ABSTRACT
BACKGROUND & AIMS: Separation of newborn rats from their mothers induces visceral hypersensitivity and impaired epithelial secretory cell lineages when they are adults. Little is known about the mechanisms by which maternal separation causes visceral hypersensitivity or its relationship with defects in epithelial secretory cell lineages. METHODS: We performed studies with C3H/HeN mice separated from their mothers as newborns and mice genetically engineered (Sox9flox/flox-vil-cre on C57BL/6 background) to have deficiencies in Paneth cells. Paneth cell deficiency was assessed by lysozyme staining of ileum tissues and lysozyme activity in fecal samples. When mice were 50 days old, their abdominal response to colorectal distension was assessed by electromyography. Fecal samples were collected and microbiota were analyzed using Gut Low-Density Array quantitative polymerase chain reaction. RESULTS: Mice with maternal separation developed visceral hypersensitivity and defects in Paneth cells, as reported from rats, compared with mice without maternal separation. Sox9flox/flox-vil-Cre mice also had increased visceral hypersensitivity compared with control littermate Sox9flox/flox mice. Fecal samples from mice with maternal separation and from Sox9flox/flox-vil-cre mice had evidence for intestinal dysbiosis of the microbiota, characterized by expansion of Escherichia coli. Daily gavage of conventional C3H/HeN adult mice with 109 commensal E coli induced visceral hypersensitivity. Conversely, daily oral administration of lysozyme prevented expansion of E coli during maternal separation and visceral hypersensitivity. CONCLUSIONS: Mice with defects in Paneth cells (induced by maternal separation or genetically engineered) have intestinal expansion of E coli leading to visceral hypersensitivity. These findings provide evidence that Paneth cell function and intestinal dysbiosis are involved in visceral sensitivity.
Subject(s)
Anxiety, Separation/complications , Escherichia coli/growth & development , Gastrointestinal Microbiome , Hyperalgesia/etiology , Paneth Cells/microbiology , Visceral Pain/etiology , Age Factors , Animals , Animals, Newborn , Anxiety, Separation/metabolism , Anxiety, Separation/microbiology , Anxiety, Separation/physiopathology , Disease Models, Animal , Dysbiosis , Feces/microbiology , Female , Genetic Predisposition to Disease , Hyperalgesia/metabolism , Hyperalgesia/microbiology , Hyperalgesia/physiopathology , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Muramidase/administration & dosage , Muramidase/metabolism , Paneth Cells/metabolism , Phenotype , SOX9 Transcription Factor/genetics , SOX9 Transcription Factor/metabolism , Visceral Pain/metabolism , Visceral Pain/microbiology , Visceral Pain/physiopathologySubject(s)
Autoimmune Diseases/microbiology , Child Behavior Disorders/microbiology , Pharyngitis/complications , School Nursing/methods , Streptococcal Infections/complications , Anxiety, Separation/microbiology , Attention Deficit Disorder with Hyperactivity/microbiology , Autoimmune Diseases/nursing , Child , Child Behavior Disorders/nursing , Humans , Nurse's Role , Obsessive-Compulsive Disorder/microbiology , Personality Disorders/microbiology , Syndrome , Tics/microbiologyABSTRACT
The integrity of the indigenous microflora of the intestines after maternal separation was investigated in infant rhesus monkeys to determine whether psychological stress may lead to an internal environment conducive to pathogen infection. The stability of the indigenous microflora were estimated by enumeration of total and gram-negative aerobic and facultatively anaerobic bacterial species, specifically Lactobacilli, from coprocultures taken before and after maternal separation. In addition, behavioral and cortisol responses to separation were correlated to the microflora. A significant decrease in fecal bacteria, especially Lactobacilli, was evident on day 3 postseparation, with a return to baseline by the end of the week. The drop in the microflora was correlated with the display of stress-indicative behaviors, but not with cortisol secretion. In addition, infants who displayed numerous stress-indicative behaviors were more susceptible to opportunistic bacterial infection. These results suggest that strong emotional reactions to disruption of the mother-infant bond may increase vulnerability to disease.
