A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory Clostridioides difficile Infection

Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI); increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies

Inflammaging as a target for healthy ageing

Life expectancy has been on the rise for the past few decades, but healthy life expectancy has not kept pace, leading to a global burden of age-associated disorders. Advancing age is accompanied by a chronic increase in basal systemic inflammation, termed inflammaging, contributing towards an increased risk of developing chronic diseases in old age. This article reviews the recent literature to formulate hypotheses regarding how age-associated inflammaging plays a crucial role in driving chronic diseases and ill health in older adults. Here, we discuss how non-pharmacological intervention strategies (diet, nutraceutical supplements, phytochemicals, physical activity, microbiome-based therapies) targeting inflammaging restore health in older adults. We also consider alternative existing pharmacological interventions (Caloric restriction mimetics, p38 mitogen-activated protein kinase inhibitors) and explore novel targets (senolytics) aimed at combating inflammaging and optimising the ageing process to increase healthy lifespan.</p

Microbial-Immune Crosstalk in Elderly-Onset Inflammatory Bowel Disease: Unchartered Territory

Elderly-onset inflammatory bowel disease (IBD) patients exhibit a distinct natural history compared to younger IBD patients, with unique disease phenotypes, differential responses to therapy and increased surgical morbidity and mortality. Despite the foreseeable high demand for personalized medicine and specialized IBD care in the elderly, current paradigms of IBD management fail to capture the required nuances of care for elderly-onset IBD patients. Our review postulates the roles of systemic and mucosal immunosenescence, inflammaging, and a dysbiotic microbial ecosystem in the pathophysiology of elderly-onset IBD. Ultimately, a better understanding of elderly-onset IBD can lead to improved patient outcomes and the tailoring of future preventative and treatment strategies

Investigating the potential of a prematurely aged immune phenotype in severely injured patients as predictor of risk of sepsis

BACKGROUND: Traumatic injury elicits a hyperinflammatory response and remodelling of the immune system leading to immuneparesis. This study aimed to evaluate whether traumatic injury results in a state of prematurely aged immune phenotype to relate this to clinical outcomes and a greater risk of developing additional morbidities post-injury. METHODS AND FINDINGS: Blood samples were collected from 57 critically injured patients with a mean Injury Severity Score (ISS) of 26 (range 15–75 years), mean age of 39.67 years (range 20–84 years), and 80.7% males, at days 3, 14, 28 and 60 post-hospital admission. 55 healthy controls (HC), mean age 40.57 years (range 20–85 years), 89.7% males were also recruited. The phenotype and frequency of adaptive immune cells were used to calculate the IMM-AGE score, an indicator of the degree of phenotypic ageing of the immune system. IMM-AGE was elevated in trauma patients at an early timepoint (day 3) in comparison with healthy controls (p < 0.001), driven by an increase in senescent CD8 T cells (p < 0.0001), memory CD8 T cells (p < 0.0001) and regulatory T cells (p < 0.0001) and a reduction in naïve CD8 T cells (p < 0.001) and overall T cell lymphopenia (p < 0 .0001). These changes persisted to day 60. Furthermore, the IMM-AGE scores were significantly higher in trauma patients (mean score 0.72) that developed sepsis (p = 0.05) in comparison with those (mean score 0.61) that did not. CONCLUSIONS: The profoundly altered peripheral adaptive immune compartment after critical injury can be used as a potential biomarker to identify individuals at a high risk of developing sepsis and this state of prematurely aged immune phenotype in biologically young individuals persists for up to two months post-hospitalisation, compromising the host immune response to infections. Reversing this aged immune system is likely to have a beneficial impact on short- and longer-term outcomes of trauma survivors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-022-00317-5

Accelarated immune ageing is associated with COVID-19 disease severity.

BackgroundThe striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.ResultsWe performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3-5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p -ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p +ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p ConclusionsOur analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease