Clostridium Butyricum MIYAIRI 588 Modifies Bacterial Composition under Antibiotic-Induced Dysbiosis for the Activation of Interactions via Lipid Metabolism between the Gut Microbiome and the Host

The gut microbiome is closely related to gut metabolic functions, and the gut microbiome and host metabolic functions affect each other. Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1 production in host colon tissue following G protein-coupled receptor (GPR) 120 activation to protect gut epithelial cells under antibiotic-induced dysbiosis. However, how CBM 588 enhances polyunsaturated fatty acid (PUFA) metabolites remains unclear. Therefore, we focused on the metabolic function alterations of the gut microbiome after CBM 588 and protectin D1 administration to reveal the interaction between the host and gut microbiome through lipid metabolism during antibiotic-induced dysbiosis. Consequently, CBM 588 modified gut microbiome and increased the butyric acid and oleic acid content. These lipid metabolic modifications induced GPR activation, which is a trigger of ERK 1/2 signaling and directed differentiation of downstream immune cells in the host colon tissue. Moreover, endogenous protectin D1 modified the gut microbiome, similar to CBM 588. This is the first study to report that CBM 588 influences the interrelationship between colon tissue and the gut microbiome through lipid metabolism. These findings provide insights into the mechanisms of prevention and recovery from inflammation and the improvement of host metabolism by CBM 588.

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Dancing to circadian rhythms: microbes and metabolism

The Biochemist ◽

10.1042/bio03902030 ◽

2017 ◽

Vol 39 (2) ◽

pp. 30-33

Author(s):

Mrinalini C. Rao ◽

Eugene B. Chang

Keyword(s):

Circadian Rhythms ◽

Gut Microbiome ◽

Metabolic Health ◽

The Body ◽

Bioactive Molecules ◽

Negative Consequences ◽

Metabolic Disturbances ◽

Metabolic Functions ◽

Distant Organ ◽

Host Metabolism

Since the turn of the 21st century, two advances in biology have revolutionized our thinking of human metabolism. First, is the in-depth characterization of a previously recognized, but hitherto poorly defined organ system, the gut microbiome. This microbial organ exquisitely interacts with the diet which greatly influences its metabolic functions to impact host metabolism through the production of small bioactive molecules that continuously enter the bloodstream to act at local and distant organ tissues. Equally important, the host metabolism can also modulate the gut microbiome setting up the two as intricate and well-suited partners. Second, is the recognition that most of the cells and organs of the body are dependent on circadian rhythms, systemic timekeepers that play a major role in regulating behavioural and physiological functions to manage energy balance. In conditions of metabolic health, circadian rhythms are the beat to which the two well-matched partners, microbes and metabolism, dance. When these partners are out of step or mismatched, negative consequences may develop that promote metabolic disturbances and disease. Thus, unravelling this complex choreography becomes key to understanding how to maintain metabolic health and to correct missteps that may lead to the development of conditions like diet-induced obesity.

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1205. Protectin D1 Induced by Clostridium butyricum MIYAIRI 588 Has an Anti-inflammatory Effects on Antibiotic-induced Intestinal Disorder

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1390 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S624-S625

Author(s):

Tadashi Ariyoshi ◽

Mao Hagihara ◽

Shuhei Egushi ◽

Fukuda Aiki ◽

Kentaro Oka ◽

...

Keyword(s):

