Science - USA (2020-04-10)

INSIGHTS | PERSPECTIVES

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bind iron-responsive elements in DNA to
regulate the expression of iron metabolism
genes. It is controlled systemically by hep-
cidin, which induces the degradation of the
iron exporter ferroportin and thereby limits
extracellular efflux of iron ( 3 ). High hepci-
din serum concentrations occur in inflam-
matory bowel disease (IBD) patients, partic-
ularly in those with Crohn’s disease ( 5 ). This
positively correlates with the amount of the
intracellular iron storage protein ferritin
and negatively correlates with hemoglobin
concentrations in the blood, which suggests
that high serum hepcidin is associated with
chronic anemia. Bessman et al. show that
mice lacking hepcidin are as susceptible to
dextran sodium sulfate (DSS)–induced ex-
perimental colitis as wild-type animals, but
upon removal of the inflammatory insult,
they struggle to recover body weight and
have reduced mucosal healing.

The major source of hepcidin is consid-
ered to be hepatocytes; however, Bessman
et al. found that during intestinal inflam-
mation, the major producers of hepcidin
are dendritic cells (DCs) in the lamina pro-
pria of the gut in mice and IBD patients.
A similar production of hepcidin upon
parasite infection has been shown in fish
skin ( 6 ), which suggests that local induc-
tion of hepcidin in response to microbial
infection may be evolutionarily conserved.
Deletion of hepcidin in DCs resulted in the
inability to undergo mucosal healing upon
DSS removal.

The authors found that ferroportin, the

target of hepcidin, is expressed only by

colonic epithelial cells (enterocytes), mac-

rophages, and neutrophils. This suggested

that DC-released hepcidin was not acting

in an autocrine fashion. Indeed, elegant

genetic manipulations demonstrated that

macrophages and/or neutrophils were the

target of hepcidin-mediated ferroportin

degradation that is responsible for muco-

sal healing. This corroborates the idea of a

division of labor between intestinal phago-

cytes ( 7 ). The finding that enterocyte fer-

roportin is not the target of hepcidin dur-

ing mucosal healing suggests that either

iron is not reabsorbed from the intestinal

lumen, or iron is not stored within en-

terocytes but is quickly delivered to mac-

rophages or neutrophils, which preserve

it during inflammation owing to hepcidin

released by DCs.

Not all gut bacteria require iron for their

growth ( 8 , 9 ). Bessman et al. show that

hepcidin deletion in DCs resulted in differ-

ences in microbiota composition, suggest-

ing a role for hepcidin control of intestinal

iron—and consequently of the microbi-

ota—under homeostatic conditions. When

this altered gut microbiota was trans-

planted into wild-type animals that were

then treated with DSS, recovery and mu-

cosal healing were reduced. This suggests

that at least some of the effects observed

in mice with hepcidin-deficient DCs were

mediated by changes in microbiota com-

position. Bifidobacterium species, which

protect the intestinal barrier, were reduced

by hepcidin deletion in DCs; this finding

suggests that luminal iron affected this

genus ( 4 ). Bifidobacterium supplementa-

tion in mice with hepcidin-deficient DCs

facilitated mucosal healing, presumably by

controlling epithelial barrier permeability.

The study of Bessman et al. suggests that

the intracellular storage of iron by mac-

rophages or neutrophils is controlled by

inflammation-induced DC-derived hepci-

din, which blocks iron efflux from intracel-

lular pools by degrading ferroportin (see

the figure). In the absence of this control

during intestinal inflammation, iron con-

centration rises in the lumen and alters

the composition of the microbiota. Other

possible events may occur concomitantly

when iron accumulates in the intestinal lu-

men, such as loss of iron-reducing bacteria

(which may limit iron absorption from the

lumen) or an enrichment of iron-depen-

dent pathogenic Enterobacteriaceae. The

effect of increased luminal iron on muco-

sal healing may explain why oral admin-

istration of iron in anemic IBD patients

is not preferred ( 10 ). It will be interesting

to evaluate which other conditions might

lead to increased iron concentration in the

intestinal lumen and whether hepcidin

deletion in DCs in a chronic inflamma-

tory setting may affect systemic iron pools,

which may resemble IBD-associated ane-

mia. These findings provide a rationale for

the beneficial effects of Bifidobacterium

supplementation observed in IBD patients

( 11 ). Clinical trials to better understand

the precise Bifidobacterium strain and/

or iron sequestration, dosage, and time of

intervention would advance the efficacy of

this approach. j

REFERENCES AND NOTES

1. A. U. Steinbicker, M. U. Muckenthaler, Nutrients 5 , 3034
   (2013).


2. A. J. Bessman et al., Science 368 , 186 (2020).


3. G. J. Anderson, D. M. Frazer, Am. J. Clin. Nutr. 106 (suppl.
   6), 1559S (2017).


4. T. Jaeggi et al., Gut 64 , 731 (2015).


5. R. J. Basseri et al., J. Crohn’s Colitis 7 , e286 (2013).


6. Y. H u et al., Fish Shellfish Immunol. 66 , 398 (2017).


7. E. Mazzini, L. Massimiliano, G. Penna, M. Rescigno,
   Immunity 40 , 248 (2014).


8. M. Elli et al., J. Appl. Microbiol. 88 , 695 (2000).


9. K. Skrypnik, J. Suliburska, J. Sci. Food Agric. 98 , 2449
   (2018).


10. C. J. Gargallo-Puyuelo, E. Alfambra, J. A. García-Erce, F.
    Gomollon, Nutrients 10 , E1959 (2018).


11. M. J. Saez-Lara, C. Gomez-Llorente, J. Plaza-Diaz, A. Gil,
    BioMed Res. Int. 2015 , 505878 (2015).

ACKNOWLEDGMENTS

The author is supported by grants from the Italian Association

for Cancer Research (AIRC IG 17628) and the European

Research Council (ERC, no. 615735—homeogut).

10.1126/science.abb2915

Macrophage

Ferroportin

Bifdobacterium

Intestinal lumen

Barrier repair

Fe2+

Hepcidin

Dendritic cell

In the absence of DC-derived hepcidin, iron is released

extracellularly through ferroportin.

DCs release hepcidin, which induces the degradation

of ferroportin, and iron is retained intracellularly.

Intestinal infammation Hepcidin-defcient dendritic cells

130 10 APRIL 2020 • VOL 368 ISSUE 6487

Hepcidin-driven wound healing in the gut
During intestinal inflammation, dendritic cells (DCs) release hepcidin, which induces the degradation of
ferroportin in phagocytes and intracellular retention of iron. When hepcidin is deleted in DCs during
inflammation, iron accumulates in the intestinal lumen, and Bifidobacterium species (which are important
for barrier repair) are particularly reduced.