Gut Microbiota Alterations in Trace Amine-Associated Receptor 9 (TAAR9) Knockout Rats

Abstract

Trace amine-associated receptors (TAAR1-TAAR9) are a family of G-protein-coupled monoaminergic receptors which might have great pharmacological potential. It has now been well established that TAAR1 plays an important role in the central nervous system. Interestingly, deletion of TAAR9 in rats leads to alterations in the periphery. Previously, we found that knockout of TAAR9 in rats (TAAR9-KO rats) decreased low-density lipoprotein cholesterol levels in the blood. TAAR9 was also identified in intestinal tissues, and it is known that it responds to polyamines. To elucidate the role of TAAR9 in the intestinal epithelium, we analyzed TAAR9-co-expressed gene clusters in public data for cecum samples. As identified by gene ontology enrichment analysis, in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death. Additionally, TAAR9 was co-expressed with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission. To further investigate how TAAR9 might be involved in colonic mucosal homeostasis, we analyzed the fecal microbiome composition in TAAR9-KO rats and their wild-type littermates. We identified a significant difference in the number of observed taxa between the microbiome of TAAR9-KO and wild-type rats. In TAAR9-KO rats, the gut microbial community became more variable compared with the wild-type rats. Furthermore, it was found that the family Saccharimonadaceae, which is one of the top 10 most abundant families in TAAR9-KO rat feces, is almost completely absent in wild-type animal fecal samples. Taken together, these data indicate a role of TAAR9 in intestinal function.

A role of trace amine-associated receptors in the immune system function

“…In TAAR9-KO rats, the gut microbial community was more variable compared to that in the wild-type rats. The research of Taquet et al 2012 [51] detected elevated activation of TAAR2, TAAR5 and TAAR9 genes in the material obtained from a biopsy of inflamed large intestine wall tissues in patients with Crohn's disease. The work of Christian et al, 2018 suggested a TAAR-centric hypothesis for IBD, according to which a change in homeostasis of trace amines in large intestine tissue mucous membrane could lead to immune system cell hyperactivity [16].…”

“…A higher level of betaphenylethylamine in the feces could be one of the Crohn's disease markers [50]. A role of TAAR9 in intestinal function has been demonstrated in TAAR9 knockout rats [51]. First, gene ontology enrichment analysis have revealed that in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death as well as with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission.…”

Trace Amine-Associated Receptors’ Role in Immune System Functions

“…A higher level of β-phenylethylamine in the feces could be one of the Crohn's disease markers [60]. A role of TAAR9 in intestinal function has been demonstrated in TAAR9 knockout rats [61]. First, gene ontology enrichment analysis has revealed that in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death, as well as with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission.…”

“…Elevated TAAR expression was found in the large intestine wall cells of patients with Crohn's disease. [58,60,61] A study of over 350 genes for associations with fibromyalgia, in which 496 patients with fibromyalgia and 348 people without chronic pains (control) participated, found statistically significant differences for genes GABRB3 (rs4906902; P = 3.65 × 10 −6 ), TAAR1 (rs8192619; P = 1.11 × 10 −5 ), and GBP1 (rs7911; P = 1.06 × 10 −4 ). The products of these genes may promote the development of this disease and be the potential target for therapy [62].…”

Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

“…They play a critical role in detecting volatile amines associated with distinct ethological or ecological cues, and their ligands are present in decaying foods and animal body fluids as a consequence of the decarboxylation of amino acids by endogenous enzymes or through microbial metabolism . TAs mediate innate animal social communication, such as sexual attraction, predator avoidance and aversive response that are crucial for animal survival and reproduction. , Recent evidence of the presence of TAAR2–9 members in several extranasal tissues suggests their involvement in physiological processes other than olfaction. − TAAR2–9 receptors are now suggested as potential drug targets for several diseases, including food-induced inflammatory responses (e.g., Crohn′s disease, ulcerative colitis), metabolic disorders (e.g., type-2 diabetes, obesity) and even melanoma. − However, a detailed characterization of TAAR2–9 is hampered by their low expression levels and the limited number of experimentally identified ligands …”