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1 Immune Regulation by Histamine and Histamine-Secreting Bacteria

1 1 1,2 1
2 Weronika Barcik , Marcin Wawrzyniak , Cezmi A. Akdis , Liam O’Mahony

1
4 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland

2
5 Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland;

7 Corresponding Author: Dr Liam O’Mahony, SIAF, Obere Strasse 22, 7270 Davos Platz, Switzerland.
8 Ph. 0041-81-4100853; Fax 0041-81-4100840; E-mail: liam.omahony@siaf.uzh.ch

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© 2017 published by Elsevier. This manuscript is made available under the Elsevier user license
https://www.elsevier.com/open-access/userlicense/1.0/
 9 Abstract.

10 Histamine is a biogenic amine with extensive effects on many immune cell types. Histamine and its
11 four receptors (H1R – H4R) represent a complex system of immunoregulation with distinct effects
12 dependent on receptor subtypes and their differential expression. In addition to mammalian cells,
13 bacteria can also secrete histamine and the influence of microbiota-derived histamine on host
14 immunological processes is only beginning to be described. However, it is clear that histamine-
15 secreting microbes are present within the human gut microbiota and their levels are increased in
16 asthma patients. Additional studies are required to fully understand the complex regulatory interactions
17 between histamine and the host immune response to everyday microbial and environmental
18 challenges.

19

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19 Introduction.

20 The microbiota on mucosal surfaces is increasingly being recognised to play an essential role in host
21 development and in particular for inducing immune homeostatic networks. In addition to the
22 taxonomic diversity of the microbiota, its metabolic activity has profound effects on the induction of
23 immune tolerance [1-3]. Accumulating evidence suggests that certain bacterial strains and their
24 associated metabolites may provide disease protective signals while other bacterial strains may
25 stimulate aggressive and tissue damaging immune responses. Thus, the activity of the mammalian
26 immune system seems to be governed by the balance between symbiotic and pathogenic factors
27 derived from our microbial inhabitants [4].

28 One class of microbial-derived metabolites that have received significant attention are the short-chain
29 fatty acids (SCFA), which include butyrate, acetate and propionate. The production of SCFA occurs in
30 the colon following microbial fermentation of dietary fibers and SCFA can also be consumed in certain
31 foods such as butter [5]. SCFAs are an important energy source for colonocytes and regulate the
32 assembly and organization of tight junctions. Importantly, SCFA promote dendritic cell regulatory
33 activity resulting in the induction of regulatory lymphocytes and IL-10-secreting T cells. Abnormalities
34 in the production of SCFAs (due to dietary factors and/or dysbiosis) have been suggested to play a
35 role in the pathogenesis of type-2 diabetes, obesity, inflammatory bowel disease, colorectal cancer
36 and allergies [6]. The SCFA-induced immunoregulatory activities have largely been attributed to their
37 binding and activation of G protein-coupled receptors (GPCRs) such as GPR41, GPR43 and
38 GPR109a [7]. In addition to SCFAs, the microbiota can secrete a wide range of other metabolites that
39 can also influence mucosal immune responses via activation of GPCRs. One such metabolite is
40 histamine. Histamine (2-[4-imidazolyl]-ethylamine) is a low-molecular-weight biogenic amine and was
41 first chemically synthesized by Windaus and Vogt in 1907. Dale and Laidlaw reported the first
42 biological functions of histamine in 1910, whereby they demonstrated that histamine induced smooth
43 muscle-stimulating and vasodepressor action previously observed during anaphylaxis [8].
44 Subsequently histamine was isolated from many different tissues, thus its name was based on the
45 Greek word “histos”, which means tissue. Histamine binds to four known histamine receptors (HRs)
46 and a range of “blockbuster” drugs have been developed for H1R and H2R, the inventors of which
47 were awarded Nobel prizes in 1957 (Daniet Bovet) and 1988 (James Black). Drugs targeting H3R and
48 H4R are currently being evaluated.

49

50 Immune Regulation by Histamine.

51 Innate and adaptive immune cells throughout the body can produce histamine by decarboxylation of
52 the amino acid L-histidine by the enzyme histidine decarboxylase (HDC) [9]. Mast cells, basophils,
53 gastric enterochromaffin-like cells and histaminergic neurons are the best-described cellular sources
54 of histamine. Other cells such as platelets, monocytes/macrophages, dendritic cells, neutrophils and
55 lymphocytes may upon stimulation also express HDC. Activity of HDC is influenced by cytokines
3

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56 including IL-1, IL-3, IL-12, IL-18, GM-CSF, macrophage-colony stimulating factor, TNF-α and calcium
57 ionophore [10]. In the case of mast cells and basophils, histamine is stored in large quantities and
58 released upon cellular activation. All other cells secrete histamine following synthesis and do not store
59 it intracellularly [11]. Before secretion, histamine can be metabolized by ring methylation (HNMT –
60 histamine-N-methyltransferase) to N-methylhistamine, or by oxidative deamination (DAO – diamine
61 oxidase) to imidazole acetic acid. As DAO is secreted extracellularly, this enzyme may be responsible
62 for scavenging extracellular histamine, while HNMT remains within the cytosol and thereby
63 metabolizes intracellular histamine [12, 13].

