Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
Abstract
Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.
Data availability
RNA sequencing data has been deposited in GEO under accession code GSE157925Microbiome data were submitted to the European Nucleotide Archive under accession code PRJEB48232
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK120679)
- Jonathan Mark Brown
National Heart, Lung, and Blood Institute (R01 HL130819)
- Zeneng Wang
National Institute of Diabetes and Digestive and Kidney Diseases (F32 DK122623)
- Christy M Gliniak
National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007307)
- Christy M Gliniak
Leducq Transatlantic Network of Excellence awar (No grant number)
- Stanley L Hazen
American Heart Association (17POST3285000)
- Robert N Helsley
American Heart Association (15POST2535000)
- Rebecca C Schugar
Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University (4UL1TR000439)
- Belinda Willard
Case Comprehensive Cancer Center, Case Western Reserve University (P30 CA043703)
- Jonathan Mark Brown
National Heart, Lung, and Blood Institute (P01 HL146823)
- Stanley L Hazen
National Institute on Alcohol Abuse and Alcoholism (P50 AA024333)
- Jonathan Mark Brown
National Institute on Alcohol Abuse and Alcoholism (U01 AA026938)
- Jonathan Mark Brown
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK130227)
- Jonathan Mark Brown
National Cancer Institute (P50 CA150964)
- Jonathan Mark Brown
National Heart, Lung, and Blood Institute (R01 HL103866)
- Stanley L Hazen
National Heart, Lung, and Blood Institute (R01 HL147883)
- Aldons J Lusis
National Heart, Lung, and Blood Institute (R01 HL144651)
- Aldons J Lusis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were maintained in an Association for the Assessment and Accreditation of Laboratory Animal Care, International-approved animal facility, and all experimental protocols were approved by the Institutional Animal Care and use Committee of the Cleveland Clinic. (Approved IACUC protocol numbers 2015-1381, 2018-1941, and 00002499).
Copyright
© 2022, Schugar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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The IncRNA Malat1 was initially believed to be dispensable for physiology due to the lack of observable phenotypes in Malat1 knockout (KO) mice. However, our study challenges this conclusion. We found that both Malat1 KO and conditional KO mice in the osteoblast lineage exhibit significant osteoporosis. Mechanistically, Malat1 acts as an intrinsic regulator in osteoblasts to promote osteogenesis. Interestingly, Malat1 does not directly affect osteoclastogenesis but inhibits osteoclastogenesis in a non-autonomous manner in vivo via integrating crosstalk between multiple cell types, including osteoblasts, osteoclasts, and chondrocytes. Our findings substantiate the existence of a novel remodeling network in which Malat1 serves as a central regulator by binding to β-catenin and functioning through the β-catenin-OPG/Jagged1 pathway in osteoblasts and chondrocytes. In pathological conditions, Malat1 significantly promotes bone regeneration in fracture healing. Bone homeostasis and regeneration are crucial to well-being. Our discoveries establish a previous unrecognized paradigm model of Malat1 function in the skeletal system, providing novel mechanistic insights into how a lncRNA integrates cellular crosstalk and molecular networks to fine tune tissue homeostasis, remodeling and repair.
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Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.