Review: Other Helicobacter Species

DOI: 10.1111/hel.12645

SUPPLEMENT ARTICLE

Armelle Ménard1 | Annemieke Smet2

1INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, Université Abstract de Bordeaux, Bordeaux, France This article is a review of the most important, accessible, and relevant literature pub‐ 2 Laboratorium of Experimental lished between April 2018 and April 2019 in the field of Helicobacter species other than Medicine and Pediatrics, Department of Translational Research in Immunology and Helicobacter pylori. The initial part of the review covers new insights regarding the pres‐ Inflammation, Faculty of Medicine and ence of gastric and enterohepatic non‐H. pylori Helicobacter species (NHPH) in humans Health Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium and animals, while the subsequent section focuses on the progress in our understand‐ ing of the pathogenicity and evolution of these species. Over the last year, relatively Correspondence Armelle Ménard, Laboratoire de few cases of gastric NHPH infections in humans were published, with most NHPH in‐ Bactériologie, INSERM U1053, Campus de fections being attributed to enterohepatic Helicobacters. A novel species, designated Carreire, Université de Bordeaux, Bâtiment 2B RDC ‐ Case 76, 146 rue Léo Saignat, “Helicobacter caesarodunensis,” was isolated from the blood of a febrile patient and F33076 Bordeaux, France. numerous cases of human Helicobacter cinaedi infections underlined this species as a Email: [email protected] true emerging pathogen. With regard to NHPH in animals, canine/feline gastric NHPH cause little or no harm in their natural host; however they can become opportunistic when translocated to the hepatobiliary tract. The role of enterohepatic Helicobacter species in colorectal tumors in pets has also been highlighted. Several studies in rodent models have further elucidated the mechanisms underlying the development of NHPH‐ related disease, and the extra‐gastric effects of a Helicobacter suis infection on brain homeostasis was also studied. Comparative genomics facilitated a breakthrough in the evolutionary history of Helicobacter in general and NHPH in particular. Investigation of the genome of Helicobacter apodemus revealed particular traits with regard to its viru‐ lence factors. A range of compounds including mulberries, dietary fiber, ginseng, and avian eggs which target the gut microbiota have also been shown to affect Helicobacter growth, with a potential therapeutic utilization and increase in survival.

KEYWORDS non‐Helicobacter pylori Helicobacter, human and animal disease, animal studies, pathogenesis, genomics and evolution

1 | PRESENCE OF NON‐HELICOBACTER lesions which differ from the less active and less severe gastritis PYLORI HELICOBACTER SPECIES IN HUMANS usually associated with NHPH infections in humans. The patient was successfully treated with a combination of amoxicillin, clari‐ 1 A limited number of cases of gastric non‐Helicobacter pylori thromycin, and a proton pump inhibitor. Another case report de‐ Helicobacter (NHPH) infections in humans were reported this year. scribed a reddish depression lesion in the corpus of the stomach of An atypical presentation of an acute Helicobacter felis infection was a 56‐year‐old man. Gastric biopsy analysis identified a Helicobacter 2 described in a 39‐year‐old male suffering from acute abdominal pain, suis infection which was eradicated after 10 days of triple therapy. nausea, and vomiting. Gastroscopic examination revealed necrotic The presence of gastric NHPH was also reported for the first time in

