Intestinal Abnormalities in Patients With SARS-CoV-2 Infection: Histopathologic Changes Reflect Mechanisms of Disease.

Approximately 20% of patients with symptomatic syndrome-associated coronavirus-2 (SARS-CoV-2) infection have gastrointestinal bleeding and/or diarrhea. Most are managed without endoscopic evaluation because the risk of practitioner infection outweighs the value of biopsy analysis unless symptoms are life-threatening. As a result, much of what is known about the gastrointestinal manifestations of coronavirus disease-2019 (COVID-19) has been gleaned from surgical and autopsy cases that suffer from extensive ischemic injury and/or poor preservation. There are no detailed reports describing any other gastrointestinal effects of SARS-CoV-2 even though >3,000,000 people have died from COVID-19 worldwide. The purpose of this study is to report the intestinal findings related to SARS-CoV-2 infection by way of a small case series including one with evidence of direct viral cytopathic effect and 2 with secondary injury attributed to viral infection. Infection can be confirmed by immunohistochemical stains directed against SARS-CoV-2 spike protein, in situ hybridization for spike protein-encoding RNA, and ultrastructural visualization of viruses within the epithelium. It induces cytoplasmic blebs and tufted epithelial cells without inflammation and may not cause symptoms. In contrast, SARS-CoV-2 infection can cause gastrointestinal symptoms after the virus is no longer detected, reflecting systemic activation of cytokine and complement cascades rather than direct viral injury. Reversible mucosal ischemia features microvascular injury with hemorrhage, small vessel thrombosis, and platelet-rich thrombi. Systemic cytokine elaboration and dysbiosis likely explain epithelial cell injury that accompanies diarrheal symptoms. These observations are consistent with clinical and in vitro data and contribute to our understanding of the protean manifestations of COVID-19.

APB-13 improves the adverse outcomes caused by TGEV infection by correcting the intestinal microbial disorders in piglets.

Porcine transmissible gastroenteritis virus (TGEV) is an enteric coronavirus that has caused high morbidity and mortality of piglets worldwide. Previous studies have shown that the TGEV can lead to severe diarrhoea, vomiting and dehydration in 2-week-old piglets and weaned piglets, resulting in a large number of piglet deaths. Antimicrobial peptides have broad-spectrum antimicrobial activity and a strong killing effect on bacteria, especially on the drug-resistant pathogenic bacteria, and it has attracted broad concern. However, there are very few reports on the effect of APB-13 (an antimicrobial peptide) on the intestinal microbes of piglets infected with TGEV. In this study, 16S rRNA gene sequencing was used to compare the microbial phylum and the genus of piglet's enteric microorganism in different experimental groups, and to predict the metabolic function of the microbial flora. At the same time, the apparent digestibility of nutrients, digestive enzyme activity, daily weight gain and survival rate were also measured. TGEV infection could cause the imbalance of intestinal microbes in piglets, and increase of the relative abundance of Proteobacteria, and decrease of the relative abundance of Firmicutes, Bacteroidetes and Actinobacteri. With the addition of APB-13, this problem can be alleviated, which can reduce the relative abundance of Proteobacteria and improve the balance of intestinal microorganisms. At the microbial genus level, after adding APB-13, the relative abundance of Catenibacterium, Enterobacter and Streptococcus in the intestinal tract of piglets infected with TGEV showed significant decrease, while the relative abundance of Lactobacillus and Ruminococcus increased. Finally, we found that APB-13 can significantly increase the activity of digestive enzyme in the intestinal tract of piglet, thereby improving the apparent digestibility of nutrients and the growth performance of piglets. This study demonstrates that APB-13 can alleviate the adverse outcomes caused by TGEV infection by correcting the intestinal microbial disorders.

Bowel Ischemia in COVID-19 Infection: One-Year Surgical Experience.

