Nature | Vol 585 | 24 September 2020 | 591Article
The liver–brain–gut neural arc maintains the
Treg cell niche in the gut
Toshiaki Teratani^1 , Yohei Mikami^1 ✉, Nobuhiro Nakamoto^1 , Takahiro Suzuki1,2, Yosuke Harada^1 ,
Koji Okabayashi^3 , Yuya Hagihara^1 , Nobuhito Taniki^1 , Keita Kohno^4 , Shinsuke Shibata5,6,
Kentaro Miyamoto1,2, Harumichi Ishigame^7 , Po-Sung Chu^1 , Tomohisa Sujino^1 , Wataru Suda^8 ,
Masahira Hattori8,9, Minoru Matsui^10 , Takaharu Okada7,1 1, Hideyuki Okano^5 , Masayuki Inoue^12 ,
Toshihiko Yada^13 , Yuko Kitagawa^3 , Akihiko Yoshimura^14 , Mamoru Tanida^15 , Makoto Tsuda^4 ,
Yusaku Iwasaki^16 & Takanori Kanai1,1 7 ✉Recent clinical and experimental evidence has evoked the concept of the gut–brain
axis to explain mutual interactions between the central nervous system and gut
microbiota that are closely associated with the bidirectional effects of inflammatory
bowel disease and central nervous system disorders^1 –^4. Despite recent advances in our
understanding of neuroimmune interactions, it remains unclear how the gut and brain
communicate to maintain gut immune homeostasis, including in the induction and
maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues
prompt the host to protect itself from development of inflammatory bowel diseases.
Here we report a liver–brain–gut neural arc that ensures the proper differentiation and
maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are
responsible for indirectly sensing the gut microenvironment and relaying the sensory
inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal
parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of
the vagal sensory afferents at the hepatic afferent level reduced the abundance of
colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH)
expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation
of muscarinic acetylcholine receptors directly induced ALDH gene expression in both
human and mouse colonic antigen-presenting cells, whereas genetic ablation of these
receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of
left vagal sensory afferents from the liver to the brainstem in mouse models of colitis
reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These
results demonstrate that the novel vago-vagal liver–brain–gut reflex arc controls the
number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic
feedback feedforward system could help in the development of therapeutic strategies
to treat or prevent immunological disorders of the gut.FOXP3+ pTreg cells are most abundant in the mucosal tissues, especially
the colonic lamina propria, and maintain immune homeostasis in the
gut^5 ,^6. The generation of pTreg cells is promoted by a combination of
cytokines, such as TGF-β and retinoic acid, and microbial and dietary
signals, such as Clostridia clusters IV, XIVa and XVIII, Bacteroides fragilis,
microbiota-associated molecular patterns and short chain fatty acids^5 –^13.
In addition to these numerous environmental stimuli, considerable
advances have been made by recent studies showing that immune cells
are under the control of autonomic and enteric neurons^3 ,^14 –^16.
Indeed, the gastrointestinal tract is highly innervated and densely
populated by adaptive and innate immune cells^14 ,^17. Consistently,
immunohistochemical analysis of the localization of neurons
(β-tubulin III+) and major histocompatibility complex class II+ (MHC-II+)antigen-presenting cells (APCs), mainly comprising CX3CR1+ mononu-
clear phagocytes, revealed the close proximity of neurons and APCs in
the colonic lamina propria (Fig. 1a, b, Extended Data Fig. 1a, b). Intesti-
nal APCs, particularly CX3CR1+ mononuclear phagocytes and CD103+
dendritic cells, produce retinoic acid, which preferentially supports
the development of pTreg cells in the TGF-β-rich microenvironment
in the gut^8 ,^18 –^23. Despite the known immunoregulatory effects of the
autonomic nervous system^1 –^3 ,^15 –^17 , it remains incompletely understood
how the vagus nerve influences gut homeostasis by regulating intes-
tinal APCs and pTreg cells. To examine the immunological functions of
the vagus nerve, we performed subdiaphragmatic truncal vagotomy
(VGx) in wild-type C57BL/6 (B6) mice (Extended Data Fig. 1c, d). The
vagotomized mice showed a significant reduction in the number ofhttps://doi.org/10.1038/s41586-020-2425-3Received: 20 November 2019
Accepted: 4 June 2020
Published online: 11 June 2020
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