Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2021

Open Access 01-12-2021 | Mood Disorders | Research

Rifaximin-mediated gut microbiota regulation modulates the function of microglia and protects against CUMS-induced depression-like behaviors in adolescent rat

Authors: Haonan Li, Yujiao Xiang, Zemeng Zhu, Wei Wang, Zhijun Jiang, Mingyue Zhao, Shuyue Cheng, Fang Pan, Dexiang Liu, Roger C. M. Ho, Cyrus S. H. Ho

Published in: Journal of Neuroinflammation | Issue 1/2021

Login to get access

Abstract

Background

Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions.

Methods

We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis.

Results

Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS.

Conclusions

These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Dennison MJ. The importance of developmental mechanisms in understanding adolescent depression. Soc Psychiatry Psychiatr Epidemiol. 2016;51:791–3.PubMedCrossRef
4.
Jianguo L, Xueyang J, Cui W, Changxin W, Xuemei Q. Altered gut metabolome contributes to depression-like behaviors in rats exposed to chronic unpredictable mild stress. Transl Psychiatry. 2019;9:40.PubMedPubMedCentralCrossRef
5.
Sun L, Ma L, Zhang H, Cao Y, Wang C, Hou N, Huang N, von Deneen KM, Zhao C, Shi Y, et al. FTO deficiency reduces anxiety- and depression-like behaviors in mice via alterations in gut microbiota. Theranostics. 2019;9:721–33.PubMedPubMedCentralCrossRef
6.
Tremblay A, Lingrand L, Maillard M, Feuz B, Tompkins TA. The effects of psychobiotics on the microbiota-gut-brain axis in early-life stress and neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2021;105:110142.PubMedCrossRef
7.
Chaves AJM, Macedo DS, de Lucena DF, Maes M. Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities. Behav Brain Res. 2019;372:1–8.
8.
McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, Ramirez-Chan K, Wang Y, Roeth RM, Sucaldito AD, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23:1421–31.PubMedCrossRef
9.
10.
Regen F, Hellmann-Regen J, Costantini E, Reale M. Neuroinflammation and Alzheimer’s disease: implications for microglial activation. Curr Alzheimer Res. 2017;14:1140–8.PubMedCrossRef
11.
Walker DG, Lue LF. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Therapy. 2015;7:1–9.CrossRef
12.
Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, depression, and the microbiome: a role for gut peptides. Neurotherapeutics. 2018;15:36–59.PubMedCrossRef
13.
Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–77.PubMedPubMedCentralCrossRef
14.
Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, Schiweck C, Kurilshikov A, Joossens M, Wijmenga C, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4:623–32.PubMedCrossRef
15.
Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Zeng L, Chen J, Fan S, Du X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:786–96.PubMedCrossRef
16.
den Besten G, Lange K, Havinga R, van Dijk TH, Gerding A, van Eunen K, Muller M, Groen AK, Hooiveld GJ, Bakker BM, Reijngoud DJ. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. Am J Physiol Gastroint Liver Physiol. 2013;305:900–10.CrossRef
17.
van der Beek CM, Bloemen JG, van den Broek MA, Lenaerts K, Venema K, Buurman WA, Dejong CH. Hepatic uptake of rectally administered butyrate prevents an increase in systemic butyrate concentrations in humans. J Nutr. 2015;145:2019–24.PubMedCrossRef
18.
Wenzel TJ, Gates EJ, Ranger AL, Klegeris A. Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Mol Cell Neurosci. 2020;105:103493.PubMedCrossRef
19.
Breslau J, Gilman SE, Stein BD, Ruder T, Gmelin T, Miller E. Sex differences in recent first-onset depression in an epidemiological sample of adolescents. Transl Psychiatry. 2017;7:e1139.PubMedPubMedCentralCrossRef
20.
21.
Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, Chen B, Hen R. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98.PubMedPubMedCentralCrossRef
22.
Denny CA, Kheirbek MA, Alba EL, Tanaka KF, Brachman RA, Laughman KB, Tomm NK, Turi GF, Losonczy A, Hen R. Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron. 2014;83:189–201.PubMedPubMedCentralCrossRef
23.
Mahar I, Bambico FR, Mechawar N, Nobrega JN. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev. 2014;38:173–92.PubMedCrossRef
24.
Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33:88–109.PubMedCrossRef
25.
Kirby ED, Muroy SE, Sun WG, Covarrubias D, Leong MJ, Barchas LA, Kaufer D. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2. Elife. 2013;2:e00362.PubMedPubMedCentralCrossRef
26.
Radley J, Morilak D, Viau V, Campeau S. Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. Neurosci Biobehav Rev. 2015;58:79–91.PubMedPubMedCentralCrossRef
27.
Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut. 2016;65:1906–15.PubMedCrossRef
28.
Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–81.PubMedCrossRef
29.
Ponziani FR, Scaldaferri F, Petito V, Paroni Sterbini F, Pecere S, Lopetuso LR, Palladini A, Gerardi V, Masucci L, Pompili M, et al. The role of antibiotics in gut microbiota modulation: the eubiotic effects of rifaximin. Dig Dis. 2016;34:269–78.PubMedCrossRef
30.
Ponziani FR, Gerardi V, Pecere S, D’Aversa F, Lopetuso L, Zocco MA, Pompili M, Gasbarrini A. Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications. World J Gastroenterol. 2015;21:12322–33.PubMedPubMedCentralCrossRef
31.
Ponziani FR, Zocco MA, D’Aversa F, Pompili M, Gasbarrini A. Eubiotic properties of rifaximin: disruption of the traditional concepts in gut microbiota modulation. World J Gastroenterol. 2017;23:4491–9.PubMedPubMedCentralCrossRef
32.
Kim MS, Morales W, Hani AA, Kim S, Kim G, Weitsman S, Chang C, Pimentel M. The effect of rifaximin on gut flora and staphylococcus resistance. Dig Dis Sci. 2013;58:1676–82.PubMedCrossRef
33.
Bajaj JS. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment Pharmacol Ther. 2016;43:11–26.PubMedCrossRef
34.
Wang W, Qin XQ, Wang R, Xu JJ, Wu HR, Khalid A, Jiang H, Liu DX, Pan F. EZH2 is involved in vulnerability to neuroinflammation and depression -like behaviors induced by chronic stress in different aged mice. J Affect Disord. 2020;272:452–64.PubMedCrossRef
35.
Xu DB, Gao J, Gillilland M, Wu XY, Song I, Kao JY, Owyang C. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology. 2014;146:484.PubMedCrossRef
36.
Quigley EMM. Microbiota–brain–gut axis and neurodegenerative diseases. Curr Neurol Neurosci Rep. 2017;17:1–9.CrossRef
37.
Yang J, Zheng P, Li YF, Wu J, Tan XM, Zhou JJ, Sun ZL, Chen X, Zhang GF, Zhang HP, et al. Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders. Sci Adv. 2020;6:8555.CrossRef
38.
Slykerman RF, Hood F, Wickens K, Thompson JMD, Barthow C, Murphy R, Kang J, Rowden J, Stone P, Crane J, et al. Effect of Lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: a randomised double-blind placebo-controlled trial. EBioMedicine. 2017;24:159–65.PubMedPubMedCentralCrossRef
39.
Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2:256–61.PubMedCrossRef
40.
Kelly JR, Borre Y, Brien CO, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109–18.PubMedCrossRef
41.
Jiang HY, Ling ZX, Zhang YH, Mao HJ, Ma ZP, Yin Y, Wang WH, Tang WX, Tan ZL, Shi JF, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015;48:186–94.PubMedCrossRef
42.
Zhang WJ, Qu W, Wang H, Yan H. Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress. Transl Psychiatry. 2021;11:1–16.CrossRef
43.
Skonieczna-Zydecka K, Grochans E, Maciejewska D, Szkup M, Schneider-Matyka D, Jurczak A, Loniewski I, Kaczmarczyk M, Marlicz W, Czerwinska-Rogowska M, et al. Faecal short chain fatty acids profile is changed in polish depressive women. Nutrients. 2018;10:1939.PubMedCentralCrossRef
