Indigenous bacteria from the gut Microbiota regulate Host serotonin Biosynthesis 小组成员: 叶建宇14301010010 施亭 ●刘晨阳143010090 张凌哲14301050021
Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis 小组成员： 叶建宇 14301010010 施亭 14301010018 刘晨阳 14301010049 张凌哲 14301050021
○ INTRODUCTION
INTRODUCTION
SEROTONIN (5-HYDROXYTRYPTAMINE 5-HTD o a brain neurotransmitter and an important regulatory factor in the gastrointestinal (Gi)tract and other organ systems o More than 90% of the bodys 5-HT is synthesized in the gut, where 5-HT activates as many as 14 different 5-HT receptor subtypes located on enterocytes enteric neurons. and immune cell and secretory reflexes, platelet aggregation, immune responses, and bone otor o As such, gut-derived 5-HT regulates diverse functions, including enteric motor development, and cardiac function o Dysregulation of peripheral 5-hT is implicated in the pathogenesis of several diseases, including irritable bowel syndrome(BS)(肠易激综合 征) cardiovascular disease(心血管疾病), and osteoporosis(骨质疏松 症) o 5-HT is synthesized by specialized endocrine cells, called mast cells(黏膜肥大细胎(场嗜铬细胞)(ECs), as well as mucosal enterochromaffin ce and myenteric neurons s(肠肌间神经)
SEROTONIN (5-HYDROXYTRYPTAMINE [5-HT]) a brain neurotransmitter and an important regulatory factor in the gastrointestinal (GI) tract and other organ systems. More than 90% of the body’s 5-HT is synthesized in the gut, where 5-HT activates as many as 14 different 5-HT receptor subtypes located on enterocytes , enteric neurons, and immune cells. As such, gut-derived 5-HT regulates diverse functions, including enteric motor and secretory reflexes, platelet aggregation, immune responses , and bone development, and cardiac function. Dysregulation of peripheral 5-HT is implicated in the pathogenesis of several diseases, including irritable bowel syndrome (IBS) （肠易激综合 征）,cardiovascular disease（心血管疾病） , and osteoporosis（骨质疏松 症）. 5-HT is synthesized by specialized endocrine cells, called enterochromaffin cells (肠嗜铬细胞) (ECs), as well as mucosal mast cells （黏膜肥大细胞）and myenteric neurons（肠肌间神经）
BIOSYNTHESIS OF 5-T DH L-Tryptophan o In animals including N humans. serotonin is synthesized from the amino acid L-tryptophan Hydraxytetra by a short metabolic pathway consisting of two enzymes tryptophan 5-Hydroxy-L-tryptophan (5-HTP) NH2 hydroxylase (TPh) and aromatic amino acid decarboxylase resonate 5-Hydroxytryptophan decarboxylase ①DDC. The TH mediated reaction is the rate-limiting step in the pathway Serotonin (5-HT) NH? o tPh has been shown to O2 HzO Monoamine oxidase (MAO). exist in two forms: TPH1 Aldehyde dehydrogenase NH H> found in several tissues and tph2. which is a neuron-specific isoform OH 5-Hydroxyindoleacetic acid (5-HIAA)
BIOSYNTHESIS OF 5-HT In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC). The TPHmediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform
FACTS ALREADY KNOWN o Serum concentrations of 5-HT are substantially reduced in mice reared in the absence of microbial colonization (germ-free GFD, compared to conventionally- colonized(specific pathogen-free [sPFD controls o Intestinal ECs are morphologically larger in gF versus SPF rats o Some species of bacteria grown in culture can produce 5 HT
FACTS ALREADY KNOWN Serum concentrations of 5-HT are substantially reduced in mice reared in the absence of microbial colonization (germ-free [GF]), compared to conventionallycolonized (specific pathogen-free [SPF]) controls. Intestinal ECs are morphologically larger in GF versus SPF rats. Some species of bacteria grown in culture can produce 5- HT
AIMS o Determine how pathways of 5-ht metabolism are affected by the gut microbiota o Identify specific microbial communities and factors involved in conferring serotonergic effects o Evaluate how microbial modulation of peripheral 5-HT impacts host physiology
AIMS Determine how pathways of 5-HT metabolism are affected by the gut microbiota. Identify specific microbial communities and factors involved in conferring serotonergic effects. Evaluate how microbial modulation of peripheral 5-HT impacts host physiology
RESULTS elevated by Sp and hSp
RESULTS elevated by Sp and hSp
GF MICE EXHIBIT SIGNIFICANTLY DECREASED LEVELS OF seRUM colonic 5-ht A n s ★★★ 1.25 3.0 1.00 生2 0.75 1.5 10 0.25 05 0.00 0. SPF GE PO P21 P42 Po P21 P42 P42 SPF GF PO P21 P42 PO P21 P42 P42 GF+CONV SPF+ABX VEH GF+CONV. SPF+ABX VEH
GF MICE EXHIBIT SIGNIFICANTLY DECREASED LEVELS OF SERUM & COLONIC 5-HT
1000 o 5-hT are localized to colonic 8000 chromogranin A-posotive( CgA+) 600 enterochromaffin cells(ECs)(p +oo 铬粒蛋白A阳性的肠嗜铬细胞) SPF GF P21 P42 P21 P42 GFGF +Sp +Sp F+CONv.SPF十ABX +PCPA CgA+ 5-HT SPF GF
5-HT are localized to colonic chromogranin A-posotive (CgA+) enterochromaffin cells (ECs)（嗜 铬粒蛋白A阳性的肠嗜铬细胞）
o Which are the specific steps of 5-HT metabolism that are affected by the microbiota? o TPHl: the rate-limiting enzyme for 5-ht biosynthesis in ECS O SLC6A4: 5-hT transporter
Which are the specific steps of 5-HT metabolism that are affected by the microbiota? TPH1: the rate-limiting enzyme for 5-HT biosynthesis in ECs SLC6A4: 5-HT transporter