Bibliography: leaves 159-192. / viii, 192 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines aspects of the control and measurement of pyloric motor function believed to be relevant to the role(s) of the pylorus in the regulation of normal gastric emptying. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1992

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

The role of supraspinal, spinal and peripheral alpha-2 adrenoceptors in the regulation of gastrointestinal motility in mice was investigated using anatomically site specific administration of clonidine and adrenoceptor antagonists. Clonidine produced a dose-dependent inhibition of gastrointestinal transit when given by the i.c.v., i.th., or s.c. routes, and was most potent when given i.c.v. Yohimbine, an alpha-2 adrenoceptor antagonist, but not the alpha-1 antagonist prazosin, antagonized the antitransit effects of clonidine. Yohimbine was most potent in antagonizing i.c.v. clonidine; increased doses of the i.c.v. antagonist were required when the agonist was given s.c. After transection of the spinal cord, i.th. clonidine failed to produce an antitransit effect. Additionally, the i.c.v. potency of clonidine decreased approximately 7-fold in spinally-transected mice. The data suggest that the antitransit effects of clonidine occur through actions at alpha-2 adrenoceptors located at both supraspinal and peripheral sites.

Nitric oxide, a short-lived free radical and neurotransmitter, is responsible for decreased smooth muscle contractility in vitro. When in excess, NO can cause hypotension and is believed to mediate altered intestinal motility. Not enough evidence is available for morphological changes in gastrointestinal smooth muscle and its correlation with motility disorders caused by Escherichia coli-induced NO production. Male Lewis rats were treated with injections of 10 mg/kg LPS from E. coli with or without 12.5 mg/kg of NOS inhibitor, LNMMA. Eighteen to 24 hours following injection, duodenum, ileum, colon, liver, and spleen were harvested for histological analysis. Urine and fecal analysis assessed functional aspects in control and treatment groups. Muscularis externa measurements revealed significant increase in muscle thickness of LPS + LNMMA injected group compared to control and LPS group. However, the average values in control and LPS group were not significantly different. Fecal consistency was significant in all 3 groups. Mean urinary nitrite in the LPS group was 44 times higher than control and 52 times higher than the inhibitor-treated group. / Department of Physiology and Health Science

Irritable bowel syndrome (IBS), majorly characterized by irregular bowel movements and abdominal pain, is one of the most prevalent functional gastrointestinal disorders (FGIDs) in the world. Disturbance of gut microbiota, closely linking with gut dysfunction, has been regarded as one of important pathogenetic factors for IBS. However, gut microbiota-driven mechanism underlying IBS remains unclear, which leads to inefficient and non-specific effects of current microbiota-oriented therapy. In this thesis, function-based microbiota investigation with combination of metagenomic and metabolomic analyses was separately performed in IBS cohort and model to precisely link pathogenic species with disordered GI motor function. A series of microbiota manipulation studies in rodents were conducted to explore bacteria-driven molecular mechanism. Firstly, a pilot study with 'omics' analyses revealed fecal microbial structure significantly varied in IBS patients with disorder GI motility relative to healthy controls (HC). Such changed IBS enterotype was functionally characterized by disturbed metabolism of bile acids (BAs) that are previously proved to regulate GI motor function. It indicates microbiota-driven GI dysmotility relevant to disturbance of BA metabolism in IBS. Secondly, a systematic review with meta-analysis was performed to comprehensively understand existing findings related to BA metabolism and its linkage with IBS. Results showed that abnormal BA excretion, previously reported in at least one IBS subtype, is associated with dysregulation of BA synthesis, marked with abnormalities of circulating indices 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19). However, what's the role of gut microbiota in abnormal BA excretion is undetermined. Thirdly, to explore possible role of gut microbiota in abnormal BA excretion in IBS, BA metabolites and BA-related microbiome were simultaneously analyzed in stools of recruited subjects. Results found that total BA and microbiota-derived BAs were remarkably elevated in a quarter of IBS-D patients (BA+IBS-D) who exhibited more frequent defecation, higher level of serum C4 but lower level of serum FGF19 than those with normal BA excretion (BA-IBS-D). In line with metabolic results, abundances of BA-metabolizing bacteria, particularly Clostridium scindens (C. scindens) simultaneously expressed hdhA and bais that are responsible for BA 7α oxidation and dehydroxylation, were highly enriched in fecal metagenomes of such particular IBS-D population. These findings suggest the increased BA-metabolizing microbiome is associated with the dysregulated host BA synthesis in the subgroup of BA+IBS-D patients. Fourthly, by analyzing metabolites and bacteria related to BA metabolism, a neonatal maternal separation (NMS)-induced IBS-D rat model characterized by accelerated GI motility and excessive BA excretion were found to largely mimic gut microbial BA metabolism in BA+IBS-D patients. Specifically, intraluminal total and secondary BAs were significantly elevated in the large intestinal lumens (cecum, proximal colon and feces) of NMS rats, together with increased abundances of hdhA- and bais-expressing Clostridium species, including C. scindens. Moreover, quantitative polymerase chain reaction (PCR) analysis showed upregulated mRNA expression of cholesterol 7 α-hydroxylase (CYP7A1) whereas downregulated mRNA expression of small heterodimer partner (SHP) in the liver of NMS rats, indicating enhanced hepatic BA synthetic level. These observations based on such IBS-D model suggest the association of excessive BA-metabolizing microbiome and increased hepatic BA synthesis. Fifthly, to further clarify whether excessive BA-metabolizing bacteria contribute to enhanced hepatic BA synthesis and to explore the underlying molecular mechanism, we performed bacterial intervention in pseudo germ-free (GF) or/and specific pathogen free (SPF) mice by transplantation of human fecal microbiota and the signal strain C. scindens. Compared with GF mouse recipients of HC and BA-IBS-D fecal microbiota, BA+IBS-D fecal microbial recipients displayed shorter GI transit and increased subsistence of C. scindens in the cecal contents. In line with higher level of serum C4, taurine-conjugated BA contents and mRNA expressions of BA synthetase CYP7A1 and sterol 12α-hydroxylase (CYP8B1) were significantly elevated in the liver of BA+IBS-D recipients. These findings showed bioactive effects of BA+IBS-D fecal microbiota with enrichment of C. scindens on hepatic BA synthesis. Next, to further confirm the effects of the species C. scindens on host BA synthesis, we individually colonized C. scindens strains (ATCC 37504) to pseudo GF and SPF mice. Results showed both mice models with single strain colonization exhibited accelerated GI transit and higher contents of hepatic total and taurine-conjugated BAs compared with individual vehicles treated with PBS. Combining metabolic changes, the upregulated expressions of hepatic CYP7A1 mRNA in colonized mice indicate that C. scindens substantially promote hepatic BA synthesis in colonized mice. Furthermore, contents of taurine-conjugated BAs, served as natural antagonists of farnesoid X receptor (FXR) that negatively control of new BA synthesis, were elevated in ileal lumens of colonized mice. Expressions of FXR-targeted genes SHP and fibroblast growth factor 15 (FGF15) were consistently reduced in the liver and ileum tissues of colonized mice, respectively. Results suggest that suppression of FXR-mediated feedback signaling is involved in Clostridium-driven hepatic BA oversynthesis, which deserve the further investigation. Collectively, the works of this thesis integrating clinical and animal studies indicate that BA-metabolizing bacteria, particularly C. scindens, enhance hepatic BA synthesis and consequently leads to BA overexcretion. It provides novel bacteria-driven mechanism for enhanced GI motility, and supply a direction in precise microbiota-related pathogenesis and medication for IBS-D population in future.