BACKGROUND: COVID-19 is a deadly multisystemic disease, and bowel ischemia, the most consequential gastrointestinal manifestation, remains poorly described. Our goal is to describe our institution's surgical experience with management of bowel ischemia due to COVID-19 infection over a one-year period. METHODS: All patients admitted to our institution between March 2020 and March 2021 for treatment of COVID-19 infection and who underwent exploratory laparotomy with intra-operative confirmation of bowel ischemia were included. Data from the medical records were analyzed. RESULTS: Twenty patients were included. Eighty percent had a new or increasing vasopressor requirement, 70% had abdominal distension, and 50% had increased gastric residuals. Intra-operatively, ischemia affected the large bowel in 80% of cases, the small bowel in 60%, and both in 40%. Sixty five percent had an initial damage control laparotomy. Most of the resected bowel specimens had a characteristic appearance at the time of surgery, with a yellow discoloration, small areas of antimesenteric necrosis, and very sharp borders. Histologically, the bowel specimens frequently have fibrin thrombi in the small submucosal and mucosal blood vessels in areas of mucosal necrosis. Overall mortality in this cohort was 33%. Forty percent of patients had a thromboembolic complication overall with 88% of these developing a thromboembolic phenomenon despite being on prophylactic pre-operative anticoagulation. CONCLUSION: Bowel ischemia is a potentially lethal complication of COVID-19 infection with typical gross and histologic characteristics. Suspicious clinical features that should trigger surgical evaluation include a new or increasing vasopressor requirement, abdominal distension, and intolerance of gastric feeds.

Salmonella delivered Lawsonia intracellularis novel epitope-fusion vaccines enhance immunogenicity and confers protection against Lawsonia intracellularis in mice.

Attenuated Salmonella-mediated vaccine constructs were designed by employing selected discontinuous immunodominant epitopes of LatA, FliC, and PAL antigens of Lawsonia intracellularis to create vaccines against porcine proliferative enteropathy (PPE). Whole protein sequences were subjected to in silico prediction of dominant epitopes, the stability of fusions, and hydropathicity and to ensure that the fused epitopes were feasible for expression in a Salmonella system. Two fusion constructs, one comprising LatA epitopes and the other FliC-PAL-FliC epitopes, were built into a prokaryotic constitutive expression system and transformed into the auxotrophic Salmonella host strain JOL1800. Epitope selection eliminated the majority of less immunodominant regions of target proteins and resulted in an efficient secretion platform that induced significant protective responses. Overall, our results demonstrated that the Salmonella-mediated LI- multi-epitope vaccines elicited significant humoral and cellular immune responses. Additionally, the challenge study suggested that the vaccinated mice were protected against experimental Lawsonia intracellularis infection. Based on the outcomes of the study, Salmonella-mediated LI- multi-epitope vaccines have the potential to prevent PPE.

Identification of a novel statovirus in a faecal sample from a calf with enteric disease.

A novel clade of RNA viruses was identified in the mammalian gastrointestinal tract by next-generation sequencing. Phylogenetically, these viruses are related to the genera Tombusviridae (plant viruses) and Flaviviridae, which includes mammalian, avian and insect hosts. Named in line with their characterization as stool-associated Tombus-like viruses, it is unclear if statoviruses infect mammals or are dietary in origin. Here, metagenomic sequencing of faecal material collected from a 10-week-old calf with enteric disease found that 20 % of the reads mapped to a de novo-assembled 4 kb contig with homology to statoviruses. Phylogenetic analysis of the statovirus genome found a clear evolutionary relationship with statovirus A, but, with only 47 % similarity, we propose that the statovirus sequence presents a novel species, statovirus F. A TaqMan PCR targeting statovirus F performed on faecal material found a cycle threshold of 11, suggesting a high titre of virus shed from the calf with enteric disease. A collection of 48 samples from bovine enteric disease diagnostic submissions were assayed by PCR to investigate statovirus F prevalence and 6 of 48 (12.5 %) were positive. An ELISA to detect antibodies to the coat protein found that antibodies to statovirus F were almost ubiquitous in bovine serum. Combined, the PCR and ELISA results suggest that statovirus F commonly infects cattle. Further research is needed to elucidate the aetiological significance of statovirus infection.

Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8+ T cells.

The SARS-CoV-2 pandemic has so far claimed over three and a half million lives worldwide. Though the SARS-CoV-2 mediated disease COVID-19 has first been characterized by an infection of the upper airways and the lung, recent evidence suggests a complex disease including gastrointestinal symptoms. Even if a direct viral tropism of intestinal cells has recently been demonstrated, it remains unclear, whether gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or whether they are a consequence of a systemic immune activation and subsequent modulation of the mucosal immune system. To better understand the cause of intestinal symptoms we analyzed biopsies of the small intestine from SARS-CoV-2 infected individuals. Applying qRT-PCR and immunohistochemistry, we detected SARS-CoV-2 RNA and nucleocapsid protein in duodenal mucosa. In addition, applying imaging mass cytometry and immunohistochemistry, we identified histomorphological changes of the epithelium, which were characterized by an accumulation of activated intraepithelial CD8+ T cells as well as epithelial apoptosis and subsequent regenerative proliferation in the small intestine of COVID-19 patients. In summary, our findings indicate that intraepithelial CD8+ T cells are activated upon infection of intestinal epithelial cells with SARS-CoV-2, providing one possible explanation for gastrointestinal symptoms associated with COVID-19.

Pathogenesis of murine astrovirus in experimentally infected mice.

Astroviruses are often associated with gastrointestinal diseases in mammals and birds. Murine astrovirus (MuAstV) is frequently detected in laboratory mice. Previous studies on MuAstV in mice did not report any symptoms or lesions. However, little information is available regarding its pathogenicity in immunodeficient mice. Therefore, in this study, we experimentally infected germ-free NOD.Cg-PrkdcscidIl2rgtm1Sug/ShiJic (NOG) mice, which are severely immunodeficient, with MuAstV. Germ-free mice were used for experimental infection to eliminate the effects of intestinal bacteria. Mice in each group were then necropsied and subjected to PCR for MuAstV detection, MuAstV RNA quantification in each organ, and histopathological examination at 4 and 28 days post inoculation (DPI). Tissue samples from the small intestine were examined by transmission electron microscopy. No symptoms or abnormalities were detected in any mice during necropsy. The MuAstV concentration was highest in the lower small intestine, where it increased approximately 8-fold from 4 to 28 DPI. Transmission electron microscopy revealed circular virus particles of approximately 25 nm in diameter in the cytoplasm of the villous epithelial cells of the lower small intestine. Histopathological examination did not reveal any abnormalities, such as atrophy, in the intestinal villi. Our results suggest that MuAstV proliferates in the villous epithelial cells of the lower small intestine and has weak pathogenicity.

The dark side of the gut: Virome-host interactions in intestinal homeostasis and disease.

The diverse enteric viral communities that infect microbes and the animal host collectively constitute the gut virome. Although recent advances in sequencing and analysis of metaviromes have revealed the complexity of the virome and facilitated discovery of new viruses, our understanding of the enteric virome is still incomplete. Recent studies have uncovered how virome-host interactions can contribute to beneficial or detrimental outcomes for the host. Understanding the complex interactions between enteric viruses and the intestinal immune system is a prerequisite for elucidating their role in intestinal diseases. In this review, we provide an overview of the enteric virome composition and summarize recent findings about how enteric viruses are sensed by and, in turn, modulate host immune responses during homeostasis and disease.

Bowel necrosis in patient with severe case of COVID-19: a case report.