64 Histamine receptors

65 Cells of both the innate and adaptive immune system can be regulated by histamine (Figure 1).
66 Binding of histamine to four subtypes of histamine receptors shape and define the nature of histamine
67 effects in immunological responses. Histamine receptors contain 7 transmembrane domains and
68 belong to the rhodopsin-like family of GPCRs. Each HR is associated with specific Gα subunits, which
69 result in distinct molecular signalling cascades and diverse modes of action following histamine
70 binding. H1R leads to the activation of Gαq, H2R is coupled to Gαs while H3R and H4R are both
71 activators of Gαi/0 [14]. In humans, H3R and H4R display the highest affinity for histamine binding,
72 followed by H2R and H1R [15]. The different characteristics associated with each of the HRs are
73 summarised in Table 1.

74 Histamine 1 receptor

75 A broad range of cell types, including T and B lymphocytes, monocytes, dendritic cells, endothelial
76 cells, airway and vascular smooth muscle cells, hepatocytes, neurons and chondrocytes express H1R
77 [16, 17]. Histamine binding to the H1R leads to activation of phospholipase C (PLC), which produces
78 1,2-diacylglycerol and inositol-1,4,5-trisphosphate, subsequently resulting in activation of protein
79 kinase C (PKC) and release of calcium ions from intracellular stores. Activation of H1R mediates the
80 classical immediate hypersensitivity responses such as airway and vascular smooth muscle cell
81 contraction, increased vascular endothelial cell permeability, synthesis of platelet activating factor and
82 release of von Willebrand factor and nitric oxide. Consequently this results in many pathological
83 processes including allergic rhinitis, atopic dermatitis, uticaria, asthma and anaphylaxis [10, 18].
84 Furthermore, H1R mediates regulation of food and water intake, convulsion, attention and sleep
85 regulation [19].

86 Histamine 2 receptor

87 Interestingly many of the H1R-mediated effects can be antagonized by H2R. For example, H2R is
88 responsible for relaxation of blood vessel-associated smooth muscle cells found in the uterus and
89 airways [20]. H2R is an adenyl cyclase-coupled GPCR, which stimulates cAMP production and
90 downstream effects are mediated by protein kinase A (PKA) and the transcription factor cAMP
91 response element-binding protein. A wide diversity of cells and tissues including cardiac tissue, gastric

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 92 parietal cells, brain cells, smooth muscle cells, T and B lymphocytes and dendritic cells express H2R
93 which can exhibit constitutive or spontaneous activity [21]. H2R activation regulates both innate and
94 adaptive immune system responses including mast cell degranulation, dendritic cell responses to
95 microbial ligands, T cell proliferation, TH1-derived cytokine production and antibody production by B
96 cells [22, 23]. Recently, H2R was shown to regulate invariant natural killer T cell (iNKT cell) activity
97 and loss of H2R signalling on iNKT cells resulted in exaggerated inflammatory responses within the
98 lung [24]. Similarly, the transfer of H2R-deficient T cells to SCID mice was associated with more
99 severe colitis and TH17 responses within the gut, compared to mice that received wild-type T cells
100 [25]. Interestingly, mucosal histamine levels are increased in patients with irritable bowel syndrome
101 and inflammatory bowel disease, but the cellular sources of histamine in these patients is not well
102 described [26]. However, it was recently shown that inflammatory bowel disease patients do display
103 dysregulated expression of histamine receptors, with diminished anti-inflammatory effects associated
104 with H2R signalling [25]. Collectively, these studies suggest that H2R is an important
105 immunoregulatory receptor.

106 Histamine 3 receptor

107 The next histamine receptor, H3R was formerly identified as a neurotransmitter release controlling pre-
108 synaptic receptor and is characterized by a high degree of constitutive activity in vitro and a large
109 number of splice variants with similar pharmacological properties [27]. Histamine binding to H3R
110 results in the activation of mitogen-activated protein kinase (MAPK) pathways, protein kinase B (PKB)
111 and an increase in calcium ion concentration. Most of the knowledge about H3R activity comes from
112 studies using H3R-deficient mice. H3R deficient animals are characterized by the enhanced
113 expression of MIP-3 (macrophage inflammatory protein 3), IP-10 (IFN-inducible protein 10) and
114 CXCR3 expression by peripheral T cells which leads to increased severity of neuro-inflammatory
115 disease. Furthermore these animals display increased insulin and leptin levels, associated with late-
116 onset obesity partially mediated by an abnormally increased appetite [28, 29].

