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The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16  H. pylori -infected adults, and analyze the genomes of 10  H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori . Helicobacter pylori , a bacterial pathogen that infects human stomachs, has high genetic diversity across hosts. Here, Ailloud et al. reveal genetic structuring of H. pylori populations among different stomach regions of individual hosts and find signals of genetic associations with stomach region.

Key Points Inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, are important human health problems. Their pathogenesis involves both the genetic predisposition of the host and the intestinal microbiota, the highly complex community of bacteria that live in the gut. In addition, infections with certain intestinal pathogens have been shown to increase the risk of IBD development. Experimental models of intestinal inflammation using gene-targeted mice and defined bacteria have proven extremely valuable in dissecting the roles of host and bacterial factors in IBD pathogenesis. Knowledge gained from such models is the central topic of this Review, with a special focus on the role of bacteria and bacterial components in determining the risk of chronic intestinal inflammation. Germ-free mice monoassociated with several specific bacteria have provided insight into particular mechanisms of gut inflammation; some bacteria are not by themselves sufficient to induce intestinal inflammation in germ-free mice, whereas other pathogenic bacteria can induce chronic inflammatory disease alone. For example, Bacteroides fragilis toxin (BFT)-expressing bacteria can cause IBD alone. Mouse models using the Gram-negative enterobacteria Citrobacter rodentium and Salmonella enterica subspecies enterica serovar Typhimurium established that the composition of the intestinal microbiota determines susceptibility to infection, and that a gut infection itself can alter the accompanying microbiota. These models suggest that the reduction of bacterial density and diversity of the intestinal microbiota is likely to determine susceptibility to pathogen infection and chronic disease. These models also provided seminal evidence of the importance of innate immune recognition in the control of inflammatory responses elicited by these organisms. Host susceptibility by genetic deficiencies in the experimentally infected mice was also proven to be a crucial factor that can turn acute into chronic disease. The group of enterohepatic Helicobacter spp., and in particular Helicobacter hepaticus , has been investigated to dissect the role of bacterial and host components in the development of gut inflammation during chronic pathogen infection. Important findings from these models include the importance of different T cell subsets in the control of intestinal immune homeostasis and the development of IBD and colitis, the observation that T cells recognizing a single bacterial antigen can trigger colitis, and that bacterial factors such as the genotoxic cytotoxic distending toxin or the functions encoded on a pathogenicity island can affect disease. These models have also helped to recognize the contribution of the resident microbiota for the development of chronic inflammatory disease and the importance of coinfections. Other models discussed in this Review include enterotoxic B. fragilis (ETBF), Campylobacter spp. and association studies of diverse commensal bacteria, all of which — in our view — contribute unique and relevant perspectives on the complex interactions of bacteria and host cells in the intestine that decide between health and acute or chronic disease. A better understanding of the role of harmful and potentially beneficial microorganisms in IBD pathogenesis could open up new avenues for prevention and therapy of IBD, for example by probiotics; we review results obtained from mouse models that investigate mechanisms of probiotic intervention in IBD and effects of probiotics and their products on gut homeostasis. In this article the authors review what mouse models of intestinal inflammation using gene-targeted mice and defined bacteria have contributed to our understanding of the mechanisms underlying inflammatory bowel disease (IBD), focusing on the specific contribution of bacteria and bacterial components. Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a major human health problem. The bacteria that live in the gut play an important part in the pathogenesis of IBD. However, owing to the complexity of the gut microbiota, our understanding of the roles of commensal and pathogenic bacteria in establishing a healthy intestinal barrier and in its disruption is evolving only slowly. In recent years, mouse models of intestinal inflammatory disorders based on defined bacterial infections have been used intensively to dissect the roles of individual bacterial species and specific bacterial components in the pathogenesis of IBD. In this Review, we focus on the impact of pathogenic and commensal bacteria on IBD-like pathogenesis in mouse infection models and summarize important recent developments.

