eosinophils are potent effector cells implicated in allergic responses and helminth infections and have cytotoxic granules containing major basic protein ( mbp ) , eosinophil cationic protein ( ecp ) , eosinophil peroxidase ( epo ) , and eosinophil - derived neurotoxin ( edn ) ( 1 ) . responding to stimuli such as an allergen , helminth infection , or tissue injury , they release their granule - derived cytotoxic proteins and are involved in inflammatory processes . however , the intestine ( constantly in contact with the gut microbiota ) is a major site where eosinophils are abundantly present under homeostatic conditions . intestinal eosinophils rarely undergo degranulation and have a long lifespan as compared with eosinophils in the blood and lungs ( 23 ) . a possible reason is that inhibitory receptor signal regulatory protein  ( sirp)/cd172a , highly expressed on the intestinal eosinophils , inhibits degranulation of eosinophils and promotes their survival ( 2 ) . in support of this notion , the ligand for sirp/cd172a , cd47 , is expressed in the intestine ( 2 ) . in addition , intestinal eosinophils highly express common -chain , which is an integral part of the cytokine receptors for il-2 , il-4 , il-7 , il-9 , il-15 , and il-21 ; intestinal eosinophils are severely reduced in number in the common -chain - deficient mice unlike eosinophils in blood and lungs ; therefore , common -chain - dependent signals seem to play an important role in selective survival of intestinal eosinophils ( 3 ) . intestinal eosinophils are produced from hematopoietic stem cells in bone marrow and migrate into the intestine under the influence of chemokine eotaxin-1 ( 14 ) . during the development and survival of eosinophils , signaling of the common -receptor chain shared by il-3 , il-5 , and gm - csf is required ( 4 ) , and among these cytokines , il-5 is particularly important ; overproduction of il-5 in transgenic mice results in eosinophilia ( 5 ) whereas deletion of il-5 abrogates eosinophilia induced by an aeroallergen ( 6 ) . according to a recent report , il-5 is mainly produced by type 2 innate lymphoid ( ilc2 ) cells , and its production in ilc2 cells is enhanced by vasoactive intestinal peptide ( 7 ) . additionally , transcription factor gata-1 is crucial for the development of eosinophils ; deletion of the palindromic double gata high - affinity binding sites in the gata-1 promoter results in eosinophil - deficient mice ( called dbl gata-1 mice ) ( 8) . phil mice , which express diphtheria toxin a chain under the control of the eosinophil - specific epo promoter , are also eosinophil - deficient mice ( 9 ) . in recent studies on these eosinophil - deficient mice , it has been revealed why eosinophils are abundant in the intestine without inflammation and what their physiological roles are under homeostatic conditions . some papers have shown that intestinal eosinophils promote formation and maintenance of iga - expressing plasma cells ( 10 ) and abundantly produce il-1 receptor antagonist ( il-1ra ) ( 11 ) , contributing to intestinal immune homeostasis . several lines of evidence have shown that eosinophils also exist in adipose tissue and are involved in metabolic homeostasis ( 1213 ) . therefore , in this review , we summarize recent findings regarding eosinophils and discuss the homeostatic functions of these cells . recently , it has been reported that small - intestinal eosinophils produce large amounts of il-1ra ( 11 ) . the latter competes with il-1 for receptor binding and meanwhile , il-1 is primarily produced by activated macrophages and functions as a key mediator in various inflammatory diseases including inflammatory bowel disease and rheumatoid arthritis ( 14 ) . in this context , a decrease in the il-1ra to il-1 ratio is linked to inflammatory bowel disease in humans ( 15 ) . il-1ra - deficient mice spontaneously develop arthritis with a marked increase in the number of th17 cells ( 1617 ) . in line with this finding , it has been reported that microbiota - induced il-1 , but not il-6 , plays an important role in the development of th17 cells in the intestine ( 18 ) . therefore , small - intestinal eosinophils suppress the differentiation and maintenance of th17 cells by constantly secreting large amounts of il-1ra , thus contributing to intestinal immune homeostasis ( 11 ) ( fig . intestinal