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Cancer cachexia is a complex multi-organ syndrome characterized by body weight loss, weakness, muscle atrophy and fat depletion. With a prevalence of 1 million people in Europe and only limited therapeutic options, there is a high medical need for new approaches to treat cachexia. Our latest results highlighted microbial dysbiosis, characterized by a bloom in Enterobacteriaceae and altered gut barrier function in preclinical models of cancer cachexia. They also demonstrated the potential of targeting the gut microbial dysbiosis in this pathology. However, the exact mechanisms underlying the gut microbiota-host crosstalk in cancer cachexia remain elusive. In this set of studies, we identified Klebsiella oxytoca as one of the main Enterobacteriaceae species increased in cancer cachexia and we demonstrated that this bacteria acts as a gut pathobiont by altering gut barrier function in cachectic mice. Moreover, we propose a conceptual framework for the lower colonization resistance to K . oxytoca in cancer cachexia that involves altered host gut epithelial metabolism and host-derived nitrate boosting the growth of the gut pathobiont. This set of studies constitutes a strong progression in the field of gut microbiota in cancer cachexia, by dissecting the mechanism of emergence of one bacterium, K . oxytoca , and establishing its role as a gut pathobiont in this severe disease.

Infection by pathogenic organisms leads to mucosal damage and disruption of the gut's extensive commensal flora, factors which may lead to prolonged bowel dysfunction. Six to 17% of unselected irritable bowel syndrome (IBS) patients believe their symptoms began with an infection, which is supported by prospective studies showing a 4%-31% incidence of postinfectious IBS-(PI) following bacterial gastroenteritis. The wide range of incidence can be accounted for by differences in risk factors, which include in order of magnitude; severity of initial illness > bacterial toxigenicity > hypochondriasis, depression and neuroticism, and adverse life events in the previous 3 months. PI-IBS has been reported after Campylobacter, Salmonella, and Shigella infections. Serial biopsies after Campylobacter jejuni gastroenteritis show an initial inflammatory infiltrate, with an increase in enterochromaffin (EC) cells, which in most cases subsides over the next 6 months. Those who go on to develop IBS show increased numbers of EC and lymphocyte cell counts at 3 months compared with those who do not develop IBS. Interleukin-1beta mRNA levels are increased in the mucosa of those who develop PI-IBS, who also show increased gut permeability. Recover can be slow, with approximately 50% still having symptoms at 5 years. Recent studies suggest an increase in peripheral blood mononuclear cell cytokine production in unselected IBS, an abnormality that may be ameliorated by probiotic treatment. The role of small-bowel bacterial overgrowth in IBS is controversial, but broad-spectrum antibiotics do have a temporary benefit in some patients. More acceptable long-term treatments altering gut flora are awaited with interest.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. The median age of our cohort was 73·5 years (range 42–84; IQR 67·5–77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. None.

Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms and in biofilm-dispersed form. It is therefore of major importance in understanding homeostatic and altered host–microorganism interactions to consider not only the planktonic lifestyle, but also biofilms and biofilm-dispersed forms. In this Review, we discuss the natural organization of microorganisms at gastrointestinal surfaces, stratification of microbiota taxonomy, biogeographical localization and trans-kingdom interactions occurring within the biofilm habitat. We also discuss existing models used to study biofilms. We assess the contribution of the host–mucosa biofilm relationship to gut homeostasis and to diseases. In addition, we describe how host factors can shape the organization, structure and composition of mucosal biofilms, and how biofilms themselves are implicated in a variety of homeostatic and pathological processes in the gut. Future studies characterizing biofilm nature, physical properties, composition and intrinsic communication could shed new light on gut physiology and lead to potential novel therapeutic options for gastrointestinal diseases.In this Review, Motta, Vergnolle and colleagues describe the organization of microorganisms into planktonic, biofilm and biofilm-dispersed forms in the gastrointestinal tract. The role of the host–biofilm relationship in gut homeostasis and disease is discussed.

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases 1 , 2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease 3 . Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn’s disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner’s glands. Although previously linked to mucosal healing 4 , we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases. The study provides a comprehensive transcriptomic atlas of the human gastrointestinal tract across the lifespan, highlighting inflammation-induced changes in epithelial stem cells that alter mucosal architecture and promote further inflammation.

Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies. A synthetic yeast-based therapeutic that secretes an ATP-degrading enzyme in response to pro-inflammatory extracellular ATP in the gut reduces intestinal inflammation, fibrosis and dysbiosis in mouse models of colitis and enteritis.

