TLR4 regulates RORγt <sup>+</sup> regulatory T-cell responses and susceptibility to colon inflammation through interaction with <i>Akkermansia muciniphila</i>

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4 ^−/− mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism.

Methods

We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4 ^−/− mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila ( A. muciniphila)-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction.

Results

TLR4 ^−/− mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4 ^−/− mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer colitis model and bone marrow transplantation (BMT) consistently demonstrated that A. muciniphila ameliorated colitis by upregulating RORγt ⁺ Treg cell-mediated immune responses. Mucosal biopsies from human manifested parallel outcomes with colon tissue from WT mice, as evidenced by the positive correlation between TLR4 expression and intestinal A. muciniphila colonization during homeostasis.

Conclusions

Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s40168-022-01296-x.

Related collections

Most cited references 65

Record: found
Abstract: found
Article: not found

Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

Bo Qu, Gladys Ferrere, Céline Clemenson … (2018)

Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade. Metagenomics of patient stools at diagnosis revealed correlations between clinical responses to ICI and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila post-FMT with non-responder feces restored the efficacy of PD-1 blockade in an IL-12-dependent manner, by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.

0 comments Cited 1690 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

Amandine Everard, Clara Belzer, Lucie Geurts … (2013)

Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.

0 comments Cited 1060 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The gut microbiota shapes intestinal immune responses during health and disease.

June Round, Sarkis Mazmanian (2009)

Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host-symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.

0 comments Cited 821 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Xiaoyan Zhao: zhaoxiaoyan2018@126.com

Bo Tang: botangxq@tmmu.edu.cn

Shiming Yang: Yangshiming@tmmu.edu.cn

Journal

Journal ID (nlm-ta): Microbiome

Journal ID (iso-abbrev): Microbiome

Title: Microbiome

Publisher: BioMed Central (London )

ISSN (Electronic): 2049-2618

Publication date (Electronic): 27 June 2022

Publication date PMC-release: 27 June 2022

Publication date Collection: 2022

Volume: 10

Electronic Location Identifier: 98

Affiliations

[1 ]GRID grid.417298.1, ISNI 0000 0004 1762 4928, Department of Gastroenterology, , The Second Affiliated Hospital of Third Military Medical University, ; 400037 Chongqing, China

[2 ]GRID grid.412461.4, ISNI 0000 0004 9334 6536, Department of Gastroenterology, , The Second Affiliated Hospital of Chongqing Medical University, ; Chongqing, 400010 China

[3 ]GRID grid.410570.7, ISNI 0000 0004 1760 6682, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, College of Preventive Medicine, , Third Military Medical University, ; Chongqing, 400037 China

Article

Publisher ID: 1296

DOI: 10.1186/s40168-022-01296-x

PMC ID: 9235089

PubMed ID: 35761415

SO-VID: 55e35774-402a-4818-951a-d81d59f9e382

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 11 February 2022

Date accepted : 25 May 2022

Custom metadata

Data availability:

Comments

Comment on this article

scite_

Cited by 34

See all cited by

Most referenced authors 1,531

See all reference authors