Lipid Metabolism ◽

Inflammatory Cytokines ◽

Inflammatory Diseases ◽

Clostridium Butyricum ◽

Th2 Cells ◽

Research Support ◽

Colon Tissue ◽

Gut Inflammation ◽

Lipid Metabolites ◽

Anti Inflammatory

Abstract Background The administration of Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1,the anti-inflammatory lipid metabolites, in colon tissue under the antibiotic therapy. However, how CBM 588 induces protectin D1 nor whether the metabolite has anti-inflammatory effects on antibiotic-induced enteritis are unclear. Therefore, we evaluated the effect of CBM 588 on lipid metabolism and protectin D1 on immunological functions in colon tissue. Methods Mice were divided into five groups and clindamycin (CLDM), CBM 588 and/or protectin D1 were administered for 4 days (1. Control, 2. CLDM group, 3. CBM 588 group, 4. CLDM plus CBM 588 group and 5. CLDM plus protectin D1 group). After 4 days of administration, mice were reared for an additional 4 days. On day 8, colon tissues were removed to measure lipid metabolites with LC-MS/MS. Also, cytokines, lipid metabolism relative genes, enzymes were measured with qRT-PCR and ELISA. Results In the CBM588 treatment group, protectin D1, α-linolenic acid, eicosapentaenoic acid (EPA) and autoxidation product of DHA (docosahexaenoic acid) were significantly increased, compared with CLDM group and control. At the same time, genes expression levels of polyunsaturated fatty acids (PUFAs) receptors, G-protein coupled receptor 120 (GPR120) and a DHA to protectin D1 metabolizing enzyme 15- lipoxygenase (LOX) in colon tissue increased. Il-4 produced by Th2 cells, also increased in CBM588 treated groups even under CLDM co-administration. In addition, similar to CBM 588, protectin D1 administration suppressed mice’s weight loss due to gut inflammation, decreased inflammatory cytokines, while anti-inflammatory cytokine IL-10 and TGF-β1 increased. PUFAs metabolism cascade induced by CBM 588. Lipid metabolism relative genes, pro/anti-inflammatory cytokines and body weight. Conclusion Our data suggested that CBM 588 stimulated PUFAs metabolism in the intestinal tract, and that PUFAs were signaled to Th2 cells as a ligand of GPR120. It was speculated that the stimulated Th2 cells produced IL4 and activated 15-LOX, resulting in the induction of protectin D1. Also, it became clear that protectin D1 induced anti-inflammatory cytokines in controlling antibiotic-induced gut inflammation. We provide as a new insight that lipid metabolism induction for the treatment of gut inflammatory diseases with CBM 588. Anti-inflammatory pathway of protectin D1 induced by CBM 588. Disclosures Hiroshige Mikamo, M.D, Ph.D, Astellas Pharma Inc. (Grant/Research Support, Speaker’s Bureau)MSD Japan (Grant/Research Support, Speaker’s Bureau)Pfizer Japan Inc. (Grant/Research Support)Sumitomo Dainippon Pharma Co., Ltd (Grant/Research Support, Speaker’s Bureau)

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Gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway

10.21203/rs.2.17202/v1 ◽

2019 ◽

Author(s):

Baixi Shan ◽

Yonggui Song ◽

Sufen Zeng ◽

Jiagui Song ◽

Qiang Zeng ◽

...

Keyword(s):

Lactic Acid ◽

Lipid Metabolism ◽

Gut Microbiome ◽

Fecal Microbiota ◽

Chronic Unpredictable Stress ◽

Metabolism Pathway ◽

Behavioral Abnormalities ◽

Tnf Α ◽

Sphingosine 1 Phosphate ◽

G Protein Coupled

Abstract Accumulating evidence suggests that chronic stress can perturb the composition of the gut microbiota and induce host anxiety-like behavior. In particular, microorganism-derived products that can directly or indirectly signal to the nervous system. This study sought to investigate whether high levels of Lactobacillus and lactic acid in the gut of rats under chronic unpredictable stress were the factors leading to anxiety. Results: Oral lactic acid rat and transplantation of fecal microbiota from anxious rats into antibiotic-treated rat caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These rats also showed inhibition of the adenylate cyclase-protein kinase A pathway of lipolysis after activation of G protein-coupled receptor 81 (GPR81) by lactic acid in the liver, as well as increased TNF-α, compared with healthy controls. Furthermore, we show that sphingosine-1-phosphate receptor 2 (S1PR2) protein expression in hippocampus is reduced in chronic unpredictable stress compared to control subjects and its expression negatively correlates with symptom severity. Conclusions: our study suggests that the gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway.

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Gut microbiota modulation induced by Zika virus infection in immunocompetent mice

Scientific Reports ◽

10.1038/s41598-020-80893-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rafael Corrêa ◽

Igor de Oliveira Santos ◽

Heloísa Antoniella Braz-de-Melo ◽

Lívia Pimentel de Sant’Ana ◽

Raquel das Neves Almeida ◽

...

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Zika Virus ◽

Hypervariable Region ◽

Microbiota Composition ◽

Colon Tissue ◽

Zikv Infection ◽

Immunological Responses ◽

Immunocompetent Mice ◽

Gut Microbiota Composition

AbstractGut microbiota composition can modulate neuroendocrine function, inflammation, and cellular and immunological responses against different pathogens, including viruses. Zika virus (ZIKV) can infect adult immunocompetent individuals and trigger brain damage and antiviral responses. However, it is not known whether ZIKV infection could impact the gut microbiome from adult immunocompetent mice. Here, we investigated modifications induced by ZIKV infection in the gut microbiome of immunocompetent C57BL/6J mice. Adult C57BL/6J mice were infected with ZIKV and the gut microbiota composition was analyzed by next-generation sequencing of the V4 hypervariable region present in the bacterial 16S rDNA gene. Our data showed that ZIKV infection triggered a significant decrease in the bacteria belonging to Actinobacteria and Firmicutes phyla, and increased Deferribacteres and Spirochaetes phyla components compared to uninfected mice. Interestingly, ZIKV infection triggered a significant increase in the abundance of bacteria from the Spirochaetaceae family in the gut microbiota. Lastly, we demonstrated that modulation of microbiota induced by ZIKV infection may lead to intestinal epithelium damage and intense leukocyte recruitment to the intestinal mucosa. Taken together, our data demonstrate that ZIKV infection can impact the gut microbiota composition and colon tissue homeostasis in adult immunocompetent mice.

