Drinking Water with Saccharin Sodium Alters the Microbiota-Gut-Hypothalamus Axis in Guinea Pig.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC8300211 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In humans, the vaginal microbiota is thought to be the first line of defense again pathogens including Chlamydia trachomatis. The guinea pig has been extensively used as a model to study chlamydial infection because it shares anatomical and physiological similarities with humans, such as a squamous vaginal epithelium as well as some of the long-term outcomes caused by chlamydial infection. In this study, we aimed to evaluate the guinea pig-C. caviae model of genital infection as a surrogate for studying the role of the vaginal microbiota in the early steps of C. trachomatis infection in humans. We used culture-independent molecular methods to characterize the relative and absolute abundance of bacterial phylotypes in the guinea pig vaginal microbiota in animals non-infected, mock-infected or infected by C. caviae. We showed that the guinea pig and human vaginal microbiotas are of different bacterial composition and abundance. Chlamydia caviae infection had a profound effect on the absolute abundance of bacterial phylotypes but not on the composition of the guinea pig vaginal microbiota. Our findings compromise the validity of the guinea pig-C. caviae model to study the role of the vaginal microbiota during the early steps of sexually transmitted infection.
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Project description:Kisspeptin is essential for reproductive functions in humans. As a model for the human we have used the female guinea pig, which has a long ovulatory cycle similar to that of primates. Initially, we cloned a guinea pig kisspeptin cDNA sequence and subsequently explored the distribution and 17?-estradiol (E2) regulation of kisspeptin mRNA (Kiss1) and protein (kisspeptin) by using in situ hybridization, real-time PCR and immunocytochemistry. In ovariectomized females, Kiss1 neurons were scattered throughout the preoptic periventricular areas (PV), but the vast majority of Kiss1 neurons were localized in the arcuate nucleus (Arc). An E2 treatment that first inhibits (negative feedback) and then augments (positive feedback) serum luteinizing hormone (LH) increased Kiss1 mRNA density and number of cells expressing Kiss1 in the PV at both time points. Within the Arc, Kiss1 mRNA density was reduced at both time points. Quantitative real-time PCR confirmed the in situ hybridization results during positive feedback. E2 reduced the number of immunoreactive kisspeptin cells in the PV at both time points, perhaps an indication of increased release. Within the Arc, the kisspeptin immunoreactivity was decreased during negative feedback but increased during positive feedback. Therefore, it appears that in guinea pig both the PV and the Arc kisspeptin neurons act cooperatively to excite gonadotropin-releasing hormone (GnRH) neurons during positive feedback. We conclude that E2 regulation of negative and positive feedback may reflect a complex interaction of the kisspeptin circuitry, and both the PV and the Arc respond to hormone signals to encode excitation of GnRH neurons during the ovulatory cycle.
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Project description:Microbiota-driven variations in the inflammatory response are predicted to regulate host responses to infection. Increasing evidence indicates that the gastrointestinal and respiratory tracts have an intimate relationship with each other. Gut microbiota can influence lung immunity whereby gut-derived injurious factors can reach the lungs and systemic circulation via the intestinal lymphatics. The intestinal microbiota's ability to resist colonization can be extended to systemic infections or to pathogens infecting distant sites such as the lungs. Unlike the situation with large mammals, the microtus Yersinia pestis 201 strain exhibits strong virulence in mice, but nearly no virulence to large mammals (such as guinea pigs). Hence, to assess whether the intestinal microbiota from guinea pigs was able to affect the sensitivity of mice to challenge infection with the Y. pestis 201 strain, we fed mice with guinea pig diets for two months, after which they were administered 0.5 ml of guinea pig fecal suspension for 30 days by oral gavage. The stools from each mouse were collected on days 0, 15, and 30, DNA was extracted from them, and 16S rRNA sequencing was performed to assess the diversity and composition of the gut microbiota. We found that the intestinal microbiota transplants from the guinea pigs were able to colonize the mouse intestines. The mice were then infected with Yersinia pestis 201 by lung invasion, but no statistical difference was found in the survival rates of the mice that were colonized with the guinea pig's gut microbiota and the control mice. This indicates that the intestinal microbiota transplantation from the guinea pigs did not affect the sensitivity of the mice to pneumonic plague.
