"Cell": Gut fungi can also control the brain!

The human digestive tract is home to trillions of microorganisms, including viruses, parasites, and fungi in addition to the bacteria we know well
.

The vast majority of research to date has focused on gut bacteria, with fungi making up less than 1% of the gut microbiome, and their impact on host immunity and behavior is poorly understood
.

Recently, Iliyan D.
Iliev's team from Cornell University published important research results in the journal "Cell".
They found that the symbiotic fungi in the intestinal mucosa profoundly affect the host's immunity and epithelial barrier function.
Surprisingly, these Fungi also affect the host's social behavior through neuroimmunity [1]
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This study revealed a close relationship between gut mucosal fungi and the neuroimmune system, a finding that may provide new ideas for therapeutic intervention in neurodegenerative diseases characterized by social behavioral disorders
.

Different parts of the gastrointestinal tract are distributed with different microbial communities, so the fecal composition cannot fully reflect the complexity of gut microbes
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In this study, the researchers collected samples of the gastrointestinal lumen and mucosa from regions of the stomach, jejunum, ileum, cecum, and colon of C57BL/6 mice, and sequenced and analyzed fungal ribosomal DNA
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It was found that, unlike gut bacteria, the fungal flora of the gastrointestinal lumen and mucosa showed significant differences
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Regardless of longitudinal sampling location, the luminal fungal community (LUM) showed high diversity, whereas the mucosa-associated fungal community (MAF) was less diverse
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The luminal fungal community is significantly different from the mucosal (mucosal)-associated fungal community.
Since the luminal and mucosal fungal communities are significantly different in composition, do they also have a role in regulating the intestinal immune response? What's the difference? Iliyan D.
Iliev's team transplanted the identified gastrointestinal luminal or mucosal fungi into mice and evaluated the effects of chemical drug-induced intestinal damage
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It was found that transplantation of mucosal fungi prevented intestinal damage and related death in mice, but gastrointestinal fungi did not
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Similar to this finding, transplantation of mucosal fungi also prevented Citrobacter-induced colitis
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So how do mucosal fungi exert these protective effects? Iliev's team found that in the colonic lamina propria and mesenteric lymph nodes of mice transplanted with mucosal fungi, a type of helper T cells, Th17 cells, were significantly increased, and these cells can secrete large amounts of cytokines such as IL-22 and IL-17
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The researchers found that mucosal fungi-induced gut protection was dependent on the production of IL-22
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Mucosal fungal transplantation can significantly increase the proportion of intestinal Th17 cells (FoxP3-RORγt+) compared to gastrointestinal fungi.
Two-way communication
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The imbalance of gut bacteria is closely related to anxiety, depression, and even autism [2, 3]
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Several recent studies have found that the composition of the gut fungal community is altered in neuropsychiatric disorders associated with human behavioral changes [4, 5], yet little is known about the impact of the fungal community on neuroimmunity and neurodegenerative diseases
.

In this study, Iliyan D.
Iliev's team discovered an unexpected role for mucosal fungi in promoting social behavior
.

They found that compared with gut bacteria, mucosal fungi did not affect repetitive, anxiety- and compulsive-related behaviors in mice
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In contrast, mucosal fungal colonization promoted social behavior in mice that was not affected by gut bacteria
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In an experiment called the three-box social behavior test, Iliev's team found that mice colonized with the mucosal fungus became more social, and those mice spent significantly longer in the box with another mouse
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Three-box social behavior test: Mice were allowed to explore three empty boxes for 10 minutes (habituation phase, left in the figure)
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The mice were then allowed access to another mouse, age- and sex-matched, confined to a cage on one side of the box (S) with an empty cage (NS) on the other side of the box with the center in the center Room (C) (social stage, right in the picture)
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Based on previous findings in the gut, the researchers speculated that mucosal fungi-induced Th17 cell-related cytokines may play a role in this process
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Unexpectedly, however, despite the more critical role of IL-22 in mucosal fungal-induced gut immunity, the researchers found that only IL-17 production affected social behavior in mice
.

Further, when Iliev's team specifically knocked out the IL-17 receptor in the neurons of mice, the effect of the mucosal fungus on the social behavior of these mice disappeared
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These results suggest that gut mucosal fungi enhance IL-17 production, which in turn promotes social behavior in mice by acting directly on neurons
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Mechanism of Action Map Overall, this study reveals the profound impact of gut fungal communities on gut immunity and barrier function, as well as on social behavior
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Of course, there are still some unanswered questions in this study, such as which signals within neurons are activated by IL-17, and whether the findings can be extrapolated to humans
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In the long run, though, this intriguing finding may lay the groundwork for using fungi to treat inflammatory and neurodegenerative diseases
.

References 1.
I.
Leonardi et al.
, Mucosal fungi promote gut barrier function and social behavior via Type 17 immunity.
Cell 185, 831-846 e814 (2022).
2.
L.
Desbonnet et al.
, Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.
Brain Behav Immun 50, 335-336 (2015).
3.
F.
Strati et al.
, New evidences on the altered gut microbiota in autism spectrum disorders.
Microbiome 5, (2017).
4.
F.
Strati et al.
, New evidences on the altered gut microbiota in autism spectrum disorders.
Microbiome 5, 24 (2017).
5.
R.
Zou et al.
, Dysbiosis of Gut Fungal Microbiota in Children with Autism Spectrum Disorders.
J Autism Dev Disord 51, 267-275 (2021).
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