Publications by authors named "Yogesh Bhattarai"

14 Publications

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Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of Parkinson's disease.

Gut Microbes 2021 Jan;13(1):1866974

Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, MN, USA.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms' including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.
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http://dx.doi.org/10.1080/19490976.2020.1866974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833732PMC
January 2021

Bacterially Derived Tryptamine Increases Mucus Release by Activating a Host Receptor in a Mouse Model of Inflammatory Bowel Disease.

iScience 2020 Dec 13;23(12):101798. Epub 2020 Nov 13.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

Recent studies emphasize the role of microbial metabolites in regulating gastrointestinal (GI) physiology through activation of host receptors, highlighting the potential for inter-kingdom signaling in treating GI disorders. In this study, we show that tryptamine, a tryptophan-derived bacterial metabolite, stimulates mucus release from goblet cells via activation of G-protein-coupled receptor (GPCR) 5-HT4R. Germ-free mice colonized with engineered optimized to produce tryptamine (Trp D+) exhibit decreased weight loss and increased mucus release following dextran sodium sulfate treatment when compared with mice colonized with control (Trp D-). Additional beneficial effects in preventing barrier disruption and lower disease activity index were seen only in female mice, highlighting sex-specific effects of the bacterial metabolite. This study demonstrates potential for the precise modulation of mucus release by microbially produced 5-HT4 GPCR agonist as a therapeutic strategy to treat inflammatory conditions of the GI tract.
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http://dx.doi.org/10.1016/j.isci.2020.101798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702010PMC
December 2020

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome.

Cell 2020 09 10;182(6):1460-1473.e17. Epub 2020 Sep 10.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109273PMC
September 2020

Parkinson's disease: Are gut microbes involved?

Am J Physiol Gastrointest Liver Physiol 2020 11 2;319(5):G529-G540. Epub 2020 Sep 2.

Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1152/ajpgi.00058.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087343PMC
November 2020

High-fat diet-induced alterations to gut microbiota and gut-derived lipoteichoic acid contributes to the development of enteric neuropathy.

Neurogastroenterol Motil 2020 07 13;32(7):e13838. Epub 2020 Mar 13.

University of Idaho, Moscow, ID, USA.

Background: High-fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram-positive bacteria and short-chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility.

Methods: We fed germ-free (GF) and conventionally raised (CR) mice either a high-fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations.

Key Results: High-fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF-HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram-positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons.

Conclusions & Inferences: Gut microbial alterations induced increase in Gram-positive bacterial LTA may contribute to enteric neuropathy.
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http://dx.doi.org/10.1111/nmo.13838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319907PMC
July 2020

Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.

Nat Commun 2019 05 1;10(1):2012. Epub 2019 May 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55902, USA.

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.
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http://dx.doi.org/10.1038/s41467-019-09964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494866PMC
May 2019

Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion.

Cell Host Microbe 2018 06;23(6):775-785.e5

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT receptor (5-HTR), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HTR activation and is blocked by 5-HTR antagonist and absent in 5-HTR mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.chom.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055526PMC
June 2018

Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT receptor expression via acetate production.

Am J Physiol Gastrointest Liver Physiol 2017 Jul 13;313(1):G80-G87. Epub 2017 Apr 13.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;

Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT and 5-HT receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (Δ) in GF compared with HM mice. Additionally, 5-HT receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT receptor antagonist, inhibited 5-HT-evoked Δ in GF mice but not in HM mice. Furthermore, a 5-HT receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ in GF compared with HM mice. Immunohistochemistry in 5-HT-green fluorescent protein mice localized 5-HT receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ between GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT receptor expression via acetate production. Epithelial 5-HT receptor may function as a mediator of gut microbiota-driven change in intestinal secretion. We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT receptor expression in colonoids.View this article's corresponding video summary at https://www.youtube.com/watch?v=aOMYJMuLTcw&feature=youtu.be.
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http://dx.doi.org/10.1152/ajpgi.00448.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538830PMC
July 2017

Irritable bowel syndrome: a gut microbiota-related disorder?

Am J Physiol Gastrointest Liver Physiol 2017 01 23;312(1):G52-G62. Epub 2016 Nov 23.

Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders. Despite its prevalence, the pathophysiology of IBS is not well understood although multiple peripheral and central factors are implicated. Recent studies suggest a role for alterations in gut microbiota in IBS. Significant advances in next-generation sequencing technology and bioinformatics and the declining cost have now allowed us to better investigate the role of gut microbiota in IBS. In the following review, we propose gut microbiota as a unifying factor in the pathophysiology of IBS. We first describe how gut microbiota can be influenced by factors predisposing individuals to IBS such as host genetics, stress, diet, antibiotics, and early life experiences. We then highlight the known effects of gut microbiota on mechanisms implicated in the pathophysiology of IBS including disrupted gut brain axis (GBA), visceral hypersensitivity (VH), altered GI motility, epithelial barrier dysfunction, and immune activation. While there are several gaps in the field that preclude us from connecting the dots to establish causation, we hope this overview will allow us to identify and fill in the voids.
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http://dx.doi.org/10.1152/ajpgi.00338.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283907PMC
January 2017

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon.