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Project description:BackgroundPost-weaning diarrhea in piglets reduces growth performance and increases mortality, thereby causing serious economic losses. The intestinal epithelial cells and microbiota reciprocally regulate each other in order to maintain intestinal homeostasis and control inflammation. However, a relative paucity of research has been focused on the host-derived regulatory network that controls mucin O-glycans and thereby changes gut microbiota during diarrhea in infancy. At the development stage just after birth, the ontogeny of intestinal epithelium, immune system, and gut microbiota appear similar in piglets and human infants. Here, we investigated the changes of mucin O-glycans associated with gut microbiota using a diarrheal post-weaned piglet model.ResultsWe found that diarrhea disrupted the colonic mucus layer and caused aberrant mucin O-glycans, including reduced acidic glycans and truncated glycans, leading to an impaired gut microenvironment. Subsequently, the onset of diarrhea, changes in microbiota and bacterial translocation, resulting in compromised epithelial barrier integrity, enhanced susceptibility to inflammation, and mild growth faltering. Furthermore, we found the activation of NLRP3 inflammasome complexes in the diarrheal piglets when compared to the healthy counterparts, triggered the release of proinflammatory cytokines IL-1β and IL-18, and diminished autophagosome formation, specifically the defective conversion of LC3A/B I into LC3A/B II and the accumulation of p62. Additionally, selective blocking of the autophagy pathway by 3-MA led to the reduction in goblet cell-specific gene transcript levels in vitro.ConclusionsWe observed that diarrheal piglets exhibited colonic microbiota dysbiosis and mucosal barrier dysfunction. Our data demonstrated that diarrhea resulted in the activation of inflammasomes and autophagy restriction along with aberrant mucin O-glycans including reduced acidic glycans and truncated glycans. The results suggested the mucin O-glycans-microbiota axis is likely associated with diarrheal pathogenesis. Our study provides novel insights into the pathophysiology of early-weaning-induced diarrheal disease in piglets and potentially understanding of disease mechanisms of diarrhea for human infants. Understanding the molecular pathology and pathogenesis of diarrhea is a prerequisite for the development of novel and effective therapies. Our data suggest that facilitating O-glycan elongation, modifying the microbiota, and developing specific inhibitors to some key inflammasomes could be the options for therapy of diarrhea including human infants. Video abstract.
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Project description:The gut-brain axis is increasingly recognized as an important pathway of communication and of physiological regulation, and gut microbiota seems to play a significant role in this mutual relationship. Oxidative stress is one of the most important pathogenic mechanisms for both neurodegenerative diseases, such as Alzheimer's or Parkinson's, and acute conditions, such as stroke or traumatic brain injury. A peculiar microbiota type might increase brain inflammation and reactive oxygen species levels and might favor abnormal aggregation of proteins. Reversely, brain lesions of various etiologies result in alteration of gut properties and microbiota. These recent hypotheses could open a door for new therapeutic approaches in various neurological diseases.
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Project description:The increasing recognition that the gut microbiota plays a central role in behavior and cognition suggests that the manipulation of microbial taxa through diet may provide a means by which behavior may be altered in a reproducible and consistent manner in order to achieve a beneficial outcome for the host. Resistant starch continues to receive attention as a dietary intervention that can benefit the host through mechanisms that include altering the intestinal microbiota. Given the interest in dietary approaches to improve health, the aim of this study was to investigate whether the use of dietary resistant starch in mice to alter the gut microbiota also results in a change in behavior. Forty-eight 6 week-old male Swiss-Webster mice were randomly assigned to 3 treatment groups (n = 16 per group) and fed either a normal corn starch diet (NCS) or diets rich in resistant starches HA7 diet (HA7) or octenyl-succinate HA7 diet (OS-HA7) for 6 week and monitored for weight, behavior and fecal microbiota composition. Animals fed an HA7 diet displayed comparable weight gain over the feeding period to that recorded for NCS-fed animals while OS-HA7 displayed a lower weight gain as compared to either NCS or HA7 animals (ANOVA p = 0.0001; NCS:HA7 p = 0.244; HA7:OS-HA7 p<0.0001; NCS:OS-HA7 p<0.0001). Analysis of fecal microbiota using 16s rRNA gene taxonomic profiling revealed that each diet corresponded with a unique gut microbiota. The distribution of taxonomic classes