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Johnson, J. G.

Publications and source records attributed to Johnson, J. G..

7 recordsLinked to original sources
bioRxiv2026

Inflammation is the Driver of Butyrate-Producing Bacteria Change in Interleukin10 Knockout Mice

BackgroundAlterations of gut microbiota have been implicated in the development of inflammatory bowel disease. Specifically, patients with IBD show the reduced levels of gut bacteria to produce butyrate, a crucial metabolite for maintaining gut homeostasis, along with decreased levels of fecal butyrate. However, there is limited research on changes in butyrate-producing bacteria at various taxonomic levels during the development of inflammatory bowel disease. ResultsWe investigated the changes of butyrate-producing bacteria in interleukin10 knockout mice, a suitable IBD model, as these mice require gut microbiota to develop spontaneous chronic colitis. Our findings indicate increased inflammation and a metabolic shift from butyrate oxidation toward glycolysis in 9-week-old interleukin10 knockout mice. Furthermore, we observed significant changes in two terminal enzymes involved in butyrate production: a significant increase of butyrate kinase and a significant decrease of butyryl-CoA:acetate-CoA-transferase. These observations align with an increased abundance of Coprococcus comes, which utilizes butyrate kinase, and a decreased abundance of Faecalibacterium prausnitzii that utilizes butyryl-CoA:acetate-CoA-transferase. Moreover, reduced levels of acetate, a necessary co-substrate for butyryl-CoA:acetate-CoA-transferase activity, were observed in interleukin10 knockout mice. ConclusionsThese findings enhance our understanding of changes in butyrate-producing bacteria populations at various taxonomic levels, ranging from phylum to gene level in 9-week-old interleukin10 knockout mice. Furthermore, these data suggest a potential for diagnosing IBD at an early stage by analyzing the composition of butyrate-producing bacteria.

microbiology↗
bioRxiv2024

SARS-CoV-2 within-host population expansion, diversification and adaptation in zoo tigers, lions and hyenas

SARS-CoV-2 rapidly adapts to new hosts following cross-species transmission; this is highly relevant as novel within-host variants have emerged following infection of susceptible wild and domestic animal species. Furthermore, SARS-CoV-2 transmission from animals (e.g., white-tailed deer, mink, domestic cats, and others) back to humans has also been observed, documenting the potential of novel animal-derived variants to infect humans. We investigated SARS-CoV-2 evolution and host-specific adaptation during an outbreak in Amur tigers (Panthera tigris altaica), African lions (Panthera leo), and spotted hyenas (Crocuta crocuta) at Denver Zoo in late 2021. SARS-CoV-2 genomes from longitudinal samples collected from 16 individuals were evaluated for within-host variation and genomic signatures of selection. The outbreak was likely initiated by a single spillover of a rare Delta sublineage subsequently transmitted from tigers to lions to hyenas. Within-host virus populations rapidly expanded and diversified. We detected signatures of purifying and positive selection, including strong positive selection in hyenas and in the nucleocapsid (N) gene in all animals. Four candidate species-specific adaptive mutations were identified: N A254V in lions and hyenas, and ORF1a E1724D, spike T274I, and N P326L in hyenas. These results reveal accelerated SARS-CoV-2 adaptation following host shifts in three non-domestic species in daily contact with humans.

evolutionary biology↗
bioRxiv2024

Campylobacter infection of young children in Colombia and its impact on the gastrointestinal environment

Campylobacter infections are a leading cause of bacterial-derived gastroenteritis worldwide with particularly profound impacts on pediatric patients in low-and-middle income countries. It remains unclear how Campylobacter impacts these hosts, though it is becoming increasingly evident that it is a multifactorial process that depends on the host immune response, the gastrointestinal microbiota, various bacterial factors, and host nutritional status. Since these factors likely vary between adult and pediatric patients in different regions of the world, it is important that studies define these attributes in well characterized clinical cohorts in diverse settings. In this study, we analyzed the fecal microbiota and the metabolomic and micronutrient profiles of asymptomatic and symptomatic pediatric patients in Colombia that were either infected or uninfected with Campylobacter during a case-controlled study on acute diarrheal disease. Here, we report that the microbiome of Campylobacter-infected children only changed in their abundance of Campylobacter spp. despite the inclusion of children with or without diarrhea. In addition to increased Campylobacter, computational models were used to identify fecal metabolites that were associated with Campylobacter infection and found that glucose-6-phosphate and homovanillic acid were the strongest predictors of infection in these pediatric patients, which suggest that colonocyte metabolism are impacted during infection. Despite changes to the fecal metabolome, the concentrations of intestinal minerals and trace elements were not significantly impacted by Campylobacter infection, but were elevated in uninfected children with diarrhea. ImportanceGastrointestinal infection with pathogenic Campylobacter species has long been recognized as a significant cause of human morbidity. Recently, it has been observed that pediatric populations in low-and-middle income countries are uniquely impacted by these organisms in that infected children can be persistently colonized, develop enteric dysfunction, and exhibit reduced development and growth. While the association of Campylobacter species with these long-term effects continues to emerge, the impact of infection on the gastrointestinal environment of these children remains uncharacterized. To address this knowledge gap, our group leveraged clinical samples collected during a previous study on gastrointestinal infections in pediatric patients to examine the fecal microbiota, metabolome, and micronutrient profiles of those infected with Campylobacter species, and found that the metabolome was impacted in a way that suggests gastrointestinal cell metabolism is affected during infection, which is some of the first data indicating how gastrointestinal health in these patients may be affected.