2.7% of children suffering from gastric disorders in Southern Turkey, reported cases include a secondary infection following a vascular with H. suis being the most prevalent species.3 access device placement,13 chemotherapy (rituximab plus cyclo‐ Human NHPH infections reported over the last year were mostly phosphamide, doxorubicin, vincristine, and prednisone),10 or ceph‐ associated with enterohepatic Helicobacters. A proposed novel alosporin treatment (ceftriaxone).22 In the latter case, high plasma Helicobacter species “Helicobacter caesarodunensis” was isolated and cerebrospinal fluid ceftriaxone concentrations induced an from the blood of a febrile patient. This curved, rod‐shaped entero‐ encephalopathy in the hemodialysis patient.22 Anti‐cancer che‐ hepatic Helicobacter was shown to be closely related to Helicobacter motherapy and systemic steroids have been shown to be inde‐ equorum and harbors two sheathed amphitrichous flagella.4 Whole pendent risk factors for recurrent H. cinaedi‐induced bacteremia; genome sequencing revealed a genome of 1 708 265 base pairs (bp) however, evidence would suggest that selective digestive decon‐ with a G+C content of 37.80% and a total of 1697 predicted coding tamination with kanamycin could potentially be a strategy to pre‐ sequences. vent recurrence of infectious bacteremia.23 H. cinaedi is difficult to An umbrella review of 53 meta‐analyses identified 9 environ‐ identify at the species level. H. cinaedi infections can be diagnosed mental factors that increase the risk of inflammatory bowel diseases using the VersaTREKTM blood culture system.24 A multi‐step ge‐ (IBD), including infection with enterohepatic Helicobacter species.5 nome‐wide phylogenetic analysis of isolates from an intra‐hospital In contrast, H. pylori infection was shown to reduce the risk of IBD.5 outbreak of H. cinaedi‐associated bacteremia highlighted the role However, further studies are required to determine whether an en‐ of asymptomatic carriers or environmental contamination as well terohepatic Helicobacter infection is the cause or consequence of as the emergence of a subclone with increased resistance to flu‐ IBD. Analysis of microbiota in human colorectal cancer (CRC) tis‐ oroquinolones.25 Finally, H. cinaedi was also found in small sludge sues revealed that the number of Helicobacter species in patients flocs in wastewater treatment plants, indicating the human and with poorly differentiated right colon cancers was higher than in environmental health risks of activated sludge.26 Another draft well‐differentiated left colon cancers. In addition, Helicobacter bilis genome sequence of H. cinaedi isolated from a blood culture re‐ was overrepresented in poorly differentiated cancers as compared vealed a 1 995 911 bp chromosome with 39.1% G+C content.27 to well‐differentiated cancers, suggesting that H. bilis is potentially associated with a poorer differentiation and more negative progno‐ sis in patients with CRC.6 In another study, PCR‐based investigation 2 | PRESENCE OF NON‐HELICOBACTER failed to show any correlation between enterohepatic Helicobacter PYLORI HELICOBACTER SPECIES IN species (H. bilis, Helicobacter hepaticus and Helicobacter pullorum) and ANIMALS cholelithiasis, while the presence of H. pylori DNA was associated with acute gallstone cholecystitis.7 Using NGS‐based 16S rRNA se‐ In 2018, Sousa et al28 investigated the presence of NHPH in the quencing, Helicobacter species were not detected either in bile col‐ gastric mucosa of cats. They showed that all animals were predomi‐ lected from Chilean patients with gallbladder cancer,8 contradicting nantly infected with Helicobacter heilmannii, the most prevalent fe‐ previous studies. line Helicobacter species.28,29 Despite the observation of a histologic Helicobacter fennelliae was isolated from a non‐diarrheal stool mild gastritis, all animals were clinically healthy.28 This suggests that sample in a child from Cambodia. The infecting strain showed re‐ pet‐associated gastric Helicobacters cause little or no harm in their sistance to macrolides and quinolones which represent the first‐line natural host, which is in contrast to other members of the NHPH antibiotic therapy for Campylobacter‐like infections.9 group.29 However, Takemura et al30 identified gastric Helicobacters New cases of Helicobacter cinaedi‐related bacteremia have been in hepatobiliary samples from dogs with lesions in the liver. These reported in immunocompromised patients, patients with rheuma‐ authors stated that pet‐associated NHPH can become opportunistic toid arthritis and malignant lymphoma,10 a prosthetic joint infec‐ pathogens in the biliary tract when translocated from the stomach tion in an HIV‐infected man,11 X‐linked agammaglobulinemia,12 to the liver.30 De Witte et al31 analyzed fecal samples from marine