Emulsifying agents, which are common food additives in the human diet, induce low-grade inflammation and obesity/metabolic syndrome in mice, suggesting that further investigation into the potential impact of dietary emulsifiers on the gut microbiota and human heath are warranted. Harmful effects of dietary emulsifiers Non-genetic factors are important contributors to the pathogenesis of inflammatory conditions such as such as inflammatory bowel disease and metabolic syndrome. Here the authors find that mice on a diet containing emulsifying agents develop low-grade inflammation and obesity/metabolic syndrome. These conditions correlate with a decrease in gut microbiota–epithelial distance through degradation of mucus layers, altered species composition and pro-inflammatory potential. Emulsifying agents are common food additives in the human diet, and these findings suggest that further investigations are warranted into their potential impact on gut microbiota and human health. The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota–host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine 1 . Thus, agents that disrupt mucus–bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro 2 , might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century 3 . Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host–microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

Context.—Gastrointestinal (GI) and pancreatobiliary tracts contain a variety of neuroendocrine cells that constitute a diffuse endocrine system. Neuroendocrine tumors (NETs) from these organs are heterogeneous tumors with diverse clinical behaviors. Recent improvements in the understanding of NETs from the GI and pancreatobiliary tracts have led to more-refined definitions of the clinicopathologic characteristics of these tumors. Under the 2010 World Health Organization classification scheme, NETs are classified as grade (G) 1 NETs, G2 NETs, neuroendocrine carcinomas, and mixed adenoneuroendocrine carcinomas. Histologic grades are dependent on mitotic counts and the Ki-67 labeling index. Several new issues arose after implementation of the 2010 World Health Organization classification scheme, such as issues with well-differentiated NETs with G3 Ki-67 labeling index and the evaluation of mitotic counts and Ki-67 labeling. Hereditary syndromes, including multiple endocrine neoplasia type 1 syndrome, von Hippel-Lindau syndrome, neurofibromatosis 1, and tuberous sclerosis, are related to NETs of the GI and pancreatobiliary tracts. Several prognostic markers of GI and pancreatobiliary tract NETs have been introduced, but many of them require further validation. Objective.—To understand clinicopathologic characteristics of NETs from the GI and pancreatobiliary tracts. Data Sources.—PubMed (US National Library of Medicine) reports were reviewed. Conclusions.—In this review, we briefly summarize recent developments and issues related to NETs of the GI and pancreatobiliary tracts.

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

A differentiation protocol to obtain enteric nervous system (ENS) progenitors and a range of neurons from human pluripotent stem cells is developed; the cells can migrate and graft to the colon of a chick embryo and an adult mouse colon, including in a mouse model of Hirschsprung disease, in which a functional rescue is observed. Enteric nervous system precursor cells The enteric nervous system (ENS) is essential to normal gut function and works to some extent independently from other neuronal circuits. Lorenz Studer and colleagues have developed a differentiation protocol for human pluripotent stem cells to obtain ENS progenitors and a range of neurons found in the ENS. They show that these can migrate and graft to the gut of a chick embryo and adult mouse colon, including in a mouse model of Hirschsprung disease, in which they observe a functional rescue. The authors also show that ENS precursors derived from patients affected by Hirschsprung disease can be used to screen for drugs that can modulate the properties of these cells. The enteric nervous system (ENS) is the largest component of the autonomic nervous system, with neuron numbers surpassing those present in the spinal cord 1 . The ENS has been called the ‘second brain’ 1 given its autonomy, remarkable neurotransmitter diversity and complex cytoarchitecture. Defects in ENS development are responsible for many human disorders including Hirschsprung disease (HSCR). HSCR is caused by the developmental failure of ENS progenitors to migrate into the gastrointestinal tract, particularly the distal colon 2 . Human ENS development remains poorly understood owing to the lack of an easily accessible model system. Here we demonstrate the efficient derivation and isolation of ENS progenitors from human pluripotent stem (PS) cells, and their further differentiation into functional enteric neurons. ENS precursors derived in vitro are capable of targeted migration in the developing chick embryo and extensive colonization of the adult mouse colon. The in vivo engraftment and migration of human PS-cell-derived ENS precursors rescue disease-related mortality in HSCR mice ( Ednrb s-l/s-l ), although the mechanism of action remains unclear. Finally, EDNRB-null mutant ENS precursors enable modelling of HSCR-related migration defects, and the identification of pepstatin A as a candidate therapeutic target. Our study establishes the first, to our knowledge, human PS-cell-based platform for the study of human ENS development, and presents cell- and drug-based strategies for the treatment of HSCR.