microbiology↗
bioRxiv2023

Gut metabolite L-lactate supports Campylobacter jejuni population expansion during acute infection

How the microaerobic pathogen Campylobacter jejuni establishes its niche and expands in the gut lumen during infection is poorly understood. Using six-week-old ferrets as a natural disease model, we examined this aspect of C. jejuni pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with C. jejuni, ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after C. jejuni infection in ferrets reflects closely how human C. jejuni infection proceeds. Rapid growth of C. jejuni and associated intestinal inflammation was observed within two-three days of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1 in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A C. jejuni mutant lacking lctP, which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by C. jejuni to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter (lctP) led to discovery of a putative thiol based redox switch regulator (LctR) that may repress lctP transcription under anaerobic conditions. Our work provides new insights into the pathogenicity of C. jejuni. SignificanceThere is a gap in knowledge about the mechanisms by which C. jejuni populations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut after C. jejuni infection. Our study identified the gut metabolite L-lactate as playing an important role as a growth substrate for C. jejuni during acute infection. We identified a DNA binding protein, LctR, that binds to the lctP promoter and may repress lctP expression, resulting in decreased lactate transport under low oxygen levels. This work provides new insights about C. jejuni pathogenicity.

microbiology↗
bioRxiv2022

Battle for the histones: a secreted bacterial sirtuin from Campylobacter jejuni activates neutrophils and induces inflammation during infection

Histone modifications alter numerous cornerstone processes in eukaryotes, including metabolism, physiology, and immunity. Numerous bacterial pathogens can alter expression of host-derived sirtuins to deacetylate histones in order to promote infection, yet, a bacterial-derived sirtuin has yet to be investigated to deacetylate host histones. Using Campylobacter jejuni, the leading cause of bacterial-derived gastroenteritis, we found a secreted sirtuin, SliP, which binds to and deacetylates neutrophil histones. We found neutrophil activation and extrusion of neutrophil extracellular traps was SliP dependent, whereby sliP mutants are unable to activate neutrophils or promote NETosis. Leveraging the mouse model of campylobacteriosis, we further demonstrate the sliP mutant can efficiently infect IL-10-/- mice, but induction of proinflammatory cytokine production and gastrointestinal pathology is SliP-dependent. In conclusion, we investigate a unique bacterial effector which targets host histones and is responsible for the inflammatory response and tissue pathology observed during campylobacteriosis. HighlightsO_LIC. jejuni encodes a secreted effector, SliP, which functions as a canonical sirtuin C_LIO_LISliP binds to and deacetylates neutrophil histone H3 during bacterial infection C_LIO_LIC. jejuni-induced neutrophil activation and NETosis are SliP-dependent C_LIO_LIInflammation and tissue pathology during C. jejuni infection is SliP-dependent C_LI

microbiology↗
bioRxiv2022

Campylobacter jejuni induces differentiation of human neutrophils to the CD16hi/CD62Llo subtype which possess cancer promoting activities

The discovery of neutrophil subtypes has expanded what is known about neutrophil functions, yet there is still much to learn about the role of these subtypes during bacterial infection. We investigated whether Campylobacter jejuni induced differentiation of human neutrophils into the hypersegmented, CD16hi/CD62Llo subtype. In addition, we investigated whether C. jejuni-dependent differentiation of this neutrophil subtype induced cancer promoting activities of human T cells and colonocytes, which were observed in other studies of hypersegmented, CD16hi/CD62Llo neutrophils. We found that C. jejuni causes a significant shift in human neutrophil populations to the hypersegmented, CD16hi/CD62Llo subtype and that those populations exhibit delayed apoptosis, elevated arginase-1 expression, and increased reactive oxygen species production. Furthermore, incubation of C. jejuni-infected neutrophils with human T cells resulted in decreased expression of the {zeta}-chain of the T cell receptor (TCR{zeta}), which was restored upon supplementation with exogenous L-arginine. In addition, incubation of C. jejuni-infected neutrophils with human colonocytes resulted in increased HIF-1 stabilization and NF-{kappa}B activation in those colonocytes, which may result in the upregulation of pro-tumorigenic genes. This response, coupled with the ability of C. jejuni-infected neutrophils to suppress TCR{zeta} expression in T cells, could result in the promotion of colorectal tumorigenesis during infection with C. jejuni.

microbiology↗