Dysbiosis of gut microbiome affecting small intestine morphology and immune balance:a rhesus macaque model

There is a growing appreciation for the specific health benefits conferred by commensal microbiota on their hosts.Clinical microbiota analysis and animal studies in germ-free or antibiotic-treated mice have been crucial for improving our understanding of the role of the microbiome on the host mucosal surface;however,studies on the mechanisms involved in microbiome-host interactions remain limited to small animal models.Here,we demonstrated that rhesus monkeys under short-term broad-spectrum antibiotic treatment could be used as a model to study the gut mucosal host-microbiome niche and immune balance with steady health status.Results showed that the diversity and community structure of the gut commensal bacteria in rhesus monkeys were both disrupted after antibiotic treatment.Furthermore,the 16S rDNA amplicon sequencing results indicated that Escherichia-Shigella were predominant in stool samples 9 d of treatment,and the abundances of bacterial functional genes and predicted KEGG pathways were significantly changed.In addition to inducing aberrant morphology of small intestinal villi,the depletion of gut commensal bacteria led to increased proportions of CD3+T,CD4+T,and CD16+NK cells in peripheral blood mononuclear cells(PBMCs),but decreased numbers of Treg and CD20+B cells.The transcriptome of PBMCs from antibiotic-treated monkeys showed that the immune balance was affected by modulation of the expression of many functional genes,including IL-13,VCAM1,and LGR4.

Neonatal rhesus monkeys as an animal model for rotavirus infection

AIM To establish a rotavirus(RV)-induced diarrhea model using RV SA11 in neonatal rhesus monkeys for the study of the pathogenic and immune mechanisms of RV infection and evaluation of candidate vaccines.METHODS Neonatal rhesus monkeys with an average age of 15-20 d and an average weight of 500 g ± 150 g received intragastric administration of varying doses of SA11 RV( 107 PFUs/mL, 106 PFUs/mL, or 105 PFUs/mL, 10 mL/animal) to determine whether the SA11 strain can effectively infect these animals by observing their clinical symptoms, fecal shedding of virus antigen by ELISA, distribution of RV antigen in the organs by immunofluorescence, variations of viral RNA load in the organs by qRT-PCR, histopathological changes in the small intestine by HE staining, and apoptosis of small intestinal epithelial cells by TUNEL assay.RESULTS The RV monkey model showed typical clinical diarrhea symptoms in the 108 PFUs SA11 group, where we observed diarrhea 1-4 d post infection(dpi) and viral antigen shed in the feces from 1-7 dpi. RV was found in jejunal epithelial cells. We observed a viral load of approximately 5.85 × 103 copies per 100 mg in the jejunum at 2 dpi, which was increased to 1.09 × 105 copies per 100 mg at 3 dpi. A relatively high viral load was also seen in mesenteric lymph nodes at 2 dpi and 3 dpi. The following histopathological changes were observed in the small intestine following intragastric administration of SA11 RV: vacuolization, edema, and atrophy. Apoptosis in the jejunal villus epithelium was also detectable at 3 dpi.CONCLUSION Our results indicate that we have successfully established a RV SA11 strain diarrhea model in neonatal rhesus monkeys. Future studies will elucidate the mechanisms underlying the pathogenesis of RV infection, and we will use the model to evaluate the protective effect of candidate vaccines.

Nonhuman Primate Model of Oculocutaneous Albinismwith TYR and OCA2 Mutations

Human visual acuity is anatomically determined by the retinal fovea.The ontogenetic development of the fovea can be seriously hindered by oculocutaneous albinism(OCA),which is characterized by a disorder of melanin synthesis.Although people of all ethnic backgrounds can be affected,no efficient treatments for OCA have been developed thus far,due partly to the lack of effective animal models.Rhesus macaques are genetically homologous to humans and,most importantly,exhibit structures of the macula and fovea that are similar to those of humans;thus,rhesus macaques present special advantages in the modeling and study of human macular and foveal diseases.In this study,we identified rhesus macaque models with clinical characteristics consistent with those of OCA patients according to observations of ocular behavior,fundus examination,and optical coherence tomography.Genomic sequencing revealed a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2,both of which were further confirmed to affect melanin biosynthesis via in vitro assays.These rhesus macaque models of OCA will be useful animal resources for studying foveal development and for preclinical trials of new therapies for OCA.