Early life antibiotic exposure and host health: Role of the microbiota–immune interaction

Wang, Yichen; Udomkittivorakul, Natsumon; Bonfield, Madeline; Nadeem, Amraha; Gray, Jerilyn K.; Deshmukh, Hitesh

doi:10.1016/j.semperi.2020.151323

Cited by 6 publications

(4 citation statements)

References 70 publications

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“… 4 Despite this, single CRP values continue to be used in practice and drive both initiation and continuation of antibiotic therapy. 6 , 7 When used in the absence of microbiologically confirmed infection and/or appropriate clinical context, these tests can increase antibiotic overuse, 8 , 9 contribute to the adverse effects of antibiotic exposure 10 , 11 and increase microbial resistance. 12…”

Section: Introductionmentioning

confidence: 99%

Noninfectious influencers of early-onset sepsis biomarkers

Tiozzo

Mukhopadhyay

2021

Pediatr Res

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Diagnostic tests for sepsis aim to either detect the infectious agent (such as microbiological cultures) or detect host markers that commonly change in response to an infection (such as C-reactive protein). The latter category of tests has advantages compared to culture-based methods, including a quick turnaround time and in some cases lower requirements for blood samples. They also provide information on the immune response of the host, a critical determinant of clinical outcome. However, they do not always differentiate nonspecific host inflammation from true infection and can inadvertently lead to antibiotic overuse. Multiple noninfectious conditions unique to neonates in the first days after birth, can lead to inflammatory marker profiles that mimic those seen among infected infants. Our goal was to review noninfectious conditions and patient characteristics that alter host inflammatory markers commonly used for the diagnosis of early-onset sepsis. Recognizing these conditions can focus the use of biomarkers on patients most likely to benefit while avoiding scenarios that promote false positives. We highlight approaches that may improve biomarker performance and emphasize the need to use patient outcomes, in addition to conventional diagnostic performance analysis, to establish clinical utility.

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Section: Introductionmentioning

confidence: 99%

Noninfectious influencers of early-onset sepsis biomarkers

Tiozzo

Mukhopadhyay

2021

Pediatr Res

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“…Microbiota colonization begins at birth with the complexity and density of the microbiota increasing most significantly during infancy (41)(42)(43). Microbiota exposure beginning in early life promotes immunological education and disruption during this window can increase chronic inflammatory disorders (42)(43)(44)(45)(46). While it has been predicted that initial colonization at birth primes the accumulation of local T cells with specificity to commensal microbes, this has not been directly tested.…”

Section: Resultsmentioning

confidence: 99%

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

Eshleman¹,

Shao²,

Woo³

et al. 2023

Journal of Clinical Investigation

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Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we find that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibit increased accumulation of commensal-specific CD4 + T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity.Consistent with this, microbiota-specific CD4 + T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelialintrinsic ablation of HDAC3 decreased commensal-specific Tregs, increased commensalspecific Th17 cells, and promoted T cell-driven colitis. Mechanistically, HDAC3 was essential for NFκB-dependent regulation of epithelial MHC class II (MHCII). Epithelialintrinsic MHCII dampened local accumulation of commensal-specific Th17 cells in adult mice, and protected against microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in directing the dynamic balance of tissue-intrinsic CD4 + T cell subsets that recognize commensal microbes and control inflammation.

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“…Microbiota colonization begins at birth with the complexity and density of the microbiota increasing most significantly during infancy (38)(39)(40). Microbiota exposure early in life is required for effective immune education and disruption during this window can increase chronic inflammatory disorders (39)(40)(41)(42)(43). While it has been predicted that initial colonization at birth must direct development of local T cell specificity to commensal microbes, this has not been directly tested.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have highlighted that microbiota exposure early in life is required for effective immune education and that disruption to the microbiota during this early window of development may increase susceptibility to inflammatory disorders 40,41,[45][46][47] . Therefore, to investigate whether microbiota instruct development of commensal-specific T cell responses, intestinal CD4 + T cells were analyzed for reactivity to the class II-commensal flagella antigen-specific cBir1 tetramer.…”

Section: Commensal-specific Cd4 + T Cells Expand Following Post-natal Microbial Colonizationmentioning

confidence: 99%

Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells

Eshleman

Shao

Woo

et al. 2022

Preprint

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Dysregulated immune responses to resident microbes promote pathologic inflammation, however, the mechanisms instructing commensal-specific T cells remain poorly understood. Here, we find that non-hematopoietic intestinal epithelial cells (IECs) represent the primary cells expressing major histocompatibility complex (MHC) II at the intestinal host-microbiota interface. Interestingly, epithelial MHCII and commensal-specific CD4+ T cells were concurrently induced by post-natal microbiota colonization, provoking the hypothesis that epithelial MHCII regulates local commensal-specific CD4+ T cells. While MHCII on classical antigen presenting cells directs expansion of antigen-specific CD4+ T cells, loss of IEC-intrinsic MHCII surprisingly led to elevated commensal-specific CD4+ T cells in the intestine. Further, epithelial MHCII expression actively limited accumulation of antigen-specific CD4+ T cells in adult mice. Expansion of commensal-specific Th17 cells was restricted by epithelial MHCII, and remarkably mice lacking epithelial MHCII were highly susceptible to microbiota-triggered inflammation. Collectively, these data indicate that impaired epithelial MHCII-T cell regulation within mucosal tissues alters microbiota-specific immunity and predisposes to chronic inflammation.

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Early life antibiotic exposure and host health: Role of the microbiota–immune interaction

Cited by 6 publications

References 70 publications

Noninfectious influencers of early-onset sepsis biomarkers

Noninfectious influencers of early-onset sepsis biomarkers

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells

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