Am J Physiol Gastrointest Liver Physiol 2016 08 10;311(2):G210-20. Epub 2016 Jun 10.

The Neuroscience Program, Michigan State University, East Lansing, Michigan; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan;

We tested the hypothesis that colonic enteric neurotransmission and smooth muscle cell (SMC) function are altered in mice fed a high-fat diet (HFD). We used wild-type (WT) mice and mice lacking the β1-subunit of the BK channel (BKβ1 (-/-)). WT mice fed a HFD had increased myenteric plexus oxidative stress, a 28% decrease in nitrergic neurons, and a 20% decrease in basal nitric oxide (NO) levels. Circular muscle inhibitory junction potentials (IJPs) were reduced in HFD WT mice. The NO synthase inhibitor nitro-l-arginine (NLA) was less effective at inhibiting relaxations in HFD compared with control diet (CD) WT mice (11 vs. 37%, P < 0.05). SMCs from HFD WT mice had depolarized membrane potentials (-47 ± 2 mV) and continuous action potential firing compared with CD WT mice (-53 ± 2 mV, P < 0.05), which showed rhythmic firing. SMCs from HFD or CD fed BKβ1 (-/-) mice fired action potentials continuously. NLA depolarized membrane potential and caused continuous firing only in SMCs from CD WT mice. Sodium nitroprusside (NO donor) hyperpolarized membrane potential and changed continuous to rhythmic action potential firing in SMCs from HFD WT and BKβ1 (-/-) mice. Migrating motor complexes were disrupted in colons from BKβ1 (-/-) mice and HFD WT mice. BK channel α-subunit protein and β1-subunit mRNA expression were similar in CD and HFD WT mice. We conclude that HFD-induced obesity disrupts inhibitory neuromuscular transmission, SMC excitability, and colonic motility by promoting oxidative stress, loss of nitrergic neurons, and SMC BK channel dysfunction.
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http://dx.doi.org/10.1152/ajpgi.00085.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007291PMC
August 2016

Germ-Free Mice Model for Studying Host-Microbial Interactions.

Methods Mol Biol 2016 ;1438:123-35

Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Germ-free (GF) mice are a relevant model system to study host-microbial interactions in health and disease. In this chapter, we underscore the importance of using GF mice model to study host-microbial interactions in obesity, immune development and gastrointestinal physiology by reviewing current literature. Furthermore, we also provide a brief protocol on how to setup a gnotobiotic facility in order to properly maintain and assess GF status in mice colonies.
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http://dx.doi.org/10.1007/978-1-4939-3661-8_8DOI Listing
December 2017

Agaro-oligosaccharides: a new frontier in the fight against colon cancer?

Am J Physiol Gastrointest Liver Physiol 2016 Mar 11;310(6):G335-6. Epub 2016 Feb 11.

Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota

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http://dx.doi.org/10.1152/ajpgi.00049.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796294PMC
March 2016

Western blot analysis of BK channel β1-subunit expression should be interpreted cautiously when using commercially available antibodies.

Physiol Rep 2014 Oct 28;2(10). Epub 2014 Oct 28.

Neuroscience Program, Michigan State University, East Lansing, Michigan Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.

Large conductance Ca(2+)-activated K(+) (BK) channels consist of pore-forming α- and accessory β-subunits. There are four β-subunit subtypes (β1-β4), BK β1-subunit is specific for smooth muscle cells (SMC). Reduced BK β1-subunit expression is associated with SMC dysfunction in animal models of human disease, because downregulation of BK β1-subunit reduces channel activity and increases SMC contractility. Several anti-BK β1-subunit antibodies are commercially available; however, the specificity of most antibodies has not been tested or confirmed in the tissues from BK β1-subunit knockout (KO) mice. In this study, we tested the specificity and sensitivity of six commercially available antibodies from five manufacturers. We performed western blot analysis on BK β1-subunit enriched tissues (mesenteric arteries and colons) and non-SM tissue (cortex of kidney) from wild-type (WT) and BK β1-KO mice. We found that antibodies either detected protein bands of the appropriate molecular weight in tissues from both WT and BK β1-KO mice or failed to detect protein bands at the appropriate molecular weight in tissues from WT mice, suggesting that these antibodies may lack specificity for the BK β1-subunit. The absence of BK β1-subunit mRNA expression in arteries, colons, and kidneys from BK β1-KO mice was confirmed by RT-PCR analysis. We conclude that these commercially available antibodies might not be reliable tools for studying BK β1-subunit expression in murine tissues under the denaturing conditions that we have used. Data obtained using commercially available antibodies should be interpreted cautiously. Our studies underscore the importance of proper negative controls in western blot analyses.
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http://dx.doi.org/10.14814/phy2.12189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254108PMC
October 2014