Stress and the Gut-Brain Axis: Implications for Cancer, Inflammation and Sepsis.

BACKGROUND: The gut-brain axis has been discussed, directly or indirectly, for centuries, with the ideas of the gut affecting anything from moods to overall physiology being discussed across the centuries. With a recent explosion in research that looks to the microbiota as a mechanistic link between the gut and the brain, one sees that the gut-brain axis has various means of communication, such as through the vagus nerve and the enteric nervous system and can use the metabolites in the gut to communicate to the brain. METHODS: The purpose of this review is to view the gut-brain axis through the lens of stress and how stress, from the prenatal period all the way through adulthood can impact the physiology of a human being. Studies have shown multiple mechanisms of measurable change with disruption in the microbiota that lead to behavioral changes. There are also effects of gut inflammation on the brain and the corresponding systemic response observed. CONCLUSION: The overall literature is encouraging that the more understanding of the gut-brain axis, the greater ability to wield that understanding for therapeutic benefits.

RNASeq analysis reveals upregulation of complement C3 in the offspring gut following prenatal stress in mice.

Dysregulated activation of inflammatory signaling by the immature neonatal immune system could lead to the development of many pediatric diseases including necrotizing enterocolitis (NEC). While the mechanism(s) of pathogenesis is unknown, NEC is believed to have multifactorial causes. Microbial dysbiosis and intestinal immaturity have been implicated as potential triggers for this disease. We hypothesized that psychological stress during pregnancy negatively impacts the development of intestinal tissues in offspring and contributes to development of NEC. Consistent with this hypothesis, we previously observed shorter villi and a decrease in total surface area in the small intestine of pups derived from mice that were chronically stressed during gestation. In this study, we performed RNASeq analysis to determine the gene expression changes in the offspring gut following prenatal stress in pregnant mice and identified several differentially expressed genes (DEGs) and biological pathways. Notably, C3 was upregulated in the small intestine and contributed to a higher tissue injury score in a mesenteric ischemia model compared to unstressed controls. We discuss the potential implications of these stress-induced genes expression changes and their contribution to development of intestinal inflammation.

Prenatal stress increases IgA coating of offspring microbiota and exacerbates necrotizing enterocolitis-like injury in a sex-dependent manner.

Necrotizing enterocolitis (NEC) is an intestinal inflammatory disease with high morbidity and mortality that affects almost exclusively premature infants. Breast milk feeding is known to substantially lower NEC incidence, and specific components of breast milk, such as immunoglobulin (Ig) A, have been identified as mediating this protective effect. On the other hand, accumulating evidence suggests dysbiosis of the neonatal intestinal microbiome contributes to NEC pathogenesis. In mice, neonates can inherit a dysbiotic microbiome from dams that experience stress during pregnancy. Here we show that while prenatal stress lowers fecal IgA levels in pregnant mice, it does not result in lower levels of IgA in the breast milk. Nevertheless, coating of female, but not male, offspring microbiota by IgA is increased by prenatal stress. Accordingly, prenatal stress was found to alter the bacterial community composition in female neonates but not male neonates. Furthermore, female, but not male, offspring of prenatally stressed mothers exhibited more severe colonic tissue damage in a NEC-like injury model compared to offspring with non-stressed mothers. Our results point to prenatal stress as a possible novel risk factor for NEC and potentially reveal new avenues in NEC prevention and therapy.

Depletion of dietary aryl hydrocarbon receptor ligands alters microbiota composition and function.

The intestinal microbiota is critical for maintaining homeostasis. Dysbiosis, an imbalance in the microbial community, contributes to the susceptibility of several diseases. Many factors are known to influence gut microbial composition, including diet. We have previously shown that fecal immunoglobulin (Ig) A levels are decreased in mice fed a diet free of aryl hydrocarbon receptor (AhR) ligands. Here, we hypothesize this IgA decrease is secondary to diet-induced dysbiosis. We assigned mice to a conventional diet, an AhR ligand-free diet, or an AhR ligand-free diet supplemented with the dietary AhR ligand indole-3-carbinol (I3C). We observed a global alteration of fecal microbiota upon dietary AhR ligand deprivation. Compared to mice on the conventional diet, family Erysipelotrichaceae was enriched in the feces of mice on the AhR ligand-free diet but returned to normal levels upon dietary supplementation with I3C. Faecalibaculum rodentium, an Erysipelotrichaceae species, depleted its growth media of AhR ligands. Cultured fecal bacteria from mice on the AhR ligand-free diet, but not the other two diets, were able to alter IgA levels in vitro, as was F. rodentium alone. Our data point to the critical role of AhR dietary ligands in shaping the composition and proper functioning of gut microbiota.

The Effects of Gestational Psychological Stress on Neonatal Mouse Intestinal Development.

BACKGROUND: Psychological stress during pregnancy has been shown to cause subsequent harm to the fetus and newborn. Many studies focus on neurodevelopmental outcomes, but little is known about the effect of gestational stress on intestinal immunity and development. The purpose of this study was to determine the effect of psychological stress during pregnancy on intestinal architecture and growth in newborns. METHODS: Eight-week-old C57BL6 littermates underwent timed breeding. Pregnant dams were subjected to 1 h of daily psychological stress by using a well-established restraint model during days E7-E14. The distal ileum of 2-wk-old offspring of stressed mothers and nonstressed controls was harvested for histologic analysis. Slides were blinded to measure villus height and crypt depth and surface area. Serum was obtained to measure serum corticosterone levels. An explant model was used to measure corticosterone on the intestinal stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) and growth factors epidermal growth factor receptor and insulin-like growth factor-1. RESULTS: The villus height, crypt depth, and surface area were significantly decreased in newborn exposed to stress during gestation. In addition, corticosterone levels were elevated in 2-wk-old mice exposed to stress. Real-time polymerase chain reaction revealed that explants exposed to corticosterone had a decrease in LGR5 compared with controls and an increase in epidermal growth factor receptor. CONCLUSIONS: Here, we establish that neonatal mice from mothers that were subjected to psychological stress during pregnancy have significantly shorter villi and crypts compared with controls. In addition, pups from stressed mothers have decreased expression levels of the intestinal stem cell marker LGR5. These findings will aid in determining the effect of gestational psychological stress on intestinal development and stem cell plasticity.

Gastric microbiome and gastric cancer.

Cancer of the stomach is the fourth most common cancer worldwide. The single strongest risk factor for gastric cancer is Helicobacter pylori-associated chronic gastric inflammation. Among persons with H. pylori infection, strain-specific components, host immune responses, and environmental factors influence the risk for gastric disease, including adenocarcinoma of the stomach, although only a small proportion of infected persons develop the malignancy. Recent advances in DNA sequencing technology have uncovered a complex community of noncultivatable inhabitants of the human stomach. The interaction between these inhabitants, collectively referred to as the gastric microbiota, and H. pylori likely affects gastric immunobiology and possibly the sequelae of H. pylori infection. Thus, characterization of the gastric microbiota in subjects with and without H. pylori infection could provide new insight into gastric homeostasis and the pathogenesis of H. pylori-associated disease, including gastric cancer.