Abstract
Human rotavirus (HRV) is a leading cause of severe childhood diarrhea, and there is limited vaccine efficacy in the developing world. Neonatal gnotobiotic pigs consuming a prophylactic synbiotic combination of probiotics and rice bran (Pro+RB) did not exhibit HRV diarrhea after challenge. Multiple immune, gut barrier protective, and anti-diarrheal mechanisms contributed to the prophylactic efficacy of Pro+RB when compared to probiotics (Pro) alone. In order to understand the molecular signature associated with diarrheal protection by Pro+RB, a global non-targeted metabolomics approach was applied to investigate the large intestinal contents and serum of neonatal gnotobiotic pigs. The ultra-high performance liquid chromatography-tandem mass spectrometry platform revealed significantly different metabolites (293 in LIC and 84 in serum) in the pigs fed Pro+RB compared to Pro, and many of these metabolites were lipids and amino acid/peptides. Lipid metabolites included 2-oleoylglycerol (increased 293.40-fold in LIC of Pro+RB, p = 3.04E-10), which can modulate gastric emptying, andhyodeoxycholate (decreased 0.054-fold in the LIC of Pro+RB, p = 0.0040) that can increase colonic mucus production to improve intestinal barrier function. Amino acid metabolites included cysteine (decreased 0.40-fold in LIC, p = 0.033, and 0.62-fold in serum, p = 0.014 of Pro+RB), which has been found to reduce inflammation, lower oxidative stress and modulate mucosal immunity, and histamine (decreased 0.18-fold in LIC, p = 0.00030, of Pro+RB and 1.57-fold in serum, p = 0.043), which modulates local and systemic inflammatory responses as well as influences the enteric nervous system. Alterations to entire LIC and serum metabolic pathways further contributed to the anti-diarrheal and anti-viral activities of Pro+RB such as sphingolipid, mono/diacylglycerol, fatty acid, secondary bile acid, and polyamine metabolism. Sphingolipid and long chain fatty acid profiles influenced the ability of HRV to both infect and replicate within cells, suggesting that Pro+RB created a protective lipid profile that interferes with HRV activity. Polyamines act on enterocyte calcium-sensing receptors to modulate intracellular calcium levels, and may directly interfere with rotavirus replication. These results support that multiple host and probiotic metabolic networks, notably those involving lipid and amino acid/peptide metabolism, are important mechanisms through which Pro+RB protected against HRV diarrhea in neonatal gnotobiotic pigs.
Highlights
human rotavirus (HRV) is the most common cause of severe diarrhea in children under 5, and annually it is responsible for approximately 450,000 deaths worldwide (Clarke and Desselberger, 2015)
Associated with normal tissue histology and healthy levels of serum gut permeability markers throughout the HRV challenge (Yang et al, 2015). Additional studies with this pig model have demonstrated the ability of prophylactic synbiotic combination of LGG/EcN and rice bran (RB) (Pro+RB) to substantially reduce human norovirus-associated diarrhea, while stimulating more potent adaptive immune responses against viral antigens, and preserving colonic tissue architecture during infection (Lei et al, 2016). These findings suggested that the synbiotic combination of a probiotic and a prebiotic functioned through multiple immune, gut barrier protective and anti-diarrheal mechanisms to enhance protection against HRV diarrhea
Across Pro+RB and Pro treatments, 625 total metabolites were detected in the large intestinal contents (LIC) and 532 metabolites were detected in the serum (Table 1)
Summary
HRV is the most common cause of severe diarrhea in children under 5, and annually it is responsible for approximately 450,000 deaths worldwide (Clarke and Desselberger, 2015). The combination of limited vaccine efficacy and compromised gut function warrants the need for more effective preventive strategies against HRV, especially in developing countries. Probiotic bacteria, including LGG and EcN, represent a safe, alternative therapeutic that can reduce the severity of HRV diarrhea. LGG demonstrated a strong adjuvant effect when supplemented with an oral attenuated HRV vaccine and increased mucosal populations of HRV-specific IFN-gamma producing T lymphocytes (Wen et al, 2015). These results support that probiotics can function as an effective component of a prophylactic HRV treatment
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