was dynamic over the 6 week feeding period for each of the diets. At the end of the feeding periods, the distribution of taxa included statistically significant increases in members of the phylum Proteobacteria in OS-HA7 fed mice, while the Verrucomicrobia increased in HA7 fed mice over that of mice fed OS-HA7. At the class level, members of the class Bacilli decreased in the OS-HA7 fed group, and Actinobacteria, which includes the genus Bifidobacteria, was enriched in the HA7 fed group compared to the control diet. Behavioral analysis revealed that animals demonstrated profound anxiety-like behavior as observed by performance on the elevated-plus maze with time spent by the mice in the open arm (ANOVA p = 0.000; NCS:HA7 p = 0.004; NCS:OS-HA7 p = 1.000; HA7:OS-HA7 p = 0.0001) as well as entries in the open arm (ANOVA p = 0.039; NCS:HA7 p = 0.041; HA7:OS-HA7 p = 0.221; NCS:OS-HA7 p = 1.000). Open-field behavior, a measure of general locomotion and exploration, revealed statistically significant differences between groups in locomotion as a measure of transitions across quadrant boundaries. Additionally, the open-field assay revealed decreased exploration as well as decreased rearing in HA7 and OS-HA7 fed mice demonstrating a consistent pattern of increased anxiety-like behavior among these groups. Critically, behavior was not correlated with weight. These results indicate that diets based on resistant starch can be utilized to produce quantifiable changes in the gut microbiota and should be useful to "dial-in" a specific microbiome that is unique to a particular starch composition. However, undesirable effects can also be associated with resistant starch, including lack of weight gain and increased anxiety-like behaviors. These observations warrant careful consideration when developing diets rich in resistant starch in humans and animal models.
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Project description:Dietary emulsifiers are widely used in industrially processed foods, although the effects of these food additives on human gut microbiota are not well studied. Here, we investigated the effects of five different emulsifiers [glycerol monoacetate, glycerol monostearate, glycerol monooleate, propylene glycol monostearate, and sodium stearoyl lactylate (SSL)] on fecal microbiota in vitro. We found that 0.025% (w/v) of SSL reduced the relative abundance of the bacterial class Clostridia and others. The relative abundance of the families Clostridiaceae, Lachnospiraceae, and Ruminococcaceae was substantially reduced whereas that of Bacteroidaceae and Enterobacteriaceae was increased. Given the marked impact of SSL on Clostridia, we used genome reconstruction to predict community-wide production of short-chain fatty acids, which were experimentally assessed by GC-MS analysis. SSL significantly reduced concentrations of butyrate, and increased concentrations of propionate compared to control cultures. The presence of SSL increased lipopolysaccharide, LPS and flagellin in cultured communities, thereby enhancing the proinflammatory potential of SSL-selected bacterial communities.
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Project description:HypothesisTo determine the pharmacokinetics of sodium thiosulfate in the inner ear perilymph following middle ear application in Guinea pigs.BackgroundCisplatin chemotherapy is often associated with a dose-dependent high frequency sensorineural hearing loss. Sodium thiosulfate has been shown to reduce cisplatin-induced ototoxicity when given intravenously, but this may limit the tumoricidal effects of the chemotherapy. Recent animal studies looking at middle ear application of sodium thiosulfate have shown prevention of outer hair cell and hearing loss, but the perilymph pharmacokinetics have not yet been established.MethodsTwenty Guinea pig ears were split into two groups and administered sodium thiosulfate to the middle ear at either a concentration of 250 mg/mL or 50 mg/mL for 30 min. Perilymph samples were then obtained serially through the round window over 6 h. Sodium thiosulfate concentrations were obtained using high-pressure liquid chromatography.ResultsThe 250 mg/mL group had a maximum perilymph concentration of 7.27 mg/mL (±0.83) that decreased to 0.94 mg/mL (±0.03) over 6 h. The 50 mg/mL group had an initial concentration of 1.63 mg/mL (±0.17) and was undetectable after 1 h. The half-life of sodium thiosulfate within perilymph was 0.74 h.Conclusionsand Relevance: The results of this study show that sodium thiosulfate is capable of diffusing through round window and into the inner ear perilymph. Peak levels decline over several hours after exposure. This has a potential application as a localized therapy in the prevention of cisplatin induced ototoxicity.
| S-EPMC6291635 | biostudies-literature
Project description:It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other's experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer's disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.
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