Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model
Authors: Bose, Dipro; Saha, Punnag; Mondal, Ayan; Fanelli, Brian; Seth, Ratanesh K.; Janulewicz, Patricia; Sullivan, Kimberly; Lasley, Stephen; Horner, Ronnie; Colwell, Rita R.; Shetty, Ashok K.; Klimas, Nancy; Chatterjee, Saurabh
Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1 beta in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1 beta, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.
Maternal administration of probiotics promotes gut development in mouse offsprings
Authors: Yu, Yueyue; Lu, Jing; Oliphant, Kaitlyn; Gupta, Nikhilesh; Claud, Katerina; Lu, Lei
Necrotizing enterocolitis is the most common gastrointestinal disorder in premature neonates. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development. Studies have shown that probiotic administration can decrease NEC incidence and mortality. The proposed mechanisms of probiotics for the prevention of NEC are: promotion of intestinal development; improved barrier function through decreased apoptosis and improved mucin production; decreased expression of proinflammatory cytokines IL6, IL8, and TNF alpha, and modulation of microbiota dysbiosis in preterm infants. However, reported sepsis in the immunocompromised preterm host has deterred routine prophylactic administration of probiotics in the neonatal intensive care unit. We hypothesize that maternal administration of probiotics to pregnant mouse dams can recapitulate the beneficial effects observed in neonates fed with probiotics directly. We exposed pregnant mice to the probiotics and monitored the changes in the developing intestines of the offspring. Pregnant mice were fed daily with the probioticsLactobacillus acidophilusandBifidobacterium infantis(LB) from embryonic day15 to 2-week-old postnatally. Intraperitoneal administration of IL-1 beta in the pups was used to model proinflammatory insults. Sera were collected at 2 weeks of age and evaluated for inflammatory cytokines by enzyme-linked-immunosorbent-assay and gut permeability by Fluorescein isothiocyanate-dextran tracer assay. Ileal tissues were collected for the evaluation of apoptosis and proliferation of the intestinal epithelium; as well as mucin and tight junction integrity at mucosal surface by immunofluorescent staining. We find that maternal LB exposure facilitated intestinal epithelial cell differentiation, prevented loss of mucin and preserved the intestinal integrity and barrier function and decreased serum levels of IL-1 beta, TNF-alpha and IL-6 in the preweaned offsprings. in LB exposed pups. We demonstrate that maternal probiotic supplementation promotes gut maturation in developing offspring. This is potentially a safe alternative therapy to induce intestinal maturation and prevent prematurity-associated neonatal disorders.