117 Histamine 4 receptor

118 The most recently described histamine receptor, H4R, shares some molecular, pharmacological and
119 signal transduction features with H3R but the expression pattern is different to H3R as it is found on
120 keratinocytes, Langerhans cells, dendritic cells, neutrophils, mast cells, basophils and lymphocytes
121 [30]. Histamine receptor 4 is involved in cytokine production and chemoattraction of eosinophils, mast
122 cells and basophils as well as T lymphocytes and dendritic cells [31, 32]. Data from animal models
123 suggest that treatment with H4R antagonists supports the importance of this receptor in regulation of
124 immunological processes in colitis, arthritis and asthma [33, 34].

125

126 Histamine-Secreting Bacteria.

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127 In addition to mammalian cells, a number of different bacterial strains have been identified as being
128 able to secrete histamine following decarboxylation of histidine via HDC activity. The best described
129 are those bacteria that are able to secrete histamine in food products. Their presence is monitored and
130 controlled in cheese, meat, vegetables, dairy products and also during beer and wine fermentation
131 [35, 36]. However the most notorious examples of histamine secreting bacteria are those associated
132 with spoiled fish and sea food products. Histamine fish poisoning (HFP), or scombroid food poisoning,
133 is an illness associated with consumption of high levels of histamine in fish, following the metabolism
134 of histidine in the fish by bacteria during inappropriate handling during storage or processing [37, 38].
135 The earliest record of the disease was in 1799. Symptoms of HFP resemble those of food allergy and
136 can include facial itching, torso or body rash, nausea, vomiting, diarrhoea, tachycardia, hypotension,
137 respiratory distress and in rare severe cases may result in death [39]. HFP is often misdiagnosed as a
138 food allergic response. The bacterial species with histidine decarboxylase activity and which have
139 been implicated in HFP include Morganella morganii, Eschericha coli, Hafnia alvei, Proteus vulgaris,
140 Proteus milabilis, Enterobacter aerogenes, Raoultella planticola, Raoultella ornithinolytica, Citrobacter
141 freundii, Pseudomonas fluorescens and Photobacterium damselae [40].
142
143 Although the presence of histamine-secreting bacteria has been well documented in foods, their
144 presence within the human gut microbiota has not been investigated in detail. We recently performed
145 an analysis of fecal samples from 161 volunteers to quantify the presence of bacterial HDC, using
146 primers that do not amplify human HDC. Microbial-specific HDC was detected in all fecal samples,
147 however a wide inter-individual range was evident [41]. Interestingly, bacterial HDC gene levels were
148 significantly elevated in adult patients with asthma compared to healthy controls. In addition, non-
149 obese patients with asthma had the highest level of the bacterial HDC gene compared with obese
150 patients with asthma. The difference in HDC positive bacteria between obese and non-obese asthma
151 patients suggests that factors other than histamine secretion by microbes in the gut may be more
152 important for the development of asthma in obese patients. The bacteria isolated from these fecal
153 samples, which were able to secrete the highest levels of histamine, belong to Escherichia coli,
154 Morganella morganii and Lactobacillus vaginalis species [41]. The level of histamine secretion
155 depended on the strain and in vitro culture conditions that were used (e.g. pH and culture media
156 composition). Of note, Escherichia coli and Morganella morganii were commonly reported to be the
157 causative isolates associated with cases of HFP. Intriguingly, increased levels of Morganella morganii
158 were positively associated with more severe asthma symptoms. Based on these observations, one
159 might speculate that increased levels of bacterial-derived histamine in certain adult asthma patients
160 may contribute to histamine-mediated pathologies due to a higher systemic level of histamine, which
161 then reduces the level required for host-derived histamine to drive allergic responses following
162 allergen exposure. However, this hypothesis remains unproven. In addition, certain bacterial strains
163 can degrade histamine and it is currently unknown if the levels of these bacteria are altered in
164 inflammatory disorders such as asthma [42].
165
166 Immune Regulation by Histamine-Secreting Bacteria.
6