Key Points The human gastric pathogen Helicobacter pylori displays a high degree of intraspecies allelic diversity and variability. Almost every infected person carries one or multiple unique H. pylori strains that can be readily distinguished by MLST or other typing methods. Diversity within H. pylori is generated by the unusual combination of an elevated mutation rate and frequent interstrain recombination during mixed infections. Unusually short DNA fragments are incorporated into the H. pylori genome in the course of recombination events, further contributing to allelic diversification. Modern H. pylori bacteria can be subdivided into six main populations with distinct geographic distribution patterns. These modern populations are derived from five ancestral populations, and the distribution of ancestral nucleotides over the globe reflects ancient and more recent human migrations. Many H. pylori genes contain hypermutable sequences, such as homopolymeric nucleotide repeats. Any large H. pylori population will therefore consist of multiple subpopulations with specific activity patterns for these so-called contingency genes (bacterial quasispecies). Genetic variability that is due to intrastrain diversification and interstrain recombination is hypothesized to help the bacteria adapt to individual hosts after transmission. Although experimental evidence is still scarce, this concept is supported by the finding that extensive genetic and phenotypic variation is displayed by molecules involved in interactions with the human host, including adhesins, lipopolysaccharides and components of the cag type IV secretion apparatus, including the translocated effector CagA. Helicobacter pylori is a hugely successful pathogen that exhibits extraordinary genetic heterogeneity. Here, Sebastian Suerbaum and Christine Josenhans review the genetic diversity of H. pylori and the mechanisms that mediate its diversification within the human host. Helicobacter pylori colonizes the stomachs of more than 50% of the world's population, making it one of the most successful of all human pathogens. One striking characteristic of H. pylori biology is its remarkable allelic diversity and genetic variability. Not only does almost every infected person harbour their own individual H. pylori strain, but strains can undergo genetic alteration in vivo , driven by an elevated mutation rate and frequent intraspecific recombination. This genetic variability, which affects both housekeeping and virulence genes, has long been thought to contribute to host adaptation, and several recently published studies support this concept. We review the available knowledge relating to the genetic variation of H. pylori , with special emphasis on the changes that occur during chronic colonization, and argue that H. pylori uses mutation and recombination processes to adapt to its individual host by modifying molecules that interact with the host. Finally, we put forward the hypothesis that the lack of opportunity for intraspecies recombination as a result of the decreasing prevalence of H. pylori could accelerate its disappearance from Western populations.

Helicobacter pylori Infection is formally recognised as an infectious disease, an entity that is now included in the International Classification of Diseases 11th Revision. This in principle leads to the recommendation that all infected patients should receive treatment. In the context of the wide clinical spectrum associated with Helicobacter pylori gastritis, specific issues persist and require regular updates for optimised management.The identification of distinct clinical scenarios, proper testing and adoption of effective strategies for prevention of gastric cancer and other complications are addressed. H. pylori treatment is challenged by the continuously rising antibiotic resistance and demands for susceptibility testing with consideration of novel molecular technologies and careful selection of first line and rescue therapies. The role of H. pylori and antibiotic therapies and their impact on the gut microbiota are also considered.Progress made in the management of H. pylori infection is covered in the present sixth edition of the Maastricht/Florence 2021 Consensus Report, key aspects related to the clinical role of H. pylori infection were re-evaluated and updated. Forty-one experts from 29 countries representing a global community, examined the new data related to H. pylori infection in five working groups: (1) indications/associations, (2) diagnosis, (3) treatment, (4) prevention/gastric cancer and (5) H. pylori and the gut microbiota. The results of the individual working groups were presented for a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in various clinical fields.