eosinophils also inhibit differentiation and/or proliferation of th1 cells in the lamina propria ( lp ) though less strongly in comparison with the effects on th17 cells ( 11 ) . however , because il-1ra - deficient mice do not show a significant increase in the number of th1 cells , intestinal eosinophils may suppress differentiation and/or proliferation of th1 cells by secreting other unidentified cytokines . unlike th1 and th17 cells , small - intestinal eosinophils do not affect frequencies of foxp3 regulatory t ( treg ) cells and th2 cells in the lp ( 11 ) . particularly in food allergy , intestinal eosinophils activate dendritic cells ( dcs ) through a release of epo and promote their migration from the intestine to draining lymph nodes , thus initiating a primary th2 immune response ( 19 ) . in contradiction to these findings , one group reported that the numbers of cd103 dcs and cd103 cd4 t cells including foxp3 treg cells are reduced in the lp of eosinophil - deficient mice , although they did not explain the mechanism in the paper ( 10 ) , and this phenomenon should be confirmed later . because small - intestinal eosinophils , but not eosinophils in blood and bone marrow , produce a large amount of il-1ra under homeostatic conditions , we can hypothesize that gut microbiota and its metabolites may be involved in il-1ra production . on the other hand , small - intestinal eosinophils in both spf and gf mice produce similar levels of il-1ra , and metabolites such as retinoic acid and short - chain fatty acids do not induce il-1ra production in bone marrow eosinophils ( 11 ) . instead , gm - csf , which is known to be involved in the development and survival of eosinophils , performs an important function in il-1ra production ( 11 ) . in this regard , the high basal concentration of gm - csf in the small intestine and high expression of gm - csf receptor in small - intestinal eosinophils seem to explain the unique ability of small - intestinal eosinophils to continuously secrete a large amount of il-1ra under steady - state conditions . in addition , because th17 cells can produce gm - csf in an il-1- and il-23-dependent manner ( 20 ) , it is plausible that gm - csf produced by th17 cells endows eosinophils with the superior capacity for il-1ra production and regulates th17 cell homeostasis via a negative feedback loop . in contrast , ironically , large - intestinal eosinophils , when activated by gm - csf produced by th17 cells , secret epo as well as proinflammatory cytokines tnf and il-13 , and aggravate colitis ( 21 ) . these findings imply that small - intestinal eosinophils are different from large - intestinal ones . in support of this notion , large - intestinal eosinophils produce much smaller amounts of il-1ra and show a distinctive expression pattern of surface proteins including cd11c , st2 , and ly6c as compared with small - intestinal ones ( 19 ) . in addition , although eosinophils are mainly present throughout the intestine , large - intestinal eosinophils are scarce in a steady state ( 1119 ) , and only under intestinal inflammatory conditions , does their frequency dramatically increase ( 21 ) . accordingly , large - intestinal eosinophils seem to be proinflammatory unlike their small - intestinal counterparts . most of the intestinal plasma cells are located in the lp and mostly produce iga ( 22 ) . iga is secreted into the intestinal lumen and functions as the first line of defense through neutralization and clearance of enteric pathogens . nevertheless , iga - producing b cells are generally formed in peyer 's patches ( pps ) and migrate into the lp ( 22 ) . in pps , antigen - experienced cd4 t cells migrate into b - cell follicles via cxcr5 and activate b cells ( 22 ) . these specialized cd4 t cells are called follicular b helper t ( tfh ) cells and are different from other cd4 t cell lineages . they highly express costimulatory molecules for their development and function , e.g. , cd40l , ox-40 , and programmed cell death 1 ( pd-1 ) rather than cytokines and transcription factors characteristic of th1 , th2 , and th17 cells ( 22 ) . transcription factor b cell lymphoma 6 ( bcl-6 ) plays an important role in tfh differentiation , whereas transcription factor b lymphocyte maturation protein 1 ( blimp-1 ) inhibits it ( 22 ) . the activated b cells induce activation - induced