Cholecystokinin (CCK) is a gut peptide involved in the regulation of energy homeostasis by duodenal lipids via a neuronal network. However, it is unknown whether CCK also regulates glucose homeostasis through a neuronal network. Using an in vivo rat model, we demonstrated that duodenal CCK-8 (biologically active form of CCK) can lower glucose production through the activation of a gut-brain-liver axis via CCK-A receptors, and this glucose-regulatory effect is physiologically relevant. Since duodenal lipids can also lower glucose production through a gut-brain-liver axis, we verified that this duodenal-lipid effect is mediated by CCK-A receptor activation. Lastly, in rats fed on a high-fat diet for three days, duodenal CCK failed to suppress glucose production, suggesting a state of CCK-resistance. In summary, these findings revealed that intestinal CCK can regulate glucose homeostasis through a neuronal network and suggest that intestinal CCK resistance may contribute to hyperglycemia in response to high-fat feeding.

Cholecystokinin (CCK) is a gut peptide involved in the regulation of energy homeostasis by duodenal lipids via a neuronal network. However, it is unknown whether CCK also regulates glucose homeostasis through a neuronal network. Using an in vivo rat model, we demonstrated that duodenal CCK-8 (biologically active form of CCK) can lower glucose production through the activation of a gut-brain-liver axis via CCK-A receptors, and this glucose-regulatory effect is physiologically relevant. Since duodenal lipids can also lower glucose production through a gut-brain-liver axis, we verified that this duodenal-lipid effect is mediated by CCK-A receptor activation. Lastly, in rats fed on a high-fat diet for three days, duodenal CCK failed to suppress glucose production, suggesting a state of CCK-resistance. In summary, these findings revealed that intestinal CCK can regulate glucose homeostasis through a neuronal network and suggest that intestinal CCK resistance may contribute to hyperglycemia in response to high-fat feeding.

Univ., Diss.--Paris, 1996.

Zugl.: Passau, Universiẗat, Diss., 2004.

Vagal afferents in the gut are polymodal for a multitude of chemical mediators, including beneficial and noxious sensory stimuli, and therefore must encode sensory information for the brain about the luminal environment. This sensory information has profound influence on related reflex pathways, gut function, and mood and behaviour via the gut-brain axis. Using an established mesenteric nerve recording protocol, we investigated how vagal afferents from the small intestine signal and encode information about luminal stimuli and somatic age to the brain. We investigated the role of an intramural sensory synapse between intrinsic primary afferent neurons (IPANs) of the enteric nervous system (ENS) and extrinsic vagal afferents in the gut wall in the excitatory response to luminal application of the vagus-dependent selective serotonin reuptake inhibitor (SSRI) sertraline. Vagal afferent excitation by sertraline was inhibited by intramural sensory synaptic blockade, indicating a potential role of IPAN to vagal crosstalk in the vagal response to sertraline. We examined patterns of vagal afferent firing produced by stimuli with opposing effects on behaviour to determine how the vagus encodes information pertaining to antidepressant stimuli. A distinct temporal pattern code of antidepressant vagal afferent signaling was identified that was different from the pattern code produced by non- antidepressant stimuli. Lastly, we examined how vagal afferent signaling to the brain differed in aged mice and in an aged Parkinson’s disease (PD) model. There was a significant reduction in vagal afferent firing in old and PD model mice, but this reduction was partially reversed by treatment with the excitatory aminosterol squalamine. These studies demonstrate that vagal afferent firing is critical to the communication of sensory information from the gut lumen to the brain and that this information is encoded in specific patterns of firing that are influenced by the type of stimulus and the welfare of the signalling pathway. / Thesis / Candidate in Philosophy / The vagus nerve connects the brain and gut enabling the transfer of bidirectional nervous signals, of which 80-90% transmit towards the brain. Some of these vagal signals that travel from the gut to the brain can modify behaviour or mood. We investigated a potential mechanism by which vagal afferents change firing in response to stimuli inside the gut to communicate mood-altering information to the brain and explored whether vagal signaling is vulnerable to aging. We presented evidence that the antidepressant sertraline increased vagal firing by synaptic signaling between neurons in the gut wall and vagal afferents. We demonstrated that antidepressant agents produced a specific pattern of action potential firing that might encode mood-altering information to the brain. Lastly, we found that aging and Parkinson’s disease decreased vagal afferent firing, but not insurmountably. This work identifies novel mechanisms by which intestinal vagal afferents signal the brain, which may have therapeutic applications.

The gut microbiota has been implicated in both health and disease. As such, diet is a significant determinant of gut health, whereby diet induced dysbiosis is associated with cardiometabolic risk. Interestingly, a higher proportion of Firmicutes and a lower proportion of Bacteroidetes are implicated in obesity. Strawberry polyphenols have been shown to reduce cardiovascular disease risk in addition to exhibiting prebiotic activity by increasing probiotic bacteria in the gut. Polyphenols have also been shown to reduce the ratio of Firmicutes to Bacteroidetes. Therefore, dietary modifications such as strawberry consumption may help improve health outcomes through the gut. The objective of this study was to analyze whether 13 g freeze dried strawberry powder (~1 cup/d fresh) consumption reduces the Firmicutes:Bacteroidetes ratio and increases microbial diversity and beneficial bacteria like Lactobacillus and Bifidobacterium. This study was a 5-week free-living diet intervention trial conducted at California Polytechnic State University, San Luis Obispo with expansion to the Eye Medical Center of Fresno. Participants (n=10) had a mean age of 60.5 ± 9.13 years and had a mean body weight of 74.71 ± 10.61 kg. The participants completed a 3-week washout before a 2-week diet intervention. Participants maintained their normal diet throughout the study while eliminating foods high in polyphenols and probiotics. Upon completion of the study, no significant differences were found for body weight (p=0.22) or BMI (p=0.26). Likewise, no significant differences were found for macronutrient, vitamin, or mineral intake except for sugar (p=0.03), vitamin B12 (p=0.03), and fruit (p=0.0014). Bacteria abundance and diversity were not found to be statistically significant following intervention. Since strawberry supplementation was not associated with a significant change in the relative abundance of bacteria with the dose and duration administered, a randomized controlled trial would better determine the effect of strawberry consumption on gut health.