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Bibliography: leaves 209-252. / xvi, 252 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to develop and apply accurate methods of measurement of pyloric motor function and gastric emptying to an unsedated large animal preparation. / Thesis (D.M.)--University of Adelaide, Dept. of Surgery, 1994?

Some mounted ill. / Bibliography: leaves 203-263 / vii, 263, [52], [29] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1984

In an irritable bowel syndrome (IBS) rat model, S. chinensis reversed the exaggerated visceral nocicptive responses (judged by abdominal withdrawal reflex and electromyographic measurement) to colorectal distension induced by neonatal maternal separation. Relief of visceral hypersensitivity by S. chinensis could be related to the decrease of elevated 5-HT level and the reduction in 5-HT3 receptor expression in colon. / In summary, given the modulatory effects on intestinal motility and visceral sensation, Schisandra chinensis would be potentially useful for the treatment of relieving diarrhea and visceral pain symptoms in IBS patients. Schisandra lignans, the major absorbable components, can be regarded as the active ingredients in S. chinensis for the potential treatment of IBS. / Schisandra chinensis, which is named "Wu-Wei-Zi" in Chinese Pin Yin, is widely used in Chinese medicine as an astringent, tonic and sedative agent. Dibenzo[a,c]-cyclooctadiene lignans are the major components of this herb. In the present study, the chemical constituents of S. chinensis were first characterized. A HPLC-DAD method was developed and validated for quantitative analysis of four major Schisandra lignans, namely, schisandrin (SCH-1), gomisin A (SCH-2), deoxyschisandrin (SCH-3) and gamma-schisandrin (SCH-4), in the aqueous and ethanolic extracts of S. chinensis. The ethanolic extract contains higher amount of lignan components than aqueous extract. The HPLC method has also been employed to obtain chromatographic fingerprintings to distinguish S. chinensis from a related species, S. sphenanthera. / The modulatory effects of both S. chinensis extracts and four major lignans on intestinal motility were evaluated using in vitro intestinal motility assays. The tested compounds induced relaxation on guinea pig ileum contracted by acetylcholine, serotonin and electrical field stimulation, as well as on rat colon with spontaneous contractility. While SCH-3 was most potent in inhibiting sensorimotor response in guinea pig ileum, SCH-1 displayed the highest potency of inhibition on spontaneous contraction of rat colon. / The relaxant effect on rat colon induced by SCH-1 has been demonstrated to involve two or more non-adrenergic non-cholinergic mediators. Nitric oxide was likely to be one of the inhibitory transmitters that involved cGMP-dependent pathways, whereas the non-nitrergic component was apamin-sensitive, but probably excluded vasoactive intestinal peptide (VIP) and adenosine. / With the aid of HPLC-DAD-MS for qualitative and quantitative analyses, the absorption of S. chinensis in the rat everted gut sac and human Caco-2 monolayer in vitro models have been profiled. Fifteen Schisandra lignans were identified as the major absorbable components of S. chinensis in these models. Transport study on SCH-1 has shown a passive diffusion pathway with high permeability. In an in vivo study, metabolites of Schisandra lignans could be found in rat plasma after a single oral administration of S. chinensis extract. The plasma pharmacokinetics of S. chinensis in rats was further evaluated using simultaneous quantification of four representative Schisandra lignans (SCH-1, SCH-2, SCH-3 and SCH-4). / Yang, Jiaming. / Adviser: Chun-Tao Che. / Source: Dissertation Abstracts International, Volume: 73-03, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 262-283). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.