Growth faltering regardless of chronic diarrhea is associated with mucosal immune dysfunction and microbial dysbiosis in the gut lumen

Abstract

Despite the impact of childhood diarrhea on morbidity and mortality, our understanding of its sequelae has been significantly hampered by the lack of studies that examine samples across the entire intestinal tract. Infant rhesus macaques are naturally susceptible to human enteric pathogens and recapitulate the hallmarks of diarrheal disease such as intestinal inflammation and growth faltering. Here, we examined intestinal biopsies, lamina propria leukocytes, luminal contents, and fecal samples from healthy infants and those experiencing growth faltering with distant acute or chronic active diarrhea. We show that growth faltering in the presence or absence of active diarrhea is associated with a heightened systemic and mucosal pro-inflammatory state centered in the colon. Moreover, polyclonal stimulation of colonic lamina propria leukocytes resulted in a dampened cytokine response, indicative of immune exhaustion. We also detected a functional and taxonomic shift in the luminal microbiome across multiple gut sites including the migration of Streptococcus and Prevotella species between the small and large intestine, suggesting a decompartmentalization of gut microbial communities. Our studies provide valuable insight into the outcomes of diarrheal diseases and growth faltering not attainable in humans and lays the groundwork to test interventions in a controlled and reproducible setting.

Coated Zinc Oxide Improves Growth Performance of Weaned Piglets via Gut Microbiota

“…Interestingly, our results also found Streptococcus was gathered in the colonic lumen in the CON group to some extent, rather than ileal lumen. Given that Streptococcus normally resided in the small intestine, the unusual microbiome transition indicated the disappearance of intestinal microbiome regionalization in the stress of weaning (41). Because of the drastic increase of Streptococcus in ileal lumen compared with other groups, we speculated that Streptococcus might be a mediator for the positive effect of C_ZnO.…”

Common and Not-So-Common Pathologic Findings of the Gastrointestinal Tract of Rhesus and Cynomolgus Macaques

“…28 Therefore, disturbance of the intestinal microbiota, such as may occur following growth faltering, infectious enterocolitides, or antibacterial therapy, may predispose animals to the development of chronic diarrhea syndromes. 27,29 The gastrointestinal segments are highlighted by the following colors: the esophagus is dark yellow, stomach is pink, duodenum is lilac, jejunum is periwinkle, ileum is mint green, cecum is yellow-green, ascending colon is blue, transverse colon is purple, descending colon is bright green, and rectum is yellow. Rhesus macaque, gastrointestinal tract.…”

Functional, transcriptional, and microbial shifts associated with healthy pulmonary aging in rhesus macaques

“…Indeed, aged rhesus macaques recapitulate the hallmarks of immune senescence, including the depletion of circulating naive T cells, accumulation of memory T cells, lymphoid fibrosis, and chronic low-grade inflammation ( Jankovic et al, 2003 ; Chiou et al, 2020 ; Haberthur et al, 2010 ; Thompson et al, 2019 ; Asquith et al, 2012 ). Moreover, outdoor-housed rhesus macaques experience a life-long exposure to environmental and microbial antigens and have been used to study microbiome development and stability at multiple sites ( Rhoades et al, 2019 , 2021b ; Cadena et al, 2018 ; Morris et al, 2016 ).…”