Helicobacter pylori has one of the largest repertoires of methyltransferases. Methylation has been associated with multiple functions in H. pylori , including the defense against foreign DNA and transcriptional regulation. Regulation of gene expression by methylation has the potential to influence many distant genes across the genome via target motifs in proximity to transcription start sites. Here, we sought to understand the role of M.Hpy99XIX, an orphan methyltransferase targeting the ATTAAT motif that is highly conserved in H. pylori . We show that by directly regulating specific genes involved in iron uptake via methylated ATTAAT motifs, M.Hpy99XIX has a significant effect on iron homeostasis by triggering the canonical iron regulatory pathway. Furthermore, we show that M.Hpy99XIX appears to have been acquired after the split between the two ecospecies of H. pylori , suggesting that its role in the tuning of iron homeostasis might have contributed to this divergence.

Background Bacterial epigenetics is a rapidly expanding research field. DNA methylation by diverse bacterial methyltransferases (MTases) contributes to genomic integrity and replication, and many recent studies extended MTase function also to global transcript regulation and phenotypic variation. Helicobacter pylori is currently one of those bacterial species which possess the highest number and the most variably expressed set of DNA MTases. Next-generation sequencing technologies can directly detect DNA base methylation. However, they still have limitations in their quantitative and qualitative performance, in particular for cytosine methylation. Results As a complementing approach, we used enzymatic methyl sequencing (EM-Seq), a technology recently established that has not yet been fully evaluated for bacteria. Thereby, we assessed quantitatively, at single-base resolution, whole genome cytosine methylation for all methylated cytosine motifs in two different H. pylori strains and isogenic MTase mutants. EM-Seq reliably detected both m5 C and m4 C methylation. We demonstrated that three different active cytosine MTases in H. pylori provide considerably different levels of average genome-wide single-base methylation, in contrast to isogenic mutants which completely lost specific motif methylation. We found that strain identity and changed environmental conditions, such as growth phase and interference with methyl donor homeostasis, significantly influenced quantitative global and local genome-wide methylation in H. pylori at specific motifs. We also identified significantly hyper- or hypo-methylated cytosines, partially linked to overlapping MTase target motifs. Notably, we revealed differentially methylated cytosines in genome-wide coding regions under conditions of methionine depletion, which can be linked to transcript regulation. Conclusions This study offers new knowledge on H. pylori global and local genome-wide methylation and establishes EM-Seq for quantitative single-site resolution analyses of bacterial cytosine methylation.

Infections by the basidiomycete yeast Cryptococcus neoformans are life-threatening diseases claiming more than 600,000 lives every year. The most common manifestation is cryptococcal meningitis in AIDS patients. Diagnosis primarily relies on antigen testing from serum and cerebrospinal fluid (CSF). Current guidelines recommend rapid antigen testing with a focus on point-of-care assays. Over the recent years, a range of new lateral flow assays (LFAs) was launched. There is still a lack of data evaluating the CE-certified Biosynex RDT CryptoPS LFA. We compared the performance of this LFA with a latex agglutination assay (LAA; Latex-Cryptococcus Antigen Detection System, IMMY) from blood and CSF samples. Blood and/or CSF samples of 27 patients with proven cryptococcal infections caused by different species and blood–CSF pairs of 20 controls were tested applying LFA and LAA. Upon combined analysis of blood and CSF, both assays were able to identify all C. neoformans infections. Based on CSF analysis only, the LFA and the LAA had sensitivities of 100% and 93%. Neither test gave false-positive results nor was reactive in two cases of C. non-neoformans/non-gattii species infections. Both assays have high sensitivities and specificities for the diagnosis of C. neoformans infection. Contrarily to the IMMY LAA, the RDT CryptoPS LFA is suitable as a point-of-care test but is limited in the quantification of antigen reactivity.