and acute gastroenteritis.13 H. cinaedi was also isolated from the and terrestrial mammals in zoos for the presence of gastric and en‐ blood and peritoneal fluid of a patient undergoing peritoneal di‐ terohepatic Helicobacter species. Helicobacter cetorum was the only alysis who presented with autosomal dominant polycystic kidney gastric species that could be detected in the majority of dolphins. disease and a cyst infection, showing that H. cinaedi cyst infection Furthermore, novel enterohepatic Helicobacter species were identi‐ had spread to the peritoneal fluid.14 A further study demonstrated fied in both marine and terrestrial zoo mammals.31 Another study that bacterial translocation from the intestinal tract could repre‐ also reported Helicobacter species in the stomach of aquatic marine sent one route of H. cinaedi‐induced bacteremia.15 H. cinaedi‐re‐ mammals, for example, East Asian finless porpoises (Neophocaena lated bacteremia was also reported in immunocompetent patients asiaeorientalis sunameri), and to a lesser extent in the foregut, hind‐ diagnosed with a hepatic cyst infection,16 carotid atherosclero‐ gut, and feces.32 sis,17 a thyroid abscess presenting with thyroid storm,18 and a case Proliferative and invasive colorectal tumors were investigated of atypical Raynaud’ syndrome.19 A case of H. cinaedi unique cel‐ in 20 pet dogs. H. bilis and Alistipes finegoldii were significantly en‐ lulitis20 was described, as well as a vertebral osteomyelitis caused riched in proliferative canine tumors, all harboring overactivated 21 by H. cinaedi and identified by 16S rRNA gene sequencing. Other WNT/β‐catenin pathways, recurrent CTNNB1 (β‐catenin) mutations, MÉNARD and SMET | 3 of 8 and recurrent TP53 mutations.33 These findings provide unique 3 | PATHOGENESIS OF insight into human CRC since human CRC molecular characteris‐ NON‐HELICOBACTER PYLORI HELICOBACTER tics match those of canine tumors. A further study has shown that INFECTIONS Enterobacteriaceae and Helicobacter belong to the microbiota of dogs with colorectal tumors.34 A species rarely reported in dogs, Over the last year, further evidence has emerged regarding the “Helicobacter winghamensis,” was isolated from fecal samples of pathogenicity of H. suis in the gastric mucosa. Padra et al44 re‐ working farm dogs.35 ported that H. suis binds to pig gastric mucins and glycolipids via Enterobacteriaceae dominated the gut microbial compositions in two binding modes: (a) binding to structures terminating with adult giant pandas and their cubs while Helicobacteraceae belonged galactose at neutral and acidic pH and (b) binding to negatively to the seven genera that showed great importance with respect to charged structures at acidic pH. In a follow‐up study, the same gut microbial structural determination in the nursing stage of giant group further characterized the binding properties of this path‐ panda cubs.36 ogen to mucins from uninfected and infected pigs and humans. Weaning is a crucial period leading to serious intestinal dysbiosis Based on their study, Padra et al45 concluded that H. suis infec‐ and mortality in piglets. Genera, such as Campylobacter, Veillonella, tion impairs mucin composition and glycosylation and decreases Helicobacter, and Blautia that were previously reported in intestinal the H. suis binding ability to mucins and the antiproliferative ac‐ dysbiosis, were significantly enriched in 7‐day post‐weaned pig‐ tivity that mucins can have on this pathogen. Inhibition of these lets.37 When the post‐weaning age reaches 27 days, this microbi‐ mucus‐based defenses thus creates a more stable and inhabitable ota undergoes significant changes toward a more normal state with environment for long‐term colonization of this pathogen and the other genera. A 30‐day feeding trial of piglets with alfalfa meal or outcome of infection.45 In a study by Constantino et al46, phase‐ commodity concentrated fiber resulted in an improvement in gut contrast microscopy of unlabeled bacteria revealed H. suis flagella health associated with a lower relative abundance of Helicobacter, bundles in two conformations, extended away from the body (E) or potentially explaining the reduction of piglet diarrhea.38 Effects of flipped backward and wrapped (W) around the body. By analyzing host genetics and environmental conditions on fecal microbiota the transition between these two states, three swimming modes composition in pigs revealed that sanitary stress was of relatively were observed: (a) one bundle rotating and wrapped around the minor influence on microbiota composition in high or low residual body and the other extended, (b) both extended, and 3) both feed intake pigs although there was an increase in the abundance of wrapped, with only the first and the last swimming mode being Helicobacter in low residual feed intake pigs subjected to stress.39 observed in porcine gastric mucin. The authors concluded that the Idiopathic chronic diarrhea (ICD) is a common cause of mor‐ extended bundle dominates the swimming dynamics of H. suis.46 bidity and mortality among juvenile rhesus macaques. Fecal meta‐ A further study investigated the effects of in‐feed bambermycin transcriptomics from rhesus macaque stool samples revealed that medication on the pathogenesis of gastric H. suis infections in a ICD is associated with (a) increased gene expression from bacterial mouse model.47 Bambermycin, which inhibits the synthesis of the pathogens such as Campylobacters and Helicobacters and the pro‐ bacterial wall, did not alter H. suis colonization in the stomach, but tozoan Trichomonas, (b) increased mucin degradation, and (c) al‐ decreased gastric inflammation by inhibiting its effects on parietal tered fucose utilization. These data suggest that the ICD‐affected cell loss.47 macaques produce fucosylated mucins that are leveraged by poten‐ Increasing evidence suggests that an infection with a gastric tially pathogenic microbes as a carbon source or at adhesion sites. Helicobacter species is not limited to the stomach alone, but can also On the other hand, the analysis of 35 rhesus macaques euthanized be associated with the aggravation of extra‐gastric manifestations, for ICD demonstrated that ICD was associated with dysbiosis in‐ including neurodegenerative disorders, underlining the involvement volving Campylobacter and Trichomonas, and a loss of Helicobacter of the gut‐brain axis. Indeed, evaluation of the effect of a gastric H. macacae.40 suis infection on the brain homeostasis in mice showed that this in‐ Increased abundance of Helicobacter brantae was shown in a fection induced not only inflammation in the stomach, but also in the batch of commercially hatched broiler parent chickens (over 80% of brain which was reflected in short‐term memory loss. These alter‐ ileal microbiota in individual chickens).41 ations were accompanied by leakage of the gastrointestinal barrier, Eimeria parasite coccidiosis is an economically important dis‐ low‐grade systemic inflammation, and disruption of the blood‐ce‐ ease of poultry and livestock worldwide. Enterobacteriaceae and rebrospinal fluid (CSF) barrier, suggesting that H. suis‐evoked gas‐ Helicobacter load were increased in the gut of BALB/c mice infected trointestinal permeability and subsequent peripheral inflammation with the Eimeria falciformis parasite.42 induce changes in brain homeostasis via changes in the blood‐CSF Proliferative typhlocolitis with multinucleated giant cells was barrier integrity.48 observed in immunodeficient sentinel mice from conventional and Helicobacter felis infections in mice have often been used to medium‐security facilities.43 While Helicobacter species were identi‐ study H. pylori‐related gastric disease in humans. However, H. felis fied in 40 of 143 mice, with H. hepaticus accounting for 72.5% of the lacks several important H. pylori virulence factors, and therefore, identified Helicobacter species, this H. hepaticus‐associated enterop‐ caution should be taken when extrapolating data from an H. felis athy was not specific.43 4 of 8 | MÉNARD and SMET infection mouse model to H. pylori infections in humans. However, insight into the mechanisms by which bacterial infection initiates this model remains a good and reproducible model to study host im‐ and promotes intestinal tumorigenesis.57 H. hepaticus infection bi‐ mune responses to gastric helicobacters, as well as to examine host ased the promotion of mutation frequencies in association with and environmental factors that promote gastric carcinogenesis.49 Ye an increase in epithelial iNos expression and DNA damage.57 H. et al50 highlighted the importance of bone morphogenetic protein hepaticus infection and its associated inflammation also increase (BMP) signaling in the regulation of gastric epithelial homeostasis. the levels of intestinal mucosa‐associated genotoxic colibactin‐ More specifically, they showed that H. felis infection leads to the ac‐ producing pks+ Escherichia coli.57 tivation and expansion of leucine‐rich repeat‐containing G‐protein‐ Encoding alpha kinase 1 (Alpk1) is a potent regulator of intes‐ coupled receptor 5 (Lgr5+)‐positive cells; these cells, in turn, give rise tinal inflammation. For example, H. hepaticus‐infected Alpk1−/ mice to metaplastic proliferation lineages that express markers of spas‐ display exacerbated interleukin (IL)‐12/IL‐23‐dependent colitis char‐ 50 molytic polypeptide‐expressing metaplasia (SPEM). Another study acterized by an enhanced Th1/interferon(IFN)‐γ response. Alpk1 investigated the genetic instability of SPEM cells from the stomach controls intestinal immunity via the hematopoietic system and is of H. felis‐infected mice and human clinical samples by measuring the highly expressed by mononuclear phagocytes. In response to H. he‐ length of microsatellite markers using capillary electrophoresis. The paticus, Alpk1−/− macrophages produce abnormally high amounts of results of this study clearly established elevated genetic instability IL‐12, but not IL‐23. This study demonstrates that Alpk1 promotes in SPEM glands and suggested a role for stem cells (common progen‐ intestinal homoeostasis by regulating the balance of Type 1/Type 17 itors of SPEM), as a source of genetic instability and thus key play‐ immunity following microbial challenge.58 ers in gastric carcinogenesis.51 Furthermore, Hill et al52 showed that Helicobacter saguini is an enterohepatic Helicobacter species iso‐ gastric tumorigenesis, as a consequence of hyperactive glycoprotein lated from captive cotton‐top tamarins with chronic colitis and colon 130 (gp130)/Signal Transduction and Activator of Transcription 3 cancer. A GGT paralog HSGGT1 of this bacillus exhibits gamma‐glu‐ (STAT3) signaling, is intrinsically linked with the development of sub‐ tamyl‐transpeptidase activity with an anti‐proliferative effect and mucosal tertiary lymphoid structures (TLSs) in the gastric antrum of a proinflammatory effect on colon epithelial cells.59 A study iden‐ human patients which was also observed in a chronic gastritis model tified the first N‐linked protein glycosylation system of H. pullorum, induced by H. felis infection. A study evaluated the role of STAT3 HgpA.60 in Helicobacter‐associated inflammation and carcinogenesis using The gut flora has been linked to the onset of obesity. The the H. felis mouse model.53 Loss of STAT3 signaling in the gastric Helicobacter genus has been shown to be a gut microbiota bio‐ mucosa upon H. felis infection resulted in decreased epithelial cell marker in a murine model of high‐fat diet‐induced obesity since proliferation, atrophy, and metaplasia, highlighting a key role for this genus positively correlated with obesity phenotypes before STAT3 signaling in Helicobacter‐related carcinogenesis.53 Another treatment with antibiotics and was significantly decreased by study investigated the role of regulatory B cells in H. felis infection 99.48 ± 0.21% after a 30‐day treatment with antibiotics.61 Mice in mice and demonstrated that H. felis‐stimulated B cells drive type lacking fat mass‐ and the obesity‐associated gene (Fto) exhibited 1 regulatory T‐cell differentiation through the programmed death reduced anxiety‐ and depression‐like behavior, as well as a specific 1 (PD‐1)/PD‐L1 axis and Th17 cells by secreting tumor growth fac‐ bacterial signature that suppresses inflammation, characterized 54 tor beta (TGF‐β). A further study investigated the usefulness of by a lower abundance of Porphyromonadaceae and Helicobacter Gram‐positive enhancer matrix particles (GEMs) as a supplement for and a higher abundance of Lactobacilli.62 Fecal microbiota trans‐ antibiotic