Vasoactive Intestinal Peptide Deficiency Is Associated With Altered Gut Microbiota Communities in Male and Female C57BL/6 Mice

Abstract

Vasoactive intestinal peptide (VIP) is crucial for gastrointestinal tract (GIT) health. VIP sustains GIT homeostasis through maintenance of the intestinal epithelial barrier and acts as a potent anti-inflammatory mediator that contributes to gut bacterial tolerance. Based on these biological functions by VIP, we hypothesized that its deficiency would alter gut microbial ecology. To this end, fecal samples from male and female VIP+/+, VIP+/–, and VIP–/– littermates (n = 47) were collected and 16S rRNA sequencing was conducted. Our data revealed significant changes in bacterial composition, biodiversity, and weight loss from VIP–/– mice compared to VIP+/+ and VIP+/– littermates, irrespective of sex. The gut bacteria compositional changes observed in VIP–/– mice was consistent with gut microbial structure changes reported for certain inflammatory and autoimmune disorders. Moreover, predicted functional changes by PICRUSt software suggested an energy surplus within the altered microbiota from VIP–/– mice. These data support that VIP plays an important role in maintaining microbiota balance, biodiversity, and GIT function, and its genetic removal results in significant gut microbiota restructuring and weight loss.

The G Protein-Coupled Receptor, VPAC1, is The Principle Driver for VIP Deficiency-Induced Alterations of Gut Microbiota in C57BL/6 Mice.

“…VPAC1 KO fecal samples, which showed more substantial β-diversity changes compared to VPAC2 KO animals, also showed reductions in richness and α-diversity. Moreover, altered OTUs from VPAC1 fecal samples, including Bacteroides, Parabacteroides, Lactobacillus and Parasutterella, shared signi cant agreement to altered OTUs from VIP KO samples previously published 19 . In total, these data support that VIP receptor de ciency is associated with changes in gut microbiota ecology to different magnitudes and signaling mechanisms, highlighting their importance for gut health and homeostasis.…”

“…In this report, we show that genetic deletion of VPAC1 in homozygous mutant (KO) samples was associated with substantial changes in the gut microbiota composition compared to VPAC1 heterozygous (HET) or VPAC1 wild type (WT) littermates, irrespective of sex. Interestingly, out of the 94 differentially abundant OTUs in VPAC1 KO samples, there was agreement (≈63%) with statistically altered OTUs reported for VIP KO samples 19 . VPAC2 de ciency also resulted in differences compared to littermate controls, although the difference was much more subtle relative to the differences found in VPAC1-de cient mice.…”

“…This "invisible metabolic organ" consists of trillions of microorganisms consisting of bacteria, fungi, archaea, eukaryotic parasites and viruses that play a vital role in host physiology, metabolism and immunity [reviewed in 16 ]. There are many factors that in uence the composition of the gut bacterial component of the microbiota (referred to as the gut microbiota from herein), including the mode of child birth 17 , breast feeding 18 , host genetics 19,20 , diet 21,22 and infection 23 . Diet and infection have been shown to have rapid, but reversible changes in microbiota composition.…”

“…Recently, our research group reported that VIP-de cient mice are associated with an altered gut microbiota ecology compared to wild-type (WT) littermates as assessed by culture-independent, 16S rRNA amplicon sequencing 19 . Although this report was the rst demonstration that VIP de ciency is associated with changes in the gut microbiota composition, the identity of the speci c VIP receptor driving these changes in the gut microbiota remains unknown.…”

Galanin receptor 3 attenuates inflammation and influences the gut microbiota in an experimental murine colitis model

“…It has become apparent that the intestinal microbiota not only influences disease susceptibility 35 , 36 , but also affects inflammatory processes in general 50 , 51 . Several studies have shown direct involvement of neuropeptide systems in maintaining microbiome homeostasis 52 , 53 . The composition of commensal bacteria was unaffected by loss of GAL 3 R in healthy mice; therefore, increased disease susceptibility due to alterations to the microbiota in GAL 3 R-KO mice could be excluded.…”