Sexual identity of enterocytes regulates rapamycin-mediated intestinal homeostasis and lifespan extension

Pharmacological attenuation of mTOR by rapamycin and other compounds presents a promising route for delay of ageing-related pathologies, including intestinal cancers. Here, we show that rapamycin treatment in Drosophila extends lifespan in females but not in males. Female-specific, age-related gut pathology and impaired intestinal barrier function are both markedly slowed by rapamycin treatment, mediated by increased autophagy. Upon rapamycin treatment, female intestinal enterocytes increase autophagy, via the H3/H4 histone-Bchs axis, while male enterocytes show high basal levels of autophagy that do not increase further upon rapamycin treatment. Sexual identity of enterocytes alone, determined by the expression of transformerFemale, dictates sexually dimorphic cell size, H3/H4-Bchs expression, basal rates of autophagy, fecundity, intestinal homeostasis and extension of lifespan in response to rapamycin. This study highlights that tissue sex determines regulation of metabolic processes by mTOR and the efficacy of mTOR-targeted, anti-ageing drug treatments.

Microbiota and Its Impact on the Immune System in COVID-19—A Narrative Review

The microbiota is of interest for the development of a therapeutic strategy against SARS-CoV-2 coronavirus disease 2019 (COVID-19) due to its impact on the host immune system. Proven communications of the gut microbiota with the pulmonary microbiota (gut–lung axis) and the pathway of neural connections between the gut and brain (gut–brain axis) may be important in the face of the pandemic. SARS-CoV-2 was shown to affect almost all organs because of the presence of a host receptor known as angiotensin converting enzyme 2 (ACE2). The ACE2 receptor is mainly present in the brush border of intestinal enterocytes, ciliary cells, and type II alveolar epithelial cells in the lungs. The transport function of ACE2 has been linked to the ecology of gut microbes in the digestive tract, suggesting that COVID-19 may be related to the gut microbiota. The severity of COVID-19 may be associated with a number of comorbidities, such as hypertension, diabetes, obesity, and/or old age; therefore, attention is also paid to multiple morbidities and the modulation of microbiota through comorbidities and medications. This paper reviews the research in the context of the state of the intestinal microbiota and its impact on the cells of the immune system during the SARS-CoV-2 pandemic.

Reprogramming of the intestinal epithelial-immune cell interactome during SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents an unprecedented worldwide health problem. Although the primary site of infection is the lung, growing evidence points towards a crucial role of the intestinal epithelium. Yet, the exact effects of viral infection and the role of intestinal epithelial-immune cell interactions in mediating the inflammatory response are not known. In this work, we apply network biology approaches to single-cell RNA-seq data from SARS-CoV-2 infected human ileal and colonic organoids to investigate how altered intracellular pathways upon infection in intestinal enterocytes leads to modified epithelial-immune crosstalk. We point out specific epithelial-immune interactions which could help SARS-CoV-2 evade the immune response. By integrating our data with existing experimental data, we provide a set of epithelial ligands likely to drive the inflammatory response upon infection. Our integrated analysis of intra- and inter-cellular molecular networks contribute to finding potential drug targets, and suggest using existing anti-inflammatory therapies in the gut as promising drug repurposing strategies against COVID-19.

Gastrointestinal Involvement in The Confirmed Covid-19 Patients

The current pandemic of Coronavirus disease 2019, or known as COVID-19, has been claimed as Public Health Emergency of International Concern by WHO on 30 January 2020. According to WHO, there 47.362.304 confirmed cases and 1.211.986 deaths reported due to COVID-19 and still counting. This article investigates the involvement of gastrointestinal symptoms in COVID-19 related to the pathogenesis, transmission, and severity of the disease. The data was collected by keyword searching through EBSCO, PubMed, Google scholar, and additional references from retrieved articles. This article analyzes studies investigating gastrointestinal symptoms in Covid-19. The studies found gastrointestinal symptoms in COVID-19 confirmed patients such as abdominal pain, diarrhea, nausea, vomiting, constipation, and melena. Two studies showed that COVID-19 patients with gastrointestinal symptoms tended to have more severe disease. ACE2, as the receptor of S protein, was found abundantly in intestinal enterocytes besides in the respiratory system. Enterocyte abnormality induces decreased absorption of NA+, water, and mucosal disaccharides. It leads to increased undigested mono and disaccharides, carbohydrates, fats, and protein into the colon. As a result, the colon is unable to absorb sufficient water, leading to diarrhea. Gastrointestinal symptoms are commonly found in patients with COVID‐19, and the trend is increasing in the later stage of the epidemic. SARS‐CoV‐2 enters gastrointestinal epithelial cells and the feces of COVID‐19 patients are potentially infectious. The virus also found in wastewater system and may cause water pollution. Hence, further studies investigating gastrointestinal symptoms and possibility of fecal oral transmission should be conducted.

A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally, through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organization, induces intestinal autophagy through transcriptional regulation, prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.

Gastrointestinal involvement attenuates COVID-19 severity and mortality

Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated intestinal infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its effect on disease pathogenesis. SARS-CoV-2 was detected in small intestinal enterocytes by immunofluorescence staining or electron microscopy, in 13 of 15 patients studied. High dimensional analyses of GI tissues revealed low levels of inflammation in general, including active downregulation of key inflammatory genes such as IFNG, CXCL8, CXCL2 and IL1B and reduced frequencies of proinflammatory dendritic cell subsets. To evaluate the clinical significance of these findings, examination of two large, independent cohorts of hospitalized patients in the United States and Europe revealed a significant reduction in disease severity and mortality that was independent of gender, age, and examined co-morbid illnesses. The observed mortality reduction in COVID-19 patients with GI symptoms was associated with reduced levels of key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation but was not associated with significant differences in nasopharyngeal viral loads. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.One Sentence SummaryIntestinal infection with SARS-CoV-2 is associated with a mild inflammatory response and improved clinical outcomes.

Hypoxia enhances transcytosis in intestinal enterocytes

The integrity of the intestinal epithelial cell lining is crucial for the normal intestinal function. As a rule, intestinal inflammation is associated with additional tissue hypoxia, leading to the loss of epithelial monolayer integrity. However, in the absence of visible damage to the epithelium, there still might be a risk of infection driven by changes in the intracellular transport of bacteria-containing vesicles. The aim of this study was to investigate the effects of hypoxia on transcytosis using a human intestinal enterocyte model. We found that hypoxia enhances transcytosis of the model protein ricin 1.8-fold. The comparative transcriptome and proteome analyses revealed significant changes in the expression of genes involved in intracellular vesicle transport. Specifically, the expression of apoB (the regulator of lipid metabolism) was changed at both protein (6.5-fold) and mRNA (2.1-fold) levels. Further research is needed into the possible mechanism regulating gene expression in intestinal erythrocytes under hypoxic conditions.

SARS-CoV-2 Receptor ACE2 Gene Expression in Small Intestine correlates with Age

SARS-CoV-2 binds via its spikes to its receptor angiotensin-converting enzyme 2 (ACE2). ACE2 is also expressed in small intestinal enterocytes, making the intestine a possible entry site. We examined duodenal biopsies from 43 healthy human adults. ACE2 gene expression was directly correlated with age (Spearman’s r= 0.317, p=0.039. With each year duodenal ACE2 expression increased by 0.083 RU. The higher intestinal ACE2 mRNA expression in older patients might make them more susceptible to oral SARS-CoV-2 infection.

TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases, TMPRSS2 and TMPRSS4, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into host cells. We also demonstrate that viruses released into the intestinal lumen were inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.