treatment to preserve microbial diversity. H. felis‐infected plantation (FMT) has been reported to confer the beneficial met‐ mice pre‐treated with GEMs showed a gastric immunity comparable abolic effects of diet and exercise on diet‐induced obese mice; to that of untreated mice, with elevated expression of IFN‐γ, IL‐17, these effects have been associated with bacterial genera includ‐ and several anti‐microbial factors resulting in a reduced burden of ing Helicobacters, in particular Helicobacter typhlonius, thus re‐ H. felis. On the contrary, immunity against H. felis was depleted in flecting the genus vulnerability to diet, exercise, and even FMT.63 55 mice lacking TGF‐β1 myeloid cells. Furthermore, the gut microbiota mediates the anti‐obesity effect Mice infected with genotoxic cytolethal distending toxin (cdt)‐ of calorie restriction in mice.64 Indeed, calorie restriction has been secreting H. hepaticus constitute IBD models that closely mimic shown to alter the composition of the gut microbiota with signifi‐ human IBD. H. hepaticus infection of 129/SvEvRag2−/− (Rag2−/−) cant increases in probiotic genera and a decrease in harmful bac‐ mice resulted in an increase in myeloid‐derived suppressor cells teria such as Helicobacters.64 (MDSCs) with a granulocytic and monocytic phenotype being observed in the colon and the spleen.56 In another study, a hy‐ drogen sulfide donor reduced colon inflammation by limiting the 4 | GENOMICS AND EVOLUTION recruitment of granulocytic MDSCs, suggesting the involvement OF NON‐HELICOBACTER PYLORI of the l‐cysteine/H2S metabolic pathway in the immunosuppres‐ HELICOBACTERS sive mechanism responsible for the MDSC‐promoted colitis‐asso‐ ciated cancer development. The 129/SvEv Rag2−/− IL10−/− gpt delta An important comparative genomic study was undertaken to un‐ (RagIL10gpt) mice infected with H. hepaticus have provided new veil Helicobacter evolution and, in particular, the natural history of MÉNARD and SMET | 5 of 8 gastric Helicobacter species known to date.29 Admixture analyses 5 | GROWTH AND SURVIVAL have supported the presence of boundaries between gastric and OF NON‐HELICOBACTER PYLORI enterohepatic Helicobacter populations due to ecological seg‐ HELICOBACTERS regation which prevents genetic recombination. Within the gas‐ tric species, however, evidence for gene flow events within and Various compounds have been shown to affect Helicobacter across species was shown. Genetic exchange between canine/ growth and survival, providing potential therapeutic utilization. feline Helicobacter spp. is evident as pets can be colonized with Supplementation of amylase combined with glucoamylase or protease multiple Helicobacter species. Furthermore, admixtures between changes cecal microbiota diversity and increases the growth of broiler H. pylori and its two closest relatives, H. cetorum and Helicobacter chickens fed with newly harvested corn.68 This change was associated acinonychis have also been observed. This is most likely a sign with high numbers of Campylobacter and Helicobacter species. In con‐ of shared ancestry as these species do not share the same host. trast, lactulose, a disaccharide isomerized from lactose, was shown to Subsequently, a reconstruction of the time of divergence of gas‐ improve the structure of the intestinal microbiota in C57BL/6J mice tric Helicobacters was conducted.29 This showed that the coales‐ and to increase the abundance of Helicobacters which is not able to cent for H. pylori and H. cetorum dated to ca. 600 000 years ago. metabolize lactulose but can use mucin as a carbon source.69 In con‐ This indicates that (a) H. pylori already existed in humans during trast, a high altitude hypoxia environment reduces the relative abun‐ the same timeframe when modern humans and Neanderthals di‐ dance of the Helicobacter genus in mice microbiota.70 verged and (b) H. cetorum did not co‐evolve with marine mammals Chronic alcohol exposure of male C57BL/6 mice has been as the evolution of cetaceans already occurred 5 million years ago. shown to induce gut microbiota dysbiosis and a decrease in the Furthermore, estimating the age of speciation of the canine/feline level of Helicobacter species.71 Lead (Pb) treatment has been NHPH has revealed an ancient association between these spe‐ shown to reduce the proportion of Helicobacters in mice while cies and their hosts. As no signs of admixture events were found chlorogenic acid was shown to have a remarkable reversion ef‐ between H. pylori (and its two closest relatives) and the porcine, fect on the gut microbiota composition, the change being induced canine, and feline NHPH, it was concluded that these two groups by Pb.72 Mulberry consumption effectively prevents constipa‐ did not evolve together but rather in parallel following a very dis‐ tion in mice and decreases the abundance of Helicobacteraceae tinctive evolutionary path.29 Mannion et al65 also performed a and Prevotellaceae in the feces in favor of Lactobacilli and comparative analysis of gastric and enterohepatic Helicobacter Bifidobacteria.73 Lactobacillus paracasei, expressing a nucleic acid‐ genomes to identify genetic determinants involved in host adap‐ hydrolyzing mini‐antibody (3D8 scFv) protein, was shown to en‐ tation, niche colonization, and virulence mechanisms. They con‐ hance probiotic activity in the mouse intestine and to decrease cluded that gastric and enterohepatic Helicobacters evolved for the population of harmful bacteria such as Helicobacter species.74 survival in a nutrient‐rich stomach versus a nutrient‐devoid intes‐ Long‐term intake of ginseng extracts facilitates the growth of pro‐ tinal tract, respectively, and that they utilize different pathogenic biotics in the gut microbiota of rats and inhibits the colonization mechanisms to chronically infect and cause inflammation and of some pathogenic bacteria including Helicobacter.75 A decoc‐ tissue damage in their hosts.65 A further study focused specifi‐ tion of Codonopsis pilosula Nannf (also known poor man's ginseng) cally on the outer membrane protein (OMP) repertoire of gastric was shown to alleviate gut microbial dysbiosis in a dextran sul‐ Helicobacters as compared to the enterohepatic members within fate sodium‐induced colitis in mice by simultaneously stimulating the Helicobacter genus and other genera residing in the intestinal the growth of probiotics and inhibiting the growth of pathogenic tract which identified species and infection‐site‐specific OMPs bacteria, including Desulfovibrio, Alistipes, and Helicobacter.76 as interesting candidates for future studies.66 The genome of the Paederia scandens extract, traditionally used to treat rheumatic proposed “Helicobacter apodemus” strain SCJK1 isolated from the pain, was shown to help restore the altered gut microbiota in a gastrointestinal tract of the striped field mouse has also been rheumatoid arthritis mouse model, resulting in a decreased rela‐ sequenced.67 The complete genome of “H. apodemus” has been tive abundance of inflammatory‐related microorganisms including shown to be composed of two circular contigs, one chromosome Helicobacter.77 Ovotransferrin was also shown to ameliorate gut 2 034 706 bp long and one plasmid 33,248 bp long, and to have microbiota disorders in a mouse model where mice were injected an average G+C content of 33.14% (chromosome, 33.2%; plasmid, with cyclophosphamide, resulting in a reduction of the relative 29.4%).67 The genome was predicted to harbor 1850 coding se‐ abundance of Helicobacter and Desulfovibrio.78 Egg phosvitin also quences and 103 pseudo‐genes, as well as 38 transfer (tRNA), nine reduced the number of Helicobacters in mouse models.79 ribosomal (rRNA; including three each of 5s, 16s, and 23s rRNA), Chitosan oligosaccharides were shown to improve the distur‐ and 3 noncoding RNA sequences. Interestingly, this enteric NHPH bance in glucose metabolism and relieve gut dysbiosis in diabetic harbored futA and napA genes. Furthermore, its plasmid was mice by promoting Akkermansia and suppressing Helicobacter.80 shown to include the CagX, V, E, and C (virB 9, 8, 4, and 2, respec‐ Similar effects were observed using Alpinia oxyphylla, a herbal di‐ tively) “secretion system” genes, known to be associated with the etary supplement.81 cag pathogenicity island (PAI) type IV secretion system of H. pylori. 6 of 8 | MÉNARD and SMET

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