cytidine deaminase ( aid ) and provoke class switch recombination ( 22 ) . because tgf-1 , a key cytokine for iga switching , is expressed by many cells in pps , activated b cells preferentially switch their isotype from igm to iga ( 2223 ) . moreover , il-21 secreted by tfh cells enhances the proliferation and differentiation of iga plasma cell precursors in synergy with tgf-1 ( 24 ) . meanwhile , igm b cells in the lp are activated by polyclonal stimuli or by antigens presented by dcs in the lp ( lp - dcs ) and differentiate into iga - producing plasma cells without the help of tfh cells ( 22 ) . in this t cell - independent formation of iga - producing b cells , important functions are performed by tgf-1 , b - cell activating factor of the tumor - necrosis factor family ( baff ) , and a proliferation - inducing ligand ( april ) produced by dcs and stromal cells in the lp ( 22 ) . in vitro , cytokines such as il-6 , tnf , il-10 , il-4 , and il-5 , also prolong the survival of plasma cells ( 25 ) . in this context , bone marrow eosinophils have been reported to support the survival of plasma cells by secreting april and il-6 and contribute to the long - term maintenance of plasma cells in bone marrow ( 26 ) . although intestinal eosinophils are mainly in the lp , not in pps , they are involved in the formation and maintenance of iga - producing b cells in pps as well as in the lp ( 10 ) . intestinal eosinophils express baff , tgf-1 , and matrix metalloproteases ( that are involved in the release of tgf-1 from the large latent complex ) as well as april and il-6 at the mrna level ( 10 ) . therefore , intestinal eosinophils appear to influence t - cell - independent formation and maintenance of iga - producing b cells via production of these cytokines and enzymes . accordingly , the amount of iga is dramatically reduced in the intestine of eosinophil - deficient mice ; this change increases bacterial load in the gut and affects composition of the microbiota there ( 10 ) . therefore , it seems likely that eosinophils indirectly exert their effects on t - cell - dependent formation of iga - producing b cells in pps . recently , one paper revealed that eosinophils can be involved in iga production through il-1 ( 27 ) . moreover , eosinophils can release mitochondrial dna in a catapult - like manner and kill bacteria ( 28 ) . nevertheless , the release of mitochondrial dna does not cause cell death of eosinophils . for the release of mitochondrial dna , eosinophils should be activated by lipopolysaccharide under conditions where they are primed with il-5 or ifn- ( 28 ) . in the intestinal environment , gut bacteria can exert their effects on immune cells through bacteria - derived molecules , and immune - cell populations producing ifn- ( th1 ) and il-5 ( ilc2 ) exist ; therefore , it seems plausible that intestinal eosinophils reduce the bacterial load in the gut via the release of mitochondrial dna under homeostatic conditions . accordingly , intestinal eosinophils prevent the host from bacterial invasion and contribute to homeostasis of intestinal immunity . obesity induces chronic low - grade inflammation , consequently causing insulin resistance and type 2 diabetes ( 2930 ) . in the obese state , a large number of monocytes migrate into adipose tissue and differentiate into classically activated ( m1 ) macrophages expressing tnf- and inducible nitric oxide synthase , which triggers inflammation and results in metabolic diseases ( 2930 ) . by contrast , resident adipose - tissue macrophages in the lean state express il-10 and arginase 1 , and show an anti - inflammatory phenotype of alternatively activated ( m2 ) macrophages ( 2930 ) . activation of the anti - inflammatory m2 macrophages requires th2 cytokines such as il-4 and il-13 ( fig . 1 ) , whereas activation of m1 macrophages requires th1 cytokine ifn- ( 2930 ) . eosinophils are a major il-4-expressing cell population in adipose tissue and help to sustain m2 macrophages ( 12 ) ( fig . 