44.
Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009;294:1–8.PubMedCrossRef
45.
Duncan SH, Louis P, Flint HJ. Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. Appl Environ Microbiol. 2004;70:5810–7.PubMedPubMedCentralCrossRef
46.
Louis P, Young P, Holtrop G, Flint HJ. Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene. Environ Microbiol. 2010;12:304–14.PubMedCrossRef
47.
Margolis KG, Cryan JF, Mayer EA. The microbiota–gut–brain axis: from motility to mood. Gastroenterology. 2021;160:1486–501.PubMedCrossRef
48.
49.
Li H, Wang P, Huang L, Li P, Zhang D. Effects of regulating gut microbiota on the serotonin metabolism in the chronic unpredictable mild stress rat model. Neurogastroenterol Motil. 2019;31:e13677.PubMedPubMedCentralCrossRef
50.
Liu RJ, Aghajanian GK. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci USA. 2008;105:359–64.PubMedPubMedCentralCrossRef
51.
Frank MG, Watkins LR, Maier SF. Stress- and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse. Brain Behav Immun. 2011;25:S21–8.PubMedPubMedCentralCrossRef
52.
Yamawaki Y, Yoshioka N, Nozaki K, Ito H, Oda K, Harada K, Shirawachi S, Asano S, Aizawa H, Yamawaki S, et al. Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice. Brain Res. 2018;1680:13–38.PubMedCrossRef
53.
Barch DM, Harms MP, Tillman R, Hawkey E, Luby JL. Early childhood depression, emotion regulation, episodic memory, and hippocampal development. J Abnorm Psychol. 2019;128:81–95.PubMedPubMedCentralCrossRef
54.
Geng HY, Wu F, Kong LT, Tang YQ, Zhou Q, Chang M, Zhou YF, Jiang XW, Li SB, Wang F. Disrupted structural and functional connectivity in prefrontal-hippocampus circuitry in first-episode medication-nave adolescent depression. PLoS ONE. 2016;11:1–9.CrossRef
55.
Du Preez A, Onorato D, Eiben I, Musaelyan K, Egeland M, Zunszain PA, Fernandes C, Thuret S, Pariante CM. Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice. Brain Behav Immun. 2021;91:24–47.PubMedCrossRef
56.
Kullmann DM, Lamsa KP. LTP and LTD in cortical GABAergic interneurons: emerging rules and roles. Neuropharmacology. 2011;60:712–9.PubMedCrossRef
57.
58.
Yu LC, Zhong X, He Y, Shi Y. Butyrate, but not propionate, reverses maternal diet-induced neurocognitive deficits in offspring. Pharmacol Res. 2020;160:105082.PubMedCrossRef
59.
Yang LL, Millischer V, Rodin S, MacFabe DF, Villaescusa JC, Lavebratt C. Enteric short-chain fatty acids promote proliferation of human neural progenitor cells. J Neurochem. 2020;154:635–46.PubMedCrossRef
Metadata
Title
Rifaximin-mediated gut microbiota regulation modulates the function of microglia and protects against CUMS-induced depression-like behaviors in adolescent rat
Authors
Haonan Li
Yujiao Xiang
Zemeng Zhu
Wei Wang
Zhijun Jiang
Mingyue Zhao
Shuyue Cheng
Fang Pan
Dexiang Liu
Roger C. M. Ho
Cyrus S. H. Ho
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2021
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-021-02303-y

Other articles of this Issue 1/2021

Journal of Neuroinflammation 1/2021 Go to the issue

Research

Brain profiling in murine colitis and human epilepsy reveals neutrophils and TNFα as mediators of neuronal hyperexcitability

Research

Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis

Research

High-fat diet impairs duodenal barrier function and elicits glia-dependent changes along the gut-brain axis that are required for anxiogenic and depressive-like behaviors

Correction

Correction to: Differential neurovirulence of Usutu viruslineages in mice and neuronal cells

Research

Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination

Research

Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19