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167 Given the potent immunological effects associated with histamine signalling, it is not surprising that
168 histamine from the microbiota may also influence immune responses. In vitro, culture supernatants
169 from histamine-secreting bacteria were able to stimulate CHO cells, which possessed a H1R reporter.
170 Specific activation of the H1R by bacterial-derived histamine was confirmed as activity was blocked
171 using the H1R antagonist diphenhydramine [41]. In addition, Lactobacillus reuteri-derived histamine
172 was shown to inhibit TLR-induced TNF-α production by human monocytoid cells via signaling through
173 the H2R and downstream cAMP and PKA activity [43].
174
175 In murine models, it was recently shown that gut microbiota-derived histamine influences host-
176 microbiome homeostasis via epithelial IL-18 secretion, co-modulating NLRP6 inflammasome signalling
177 and downstream anti-microbial peptide secretion [44]. Administration of the histamine-secreting
178 Lactobacillus strain 30A to mice resulted in rapid weight loss and reduced Peyer’s patch cytokine
179 secretion [45]. However, weight loss was exaggerated in H2R-deficient mice and IL-4, IL-6, and IL-17
180 secretion by Peyer’s patches was increased, an opposite result to that observed for wild-type animals.
181 This data suggests that histamine-derived from gut microbes can have immunological effects within
182 the mucosa, but the nature of these effects is determined by the histamine receptor that is triggered. In
183 a separate study, the suppression of intestinal inflammation by a Lactobacillus reuteri strain was
184 shown to be dependent on histamine secretion by the bacterium and its activation of H2R [46].
185

186 Conclusions.
187 Histamine and its four receptors represent a complex system of immunoregulation with distinct effects
188 dependent on receptor subtype expression and activity. The role for differential expression or
189 activation of histamine receptors on immune competent cells in chronic inflammatory diseases is still
190 poorly described to date and further examination of this potent immunoregulatory network will likely
191 lead to a better understanding of these disorders. Recent developments in histamine research
192 suggest that we need to re-evaluate the role that histamine plays in innate and adaptive immune
193 responses. In addition, no longer can we assume that mast cells and basophils are the principal
194 cellular sources of histamine in the human body as clearly many resident bacterial strains produce
195 histamine and their levels are increased in the gut of adult non-obese asthma patients. More accurate
196 endotyping of asthma patients (and other chronic inflammatory disorders) may be assisted by further
197 analysis of the composition and metabolic activity of an individual’s microbiome and future clinical
198 studies of new therapeutic agents should consider performing microbiome and metabolite analysis to
199 determine if specific microbiome features correlate with responses to treatment. In addition,
200 therapeutics directly targeting microbiome activities, such as histamine secretion, may be considered
201 as complementary to existing drugs.
202
203 Conflict of interests

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204 Liam O’Mahony has received research support from GSK and consulted for Alimentary Health Ltd.

205 Cezmi Akdis has received research support from Novartis and Stallergenes and consulted for

206 Actellion, Aventis and Allergopharma. Weronika Barcik and Marcin Wawrzyniak have no potential

207 conflicts of interest.

208

209
210 Acknowledgements.
211 The authors are supported by Swiss National Science Foundation grants (project numbers
212 CRSII3_154488, 310030_144219 and 310030-127356) and Christine Kühne – Center for Allergy
213 Research and Education (CK-CARE).
214
215
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335
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343
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348 IL-18 secretion, which orchestrates colonic anti-microbial peptide expression. Inflammasome
349 modulation by bacterial metabolites enables dysbiotic microbiota community transfer.
350
351 45. Ferstl R, Frei R, Schiavi E, Konieczna P, Barcik W, Ziegler M, Lauener RP, Chassard C, Lacroix
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354
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357 MBio 2015, 6:e01358-15.
358 This study suggests that supplementation with hdc(+) Lactobacillus reuteri, which can convert l-
359 histidine to histamine in the gut, resulted in suppression of colonic inflammation. These findings link
360 luminal conversion of dietary components (i.e. amino acid metabolism) by gut microbes and microbial-
361 mediated suppression of colonic inflammation.

362

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369
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370

371 Figure Legend.

372 Figure 1. Influence of histamine on mucosal-associated immune cell subsets.
373 Luminal sources of histamine include the diet and bacteria, while mast cells and basophils are the
374 primary sources of tissue-derived histamine. Epithelial cells and immune cells express histamine
375 receptors. Activation of dendritic cell (DC) H1R supports Th1 lymphocyte polarisation, while H2R
376 inhibits Th1 and Th2 lymphocyte polarisation and supports the expansion of regulatory lymphocytes.
377
378

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400 Highlights

401 • Histamine influences immune responses via binding to four different GPCRs

402 • Histamine secreting bacteria are present within the human gut

403 • Bacterial-derived histamine is immunologically active

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424 Table 1. Overview of histamine receptors.

H1R H2R H3R H4R

Chromosomal 3q25 5q35.2 20q13.33 18q11.2
location
G protein Gαq Gαs Gαi/0 Gαi/0
coupling
Intracellular Activates PLC, Increases cAMP Inhibits cAMP, Inhibits cAMP,
signal PKC and calcium and activates activates MAPK, activates MAPK,
transduction release PKA PKB and calcium PKB and calcium
release release
Tissue location Ubiquitous Ubiquitous Neurons Bone marrow,
hematopoietic
cells,
keratinocytes
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