Keszthelyi, D.

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   Histamine-Producing Bacteria: The Missing Link inIrritable Bowel Syndrome?Citation for published version (APA):Keszthelyi, D. (2023). Histamine-Producing Bacteria: The Missing Link in Irritable Bowel Syndrome?Gastroenterology, 164(1), 160-161. Advance online publication.https://doi.org/10.1053/j.gastro.2022.08.053Document status and date:Published: 01/01/2023DOI:10.1053/j.gastro.2022.08.053Document Version:Publisher's PDF, also known as Version of recordDocument license:TavernePlease check the document version of this publication:• A submitted manuscript is the version of the article upon submission and before peer-review. There canbe important differences between the submitted version and the official published version of record.People interested in the research are advised to contact the author for the final version of the publication,or visit the DOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and pagenumbers.Link to publicationGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with theserights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain• You may freely distribute the URL identifying the publication in the public portal.If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above,please follow below link for the End User Agreement:www.umlib.nl/taverne-licenseTake down policyIf you believe that this document breaches copyright please contact us at:repository@maastrichtuniversity.nlproviding details and we will investigate your claim.Download date: 02 Oct. 2023excess weight loss (EWL). Adult patients aged 21-65 yearswith a body mass index (BMI) of 30-40 kg/m2 and whofailed nonsurgical weight loss methods were randomized toreceive ESG plus moderate-intensity lifestyle modificationsor moderate-intensity lifestyle modifications alone. A totalof 187 patients were followed for 52 weeks, after whichthose in the ESG group were offered retightening of the ESG,and those in the control group could crossover into the ESGgroup and be followed for another 52 weeks.Patients in the ESG group had a mean percentage EWL of49.2% and mean percentage total body weight loss (TBWL)of 13.6%, compared with 3.2% and 0.8%, respectively,in the control group (P 0.0001). After adjusting forconfounders, patients in the ESG group had a mean differ-ence of 44.7% (95% CI 37.5%-51.9%) EWL and 12.6%(10.7%-14.5%) TBWL. In the ESG patients with extendedfollow-up at 104 weeks, 83% of the reached EWL wasmaintained (41.0% EWL and 11.4% TBWL). A total of 14patients required suture reinforcement for either failure tomeet the primary end point (n ¼ 9) or investigator discre-tion (n ¼ 5). In ESG patients with baseline comorbidities,significant improvements were noted in HbA1c levels, bloodpressure, and metabolic syndrome. Likewise, ESG patientssaw significant improvements in liver transaminases, he-patic steatosis index, aspartate transaminase–to–plateletsratio index, and C-reactive protein. Levels of high-densitylipoprotein and triglycerides and waist-to-hip ratio alsoimproved. Adverse events were reported in 92% of patientswho underwent ESG, most of which (66%) were accom-modative and expected in the post-procedure period,including pain, nausea, and vomiting. Most adverse eventsresolved within 1 week, and only 6 patients requiredadmission for medical management. Three adverse eventsrequired re-intervention, including an abdominal abscess,gastrointestinal bleeding, and a case of severe malnutrition.Overall, these data add further evidence for the role ofendoscopic therapy in the treatment of obesity. Limitationsof the study include the absence of a sham interventiongroup, as well as the absence of a control group duringextended follow-up to 104 weeks. It is also noted that thistrial occurred during the COVID-19 pandemic, which dis-rupted in-person follow-up and monitoring. ESG is also notcovered by most health payers. Nevertheless, ESG appearsto be an effective endoscopic option for weight loss.MARK HANSCOMDivision of Gastroenterology and HepatologyMayo ClinicRochester, Minnesota160 Gastro Digest Gastroenterology Vol. 164, No. 1Histamine-Producing Bacteria:The Missing Link in IrritableBowel Syndrome?De Palma G, Shimbori C, Reed DE, et al. Histamine pro-duction by the gut microbiota induces visceral hyperalgesiathrough histamine 4 receptor signaling in mice. Sci TranslMed 2022;14(655):eabj1895.The interaction between diet, intestinal microbiota, andhost plays a role in the pathophysiology of irritable bowelsyndrome (IBS). A key mediator in the development ofvisceral hypersensitivity in IBS is histamine, with its releaseacting on nociceptive afferents and generating pain signals.Although it is generally thought that histamine is derivedfrom mucosal mast cells in IBS patients, De Palma et alprovide evidence for a different source of histamine in thegut: bacteria. In an elegant series of mechanistic experi-ments, performed using germ-free mice colonized with fecalmicrobiota from patients with IBS, Klebsiella aerogenes wasidentified as a major producer of histamine by the activity ofa histidine decarboxylase gene specific to these species. Kaerogenes was abundant in the fecal microbiota of patientswith IBS, particularly in those with high and not low urinaryhistamine concentrations.In addition, Klebsiella-derived histamine led to visceralhypersensitivity in mice colonized with microbiota from IBSpatients with high urinary histamine. These effects weremediated by H4-receptor–dependent signaling; an H4-antagonist reduced visceromotor responses to colonicdistension in mice. Furthermore, an increase in mast cellswas also seen in these animals, similarly to mice mono-colonized with a single