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The relevance of adhesion G protein-coupled receptors in metabolic functions

Biological Chemistry ◽

10.1515/hsz-2021-0146 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Isabell Kaczmarek ◽

Tomáš Suchý ◽

Simone Prömel ◽

Torsten Schöneberg ◽

Ines Liebscher ◽

...

Keyword(s):

G Protein ◽

Drug Targets ◽

Metabolic Diseases ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Specific Expression ◽

Physiological Functions ◽

Metabolic Functions ◽

Central Nervous Systems ◽

G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

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Impacts of PBDE-47 exposure before, during and after pregnancy on the maternal gut microbiome and its association with host metabolism

Ecotoxicology and Environmental Safety ◽

10.1016/j.ecoenv.2021.112530 ◽

2021 ◽

Vol 222 ◽

pp. 112530

Author(s):

Hui Gao ◽

Xueyan Wan ◽

Boya Xiao ◽

Kaichao Yang ◽

Yafei Wang ◽

...

Keyword(s):

Gut Microbiome ◽

Host Metabolism

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Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming

International Journal of Molecular Sciences ◽

10.3390/ijms22126292 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6292

Author(s):

Rubén Tovar ◽

Antonio Vargas ◽

Jesús Aranda ◽

Lourdes Sánchez-Salido ◽

Laura González-González ◽

...

Keyword(s):

Lipid Metabolism ◽

Caloric Restriction ◽

Energy Homeostasis ◽

Caloric Intake ◽

Endocannabinoid System ◽

Critical Periods ◽

Nutritional Programming ◽

Metabolic Functions ◽

Gene And Protein Expression ◽

Induced Changes

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.

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The effect of microbiota-based investigational drug RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial

10.21203/rs.3.rs-17152/v1 ◽

2020 ◽

Author(s):

Suryang Kwak ◽

JooHee Choi ◽

Tiffany Hink ◽

Kimberly A. Reske ◽

Kenneth Blount ◽

...

Keyword(s):

Gut Microbiome ◽

Post Treatment ◽

Patient Specific ◽

Controlled Clinical Trial ◽

Investigational Drug ◽

Double Blind ◽

Significant Recovery ◽

Clostridioides Difficile ◽

Metabolic Functions ◽

Clostridioides Difficile Infection

Abstract Background Intestinal microbiota restoration can be achieved by replacing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another application of interest is depletion of antibiotic resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome. Results All patients exhibited significant recovery of gut microbiome diversity and decrease of ARG abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts towards healthier configurations were more significant and longer lasting in RBX2660 recipients compared to placebo. We identified 18 taxa and 21 metabolic functions distinguishing the baseline microbiome of non-transplanted patients, and the majority of features were correlated to intrinsic vancomycin resistance. We also identified 7 patient-specific and 3 RBX2660-specific ARGs and tracked their dynamics post treatment. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs. Conclusions By including a placebo group, we distinguished the effects of RBX2660 from baseline post-antibiotic microbiome dynamics. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG abundance, but RBX2660 administration more rapidly and completely changed the composition of patients’ microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product—a proxy for the donor—than an antibiotic perturbed state.

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Mannose Alters Gut Microbiome, Prevents Diet-Induced Obesity, and Improves Host Metabolism

Cell Reports ◽

10.1016/j.celrep.2018.08.064 ◽

2018 ◽

Vol 24 (12) ◽

pp. 3087-3098 ◽

Cited By ~ 31

Author(s):

Vandana Sharma ◽

Jamie Smolin ◽

Jonamani Nayak ◽

Julio E. Ayala ◽

David A. Scott ◽

...

Keyword(s):

Gut Microbiome ◽

Diet Induced Obesity ◽

Host Metabolism

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Gut microbiome, metabolic syndrome, and atherosclerosis

ESC CardioMed ◽

10.1093/med/9780198784906.003.0263 ◽

2018 ◽

pp. 1082-1085

Author(s):

Eduard F. Stange

Keyword(s):

Metabolic Syndrome ◽

Gut Microbiome ◽

Peptide Yy ◽

Endocannabinoid System ◽

Gut Hormones ◽

Adenosine Monophosphate ◽

Farnesoid X Receptor ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled ◽

Definite Role

The link between the gut microbiome and metabolic syndrome is complicated and reaches far beyond energy conservation from dietary fibre through bacterial glycosidases. Involved mechanisms include fasting-induced adipose factor affecting lipoprotein lipase, adenosine monophosphate-activated protein kinase regulating lipogenesis, and G protein-coupled receptors acting through the gut hormones peptide YY and glucagon-like peptide-1. In addition, farnesoid X receptor via ceramide secretion as well as the endocannabinoid system may induce obesity. Finally, there appears to be a definite role for gut bacteria-induced chronic (subclinical) inflammation. This state of metabolic syndrome, insulin resistance, and obesity clearly is a major risk factor for atherosclerosis.

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