1 ) . high - fat diet - induced obesity significantly reduces the number of eosinophils in adipose tissue ( 12 ) . therefore , eosinophil - deficient mice show aggravation of obesity - induced metabolic diseases via a dramatic reduction in the number of m2 macrophages in adipose tissue , indicating that eosinophils are intimately involved in metabolic homeostasis ( 12 ) . besides , ilc2 cells promote accumulation of eosinophils and activate m2 macrophages in adipose tissue through production of il-5 and il-13 and are implicated in metabolic homeostasis ( 3132 ) . the latter represents clusters of uncoupling protein 1 ( ucp-1)-expressing adipocytes in white adipose tissue and functions in heat production under conditions of increased energy expenditure , such as cooling and exercise ( 3435 ) . thus , beige adipocytes contribute to suppression of obesity and alleviation of metabolic diseases . by contrast , white adipocytes do not express ucp-1 and are not involved in thermogenesis ; instead , they participate in fat storage , contributing to obesity - induced metabolic diseases ( 35 ) . il-4 released by eosinophils induces the tyrosine hydroxylase expression of m2 macrophages under cold conditions and drives these macrophages to produce catecholamines such as norepinephrine ( 13 ) . the macrophage - derived catecholamines trigger expression of the ucp-1 gene in subcutaneous white adipose tissue and are involved in the development of beige fat ( 13 ) . in addition , meteorinlike ( metrnl ) , which is a hormone induced in muscle after exercise and in adipose tissue upon cold exposure , exerts its effect on eosinophils and increases their expression levels of th2 cytokines such as il-4 and il-13 , consequently promoting the development of ( and thermogenesis in ) beige fat ( 36 ) . in particular , ilc2 cells contribute to the biogenesis of beige fat through production of methionine - enkephalin peptide as well as via activation by il-33 receptor signaling ( 32 ) . increasing evidence suggests that obesity and other metabolic syndrome are associated with altered composition of the gut microbiota ( 37 ) . in agreement with this notion , the transfer of gut microbiota from obese to germ - free mice increases obesity more than gut microbiota from lean mice does ( 38 ) . microbiota depletion either by antibiotic treatment or in germ - free mice promotes beige fat biogenesis and alleviates obesity and other metabolic syndrome ; these effects are mediated by eosinophil accumulation , enhanced th2 cytokine signaling , and m2 macrophage polarization in white adipose tissue of microbiota - depleted mice ( 39 ) . in this regard , intestinal eosinophils may inhibit obesity and other metabolic syndrome through a reduction of bacterial burden via iga production ( 1027 ) . in addition , because obesity - induced metabolic diseases show elevated levels of il-1 ( 29 ) , intestinal eosinophils may alleviate inflammation by producing large amounts of il-1ra and thus alleviate metabolic diseases . according to recent reports , eosinophils are a heterogeneous cell population and have different characteristics depending on the site of residence ( 3111921 ) . although eosinophils are mainly distributed in the intestine , the phenotype of large - intestinal eosinophils is different from that of small - intestinal ones , and the number of large - intestinal eosinophils in a steady state is much smaller than that of their small - intestinal counterparts ( 111921 ) . moreover , small - intestinal eosinophils in response to gm - csf produce large amounts of il-1ra and exert an anti - inflammatory function ( 11 ) , whereas large - intestinal eosinophils increase production of proinflammatory cytokines tnf- and il-13 and promote colitis ( 21 ) . these observations mean that eosinophils do not all have an identical function , but rather their function is likely controlled by local milieu . thus , if anti - inflammatory eosinophils can be upregulated or inflammatory eosinophils can be converted into anti - inflammatory ones , then these modalities should help to combat inflammatory diseases such as allergies , inflammatory bowel disease , and obesity - related metabolic diseases . to this end , it would be worthwhile to identify the surface markers that can distinguish homeostatic and inflammatory eosinophils . japonica nakai increases the number of small - intestinal eosinophils and suppresses differentiation and/or proliferation of th1 and th17 cells ( 40 ) . regulatory eosinophil - recruiting prebiotics or probiotics may be useful for prevention of inflammatory and metabolic diseases . more studies should be conducted in this field for successful development of eosinophil - targeting treatments .