bacterial strain of K aerogenes,capable of producing high amounts of histamine.Notably, K aerogenes derives its name from its ability toproduce gas, in particular hydrogen, and can metabolizedifferent sugars, including lactose and fructose. This couldalso explain why its abundance decreased when patientswith high urinary histamine ate a low–fermentable carbo-hydrate diet, as observed by reanalyzing fecal samples froma previous study (Gut 2017;66:1241-1251). Could urinaryhistamine profile be used to select IBS patients harboringthe histamine-producing K. aerogenes to increase efficacy oftherapies such as the low-FODMAP diet?What remains unclear is how bacterial histamine fromthe lumen can reach high concentrations in urine withoutany concurrent increase in intestinal permeability or anyother mechanism at operation allowing transepithelial pas-sage of large amounts of histamine. Alternatively, high uri-nary histamine could be the result of endogenous ratherthan bacterial histamine production due to the increasedinflux of mucosal mast cells, which can be induced by thechemo-attractive effects of K aerogenes.Although the novel disease mechanism presented here isparticularly intriguing, the fecal microbiota used for themechanistic studies was derived from just 2 patients withIBS (one with high and the other with low urinary hista-mine, with different IBS subtypes and different sexes) and ahealthy control subject. Whether such a mechanism isoperating in a broader group of patients warrants furtherinvestigation, and if confirmed, it could represent a truebreakthrough in mechanism-driven treatment in IBS.DANIEL KESZTHELYIDivision of Gastroenterology-HepatologyDepartment of Internal MedicineMaastricht University Medical CenterMaastricht, the Netherlandscell-specific anatomic, chemogenetic, and ablation ap-proaches, the investigators established the neural pathwaysinvolved. Surprisingly, they found that spinal and not vagalsensory innervation was instrumental in conveying GLP-1–January 2023 Gastro Digest 161Conflicts of interestThe author discloses the following: Daniel Keszthelyi has received researchfunding from Allergan, Grunenthal, Will Pharma, UEG, ZonMw, Horizon 2020,Rome Foundation, and MLDS; and has received speaker’s fee from Dr Falk(payment to host institution).How the Gut Feeds the Brain:A Newly Uncovered Gut-BrainCircuit for AppetiteSuppressionZhang T, Perkins MH, Chang H, Han W, de Araujo IE. Aninter-organ neural circuit for appetite suppression. Cell2022;185:2478-2494.Gastric motility disorders, and the bloating and anorexiathat accompany them, are increasingly common yet remainchallenging to treat owing to a paucity of understandingregarding their underlying pathophysiology. Glucagon-likepeptide 1 (GLP-1), released from intestinal enter-oendocrine L cells, exerts appetite-suppressing effects anddelays gastric emptying by inducing gastric fundus relaxa-tion. However, the vast majority of GLP-1 is inactivatedbefore exiting the gut, implying that endogenous GLP-1 actslocally to initiate these distal effects on the stomach andbrain. Through a comprehensive set of anatomical, chemo-genetic, and ablation approaches in mice, Zhang et al iden-tified a novel GLP-1 signaling pathway that ultimately linksgastric distention to appetite suppression.Through L cell–specific opto- and chemogenetic activa-tion or GLP-1 receptor (GLP-1R) antagonism, the in-vestigators demonstrated that L cell–secreted GLP-1 isrequired for gastric enlargement and appetite suppression.GLP-1R activation also resulted in Fos activation in neuronsof the abdominal sympathetic ganglia, thus defining the keysubset of neurons responsible for ileal GLP-1 neurotrans-mission as intestinofugal neurons. Ablation of intestinofugalneurons eradicated the effects induced by ileal GLP infusion,although activation mimicked its effects. Using similarinduced signaling to the brain.Some limitations of the study are secondary to theconstraints inherent in currently available technologies.Although the intravital microscopy technique allowed forimaging of enteric neurons in live mice, animal anesthesiawas required to allow for visualization. Therefore, it re-mains unknown precisely how enteric neuronal and brain-gut circuit activity ensue in awake animals, when feedingis actively taking place. Similarly, a greater understandingof how L-cell activity and ileal GLP-1 secretion in real timeaffect feeding behavior would also be of significance.Despite these limitations, Zhang et al delineated a novelgut-brain sensorimotor circuit that forms an inter-organneural network connecting the intestine, via the stomach,to the medullary reticular formation and hypothalamus andfinally to the craniofacial muscles to instigate both gastricfundal enlargement and appetite suppression. This highlynovel finding, that enteric gastric neurons may be criticalmodulators of gastric relaxation and appetite, are likely tolead to further investigation of these neural circuits astherapeutic targets for the symptoms of bloating andanorexia that accompany gastric motility disorders, such asgastroparesis, or those that accompany some disorders ofgut-brain interaction.KARA G. MARGOLISDepartment of Molecular PathobiologyNew York University, andDepartment of PediatricsNew York University Grossman School of MedicineNew York, New YorkFundingKara G. Margolis acknowledges support from the following grants: DoDPR160365, DoD W911NF, RO1DK130518, RO1DK126644, andRO1NS015547.

Histamine-Producing Bacteria: The Missing Link in Irritable Bowel Syndrome?

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Histamine-Producing Bacteria: The Missing Link in Irritable Bowel Syndrome?

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