Gut Microbiome: Everyone wins
Aeromonas bacteria living in the gut of zebrafish produce a specific molecule to pacify the immune system of their host.
- Université Claude Bernard Lyon-1, France
- Ecole Normale Supérieure de Lyon, France
Microbes can be found in almost every environment – including other organisms. Some cause disease, but many of them live with their hosts in a mutually beneficial relationship, a type of symbiosis called mutualism (McFall-Ngai et al., 2013). These microbial communities are in constant communication with the organisms hosting them, and gut bacteria in particular are known to influence the development, metabolism, immune system and behavior of their hosts (Fraune and Bosch, 2010; Kohl and Carey, 2016).
To peacefully cohabit with each other, the immune system of the host needs to control the number of bacteria without resorting to levels of inflammation that would harm either the bacteria or the host. As in many other areas of research, model organisms are widely used to dissect the molecular mechanisms that orchestrate such complex interactions. For example, the zebrafish – often used for studying development – is a powerful model that can be used to investigate such associations at the tissue, cell and molecular levels.
Most research to date has focused on how the host benefits from symbiosis, and the question of how the microbes benefit has been largely overlooked. Now, in eLife, Karen Guillemin and colleagues at the University of Oregon and the Canadian Institute for Advanced Research – including Annah Rolig as first author – report new details about the relationship between zebrafish larvae and one of their gut symbionts, Aeromonas veronii (Rolig et al., 2018).
Aeromonas are the only group of bacteria that are present throughout the zebrafish life cycle, and they play important roles in immune defense, gut cell growth and the development of the pancreas (Stephens et al., 2015; Burns and Guillemin, 2017). Rolig et al. used a specific strain of A. veronii (Hm21) to study the interactions between the bacteria and immune cells called neutrophils, which are the first immune cells to respond to inflammation and travel to the infected area (Brugman, 2016).
The fish were raised in sterile environments and were devoid of any microbes. Then, single bacteria were added and the interactions with the immune system were analyzed. This revealed that the bacteria produce a molecule that dampens the immune response of the neutrophils and so reduces inflammation.
The sequence of the molecule, which they named AimA (short for Aeromonas immune modulator A), did not resemble any known molecule, but its 3D crystal structure was similar to a molecule secreted by human neutrophils known as Lipocalin-2. Indeed, in experiments mimicking injuries to the zebrafish gut, the protective effect of AimA against inflammation was compromised when mouse Lipocalin-2 was added to the mix. This suggests that both molecules compete for the same receptors on the immune cells because they have similar structures.
Next, Rolig et al. investigated how AimA affected the ‘fitness’ of the Aeromonas and the zebrafish. The researchers created bacteria that lacked AimA and its close paralog AimB, and evaluated their ability to colonize larval zebrafish. Without AimA and AimB, the bacteria were unable to colonize the gut and the number of neutrophils increased, which in turn lead to more inflammation in the gut. However, when purified AimA was added, the mutant bacteria were able to accumulate in the gut and the number of neutrophils went back to normal.
This suggests that AimA mediates the interactions between zebrafish and the Aeromonas bacteria for the benefit of both partners, illustrating a prototypical example of mutualism. AimA is a colonization factor that intervenes early in the establishment of the bacteria in the gut, suppressing the immune response and inflammation in the gut to ensure the survival of the bacteria and the host. By doing so, it potentially allows bacteria to produce different molecules, which may benefit the host in other ways.
Symbiotic relationships have largely been described with a host-centric view, hence many molecular mechanisms may have been overlooked. Rolig et al. add AimA to the sparse list of known mutualistic factors, such as a specific polysaccharide that allows the bacterium Bacteroides fragilis to colonize the gut by activating tolerance in specific immune cells (Round et al., 2011). The anti-inflammatory potential of AimA and its atomic structure pave the way for researchers to test its potential as a therapeutic agent. The study of Rolig et al. highlights the importance of unbiased basic research in the host-microbe field using simple animal models.
References
-
The zebrafish as a model to study intestinal inflammationDevelopmental & Comparative Immunology 64:82–92.https://doi.org/10.1016/j.dci.2016.02.020
-
The scales of the zebrafish: host-microbiota interactions from proteins to populationsCurrent Opinion in Microbiology 38:137–141.https://doi.org/10.1016/j.mib.2017.05.011
-
A place for host-microbe symbiosis in the comparative physiologist's toolboxJournal of Experimental Biology 219:3496–3504.https://doi.org/10.1242/jeb.136325
Article and author information
Author details
Publication history
Copyright
© 2018, Matos et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,865
- views
-
- 142
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Gut Microbiome: Everyone wins
eLife 7:e42676.
https://doi.org/10.7554/eLife.42676
Further reading
-
- Immunology and Inflammation
Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.
-
- Immunology and Inflammation
Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10, are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.