Helicobacter pylori infects the stomachs of one in two humans and can cause sequelae that include ulcers and cancer. Here we sequenced the genomes of 97 H. pylori isolates from 52 members of two families living in rural conditions in South Africa. From each of 45 individuals, two H. pylori strains were isolated from the antrum and corpus parts of the stomach, and comparisons of their genomes enabled us to study within-host evolution. In 5 of these 45 hosts, the two genomes were too distantly related to be derived from each other and therefore represented evidence of multiple infections. From the remaining 40 genome pairs, we estimated that the synonymous mutation rate was 1.38 × 10 ⁻⁵ per site per year, with a low effective population size within host probably reflecting population bottlenecks and immune selection. Some individuals showed very little evidence for recombination, whereas in others, recombination introduced up to 100-times more substitutions than mutation. These differences may reflect unequal opportunities for recombination depending on the presence or absence of multiple infections. Comparing the genomes carried by distinct individuals enabled us to establish probable transmission links. Transmission events were found significantly more frequently between close relatives, and between individuals living in the same house. We found, however, that a majority of individuals (27/52) were not linked by transmission to other individuals. Our results suggest that transmission does not always occur within families, and that coinfection with multiple strains is frequent and evolutionarily important despite a fast turnover of the infecting strains within-host.

Secretory IgA (SIgA) shapes the gut microbial composition. Pabst and colleagues show that the IgA-secreting plasma cell repertoire, once established, is remarkably resilient to changes in microbial populations that occur upon infection or antibiotic treatment. Secretory immunoglobulin A (SIgA) shields the gut epithelium from luminal antigens and contributes to host-microbe symbiosis. However, how antibody responses are regulated to achieve sustained host-microbe interactions is unknown. We found that mice and humans exhibited longitudinal persistence of clonally related B cells in the IgA repertoire despite major changes in the microbiota during antibiotic treatment or infection. Memory B cells recirculated between inductive compartments and were clonally related to plasma cells in gut and mammary glands. Our findings suggest that continuous diversification of memory B cells constitutes a central process for establishing symbiotic host-microbe interactions and offer an explanation of how maternal antibodies are optimized throughout life to protect the newborn.

Helicobacter pylori is one of the most common and genetically diverse human bacterial pathogens. It is responsible for chronic gastritis and represents the main risk factor for gastric cancer. Helicobacter pylori is a Gram-negative bacterial carcinogenic pathogen that infects the stomachs of half of the human population. It is a natural mutator due to a deficient DNA mismatch repair pathway and is naturally competent for transformation. As a result, it is one of the most genetically diverse human bacterial pathogens. The length of chromosomal imports in H. pylori follows an unusual bimodal distribution consisting of macroimports with a mean length of 1,645 bp and microimports with a mean length of 28 bp. The mechanisms responsible for this import pattern were unknown. Here, we used a high-throughput whole-genome transformation assay to elucidate the role of nucleotide excision repair pathway (NER) components on import length distribution. The data show that the integration of microimports depended on the activity of the UvrC endonuclease, while none of the other components of the NER pathway was required. Using H. pylori site-directed mutants, we showed that the widely conserved UvrC nuclease active sites, while essential for protection from UV light, one of the canonical NER functions, are not required for generation of microimports. A quantitative analysis of recombination patterns based on over 1,000 imports from over 200 sequenced recombinant genomes showed that microimports occur frequently within clusters of multiple imports, strongly suggesting they derive from a single strand invasion event. We propose a hypothetical model of homologous recombination in H. pylori , involving a novel function of UvrC, that reconciles the available experimental data about recombination patterns in H. pylori . IMPORTANCE Helicobacter pylori is one of the most common and genetically diverse human bacterial pathogens. It is responsible for chronic gastritis and represents the main risk factor for gastric cancer. In H. pylori , DNA fragments can be imported by recombination during natural transformation. The length of those fragments determines how many potentially beneficial or deleterious alleles are acquired and thus influences adaptation to the gastric niche. Here, we used a transformation assay to examine imported fragments across the chromosome. We show that UvrC, an endonuclease involved in DNA repair, is responsible for the specific integration of short DNA fragments. This suggests that short and long fragments are imported through distinct recombination pathways. We also show that short fragments are frequently clustered with longer fragments, suggesting that both pathways may be mechanistically linked. These findings provide a novel basis to explain how H. pylori can fine-tune the genetic diversity acquired by transformation.