheimer’s disease (AD)-affected neurons has been found. Microbiome-generated LPSs and other endotoxins cross GI-tract biophysiological barriers into the systemic circulation and across the blood–brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including ‘leaky gut syndrome’. Further evidence indicates that LPSs up-regulate pro-inflammatory transcription factor complex NF-kB (p50/p65) and subsequently a set of NF-kB-sensitive microRNAs, including miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155. These up-regulated miRNAs in turn down-regulate a family of neurodegeneration-associated messenger RNA (mRNA) targets, including the mRNA encoding the neuron-specific neurofilament light (NF-L) chain protein. While NF-L has been reported to be up-regulated in peripheral biofluids in AD and other progressive and lethal pro-inflammatory neurodegenerative disorders, NF-L is significantly down-regulated within neocortical neurons, and this may account for neuronal atrophy, loss of axonal caliber and alterations in neuronal cell shape, modified synaptic architecture and network deficits in neuronal signaling capacity. This paper reviews and reveals the most current findings on the neurotoxic aspects of LPSs and how these pro-inflammatory glycolipids contribute to the biological mechanism of progressive, age-related and ultimately lethal neurodegenerative disorders. This recently discovered gut-microbiota-derived LPS–NF-kB–miRNA-30b–NF-L pathological signaling network: (i) underscores a direct positive pathological link between the LPSs of GI-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic-signaling of the AD brain and stressed human brain cells in primary culture; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-mediated actions on the expression of NF-L, an abundant filamentous protein known to be important in the maintenance of neuronal and synaptic homeostasis.

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Impact of intestinal disorders on central and peripheral nervous system diseases

Cited by 30 publications

References 157 publications

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data

Food-Specific IgG4 Antibody-Guided Exclusion Diet Improves Conditions of Patients with Chronic Pain

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

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