The human gut microbiome is the collection of all organisms and their genetic content that inhabit the gastrointestinal tract. An overwhelming number of studies have associated the gut microbiota with health and disease, but with little consensus on which specific bacterial groups are important for causing or maintaining either state. A majority of microbiome studies only identify associations between the gut microbiome and health status, and determining causation requires the isolation and growth of bacterial isolates for further experiments. The goal of this thesis is to demonstrate that the combination of culture-based and culture-independent methods describes greater complexity and diversity in the human gut microbiota than observed by either approach alone. In the first study, a method of culture-enriched molecular profiling could capture the majority of bacterial groups found in fecal samples. Additionally, when compared to culture-independent 16S rRNA gene sequencing, culture detected more bacterial taxa. This method was applied to the targeted culture of the commensal Lachnospiraceae family. The second study explored the diversity in the isolated Lachnospiraceae strains, and compared the genetic diversity of the strains to reference genomes, revealing functional and genetic heterogeneity within the bacterial family. The third study characterized the intra-species phenotypic and genetic diversity in Escherichia coli. E. coli diversity was extensive between individuals, but also within-individuals, in both the phenotypes and genetic profiles. Lastly, a method of culture-enriched metagenomics was applied to a murine IBS microbiota transfer model to identify bacterial members of the microbiota and their functional pathways that may be responsible for the development of gastrointestinal and behavioural IBS phenotypes, although no bacterial groups could be conclusively associated with symptoms. Together, the work described demonstrates that culture and culture-independent methods are complementary, and provides more resolution into the structure and diversity of the human gut microbiome than either approach in isolation. / Thesis / Doctor of Philosophy (PhD) / Bacteria that inhabit the human intestine are important for health, and are involved in several diseases; therefore, it is critical to determine the roles of specific bacteria. I describe a method that results in the growth and recovery of most bacteria in stool, which allows them to be studied in detail. The differences, both in behaviour and in DNA sequences, found within two different bacterial groups were characterized, and extensive variability was observed between closely related bacteria. I studied which bacteria and their functions might be important in Irritable Bowel Syndrome (IBS) by using our method for growing stool bacteria combined with sequencing of all DNA in the stool, but could not find strong support for specific bacteria causing IBS symptoms. This work shows how the ability to grow and isolate bacteria, combined with studying their DNA, allows for better understanding of their functions in the human intestine.

Depression and anxiety disorders affect upwards of one in six individuals at some point in their life making them the most prevalent mental illnesses today. Recent evidence has suggested a possible correlation between the human gut microbiota and the development of depressive and anxiety-like symptoms through a signaling pathway termed the microbiota-gut-brain axis. In both animals and individuals suffering from depression and anxiety-like symptoms, alterations in their gut microbial composition seem to compromise the function of this pathway. In addition to this microbiota-gut-brain axis, other microbiota-derived molecules have been linked to symptoms of depression and anxiety. Given this emerging role of the gut microbiome and gut–brain axis, it is crucial to understand the factors shaping our gut microbiome in order to determine potential therapeutic strategies to treat depression and anxiety. Following a concise review of the human microbiome, depression/anxiety, and the gut-brain axis, I will examine the gut microbiota role as a regulator of depression and anxiety. In addition, other biological markers associated with both the gut microbiome and these disorders will be reviewed. Lastly, I will evaluate the gut microbiome as a prospective therapeutic target for mental illnesses such as depression and anxiety.

No description available.

The composition and metabolic activity of the microbiome affect many aspects of health, and there is current interest in dietary constituents that may affect this system. The purpose of this study was to evaluate the effects of a mix of probiotics, a mix of prebiotics and a bioactive protein fraction on the microbiome, when fed to mice individually and in combination. Mice were fed the total western diet (TWD) supplemented with prebiotics, probiotics, and Tri-Factor (bioactive proteins) individually and in combination for four weeks. Subsequently, effects on the composition of gut microbiome, gut short chain fatty acids (SCFAs) concentration, gut inflammation and integrity of the mucosal barrier were analyzed. Ruminococcus gnavus was increased in mice gut microbiome after feeding prebiotics. Bifidobacterium longum was increased after feeding probiotics. Probiotic was associated with higher level of Clostridium neonatale. The treatments affected beta-diversity with exception of Tri-Factor, but not alpha diversity of microbiome. All treatments were associated with lower plasma zonulin, compared to the control group, indicating an effect on gut permeability. There were no treatment effects on cecal or fecal SCFAs, and the treatments did not affect gut inflammation as measured by fecal calprotectin.