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Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness.

ABSTRACT: The microbiota's influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut-brain-immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.

SUBMITTER: Mote RS

PROVIDER: S-EPMC7579323 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness.

Mote Ryan S RS Carpenter Jessica M JM Dockman Rachel L RL Steinberger Andrew J AJ Suen Garret G Norberg Thomas T Harn Donald A DA Wagner John J JJ Filipov Nikolay M NM

International journal of environmental research and public health 20200927 19

The microbiota's influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut-brain-immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for ...[more]

PMID: 32992640

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Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.

Project description:Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to endure. These symptoms culminate into a disease known as Gulf War Illness (GWI) and affect about a third of the GW veteran population. Currently, comprehensive effective GWI treatment options are unavailable. Here, an established GWI mouse model was utilized to explore the (1) long-term behavioral and neuroinflammatory effects of deployment-related GWI chemicals exposure and (2) ability of the immunotherapeutic lacto-N-fucopentaose III (LNFPIII) to improve deficits when given months after the end of exposure. Male C57BL6/J mice (8-9 weeks old) were administered pyridostigmine bromide (PB) and DEET for 14 days along with corticosterone (CORT; latter 7 days) to emulate wartime stress. On day 15, a single injection of the nerve agent surrogate diisopropylfluorophosphate (DFP) was given. LNFPIII treatment began 7 months post GWI chemicals exposure and continued until study completion. A battery of behavioral tests for assessment of cognition/memory, mood, and motor function in rodents was performed beginning 8 months after exposure termination and was then followed by immunohistochemcal evaluation of neuroinflammation and neurogenesis. Within tests of motor function, prior GWI chemical exposure led to hyperactivity, impaired sensorimotor function, and altered gait. LNFPIII attenuated these motor-related deficits and improved overall grip strength. GWI mice also exhibited more anxiety-like behavior that was reduced by LNFPIII; this was test-specific. Short-term, but not long-term memory, was impaired by prior GWI exposure; LNFPIII improved this measure. In the brains of GWI mice, but not in mice treated with LNFPIII, glial activation was increased. Overall, it appears that months after exposure to GWI chemicals, behavioral deficits and neuroinflammation are present. Many of these deficits were attenuated by LNFPIII when treatment began long after GWI chemical exposure termination, highlighting its therapeutic potential for veterans with GWI.

Dataset Information

Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness.

Publications

Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness.

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