BACKGROUND: In patients who are critically ill with COVID-19, multiple extrapulmonary manifestations of the disease have been observed, including gastrointestinal manifestations. CASE PRESENTATION: We present a case of a 65 year old man with severe COVID-19 pneumonia that developed hypercoagulation and peritonitis. Emergent laparotomy was performed and we found bowel necrosis in two sites. CONCLUSIONS: Although rare, the presentation of COVID-19 with bowel necrosis requires emergency treatments, and it has high mortality rate.

Features of Intestinal Disease Associated With COVID-Related Multisystem Inflammatory Syndrome in Children.

ABSTRACT: Multisystem inflammatory syndrome in children (MIS-C) is a recently identified syndrome that appears to be temporally associated with novel coronavirus 2019 infection. MIS-C presents with fever and evidence of systemic inflammation, which can manifest as cardiovascular, pulmonary, neurologic, and gastrointestinal (GI) system dysfunction. Presenting GI symptoms are seen in the majority, including abdominal pain, diarrhea, and vomiting. Any segment of the GI tract may be affected; however, inflammation in the ileum and colon predominates. Progressive bowel wall thickening can lead to luminal narrowing and obstruction. Most will have resolution of intestinal inflammation with medical therapies; however, in rare instances, surgical resection may be required.

Systemic inflammatory response and thrombosis due to alterations in the gut microbiota in COVID-19

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Rapid and efficient detection methods of pathogenic swine enteric coronaviruses.

Porcine enteric coronaviruses (CoVs) cause highly contagious enteric diarrhea in suckling piglets. These COV infections are characterized by clinical signs of vomiting, watery diarrhea, dehydration, and high morbidity and mortality, resulting in significant economic losses and tremendous threats to the pig farming industry worldwide. Because the clinical manifestations of pigs infected by different CoVs are similar, it is difficult to differentiate between the specific pathogens. Effective high-throughput detection methods are powerful tools used in the prevention and control of diseases. The immune system of piglets is not well developed, so serological methods to detect antibodies against these viruses are not suitable for rapid and early detection. This paper reviews various PCR-based methods used for the rapid and efficient detection of these pathogenic CoVs in swine intestines. KEY POINTS: 1. Swine enteric coronaviruses (CoVs) emerged and reemerged in past years. 2. Enteric CoVs infect pigs at all ages with high mortality rate in suckling pigs. 3. Rapid and efficient detection methods are needed and critical for diagnosis.

Ileocolic Intussusception as the Presenting Symptom of Primary Enteric Varicella-Zoster Virus Infection in a 7-Month-Old Infant.

Ileocolic intussusception is the invagination of ileum into the colon. In a subset of patients, the disease is caused by mesenteric lymphadenopathy in response to (viral) infection. We present a case of an ileocolic intussusception necessitating surgery in a 7-month-old immunocompetent infant with concurrent primary wild-type varicella-zoster virus (VZV) infection, in whom chickenpox rash developed 2 days after surgery. Detailed in situ analyses of resected intestine for specific cell type markers and VZV RNA demonstrated VZV-infected lymphocytes and neurons in the gut wall and in ganglion cells of the myenteric plexus.

Using Diverse Model Systems to Define Intestinal Epithelial Defenses to Enteric Viral Infections.

The intestine is an essential physical and immunological barrier comprised of a monolayer of diverse and specialized epithelial cells that perform functions ranging from nutrient absorption to pathogen sensing and intestinal homeostasis. The intestinal barrier prevents translocation of intestinal microbes into internal compartments. The microbiota is comprised of a complex community largely populated by diverse bacterial species that provide metabolites, nutrients, and immune stimuli that promote intestinal and organismal health. Although commensal organisms promote health, enteric pathogens, including a diverse plethora of enteric viruses, cause acute and chronic diseases. The barrier epithelium plays fundamental roles in immune defenses against enteric viral infections by integrating diverse signals, including those from the microbiota, to prevent disease. Importantly, many model systems have contributed to our understanding of this complex interface. This review will focus on the antiviral mechanisms at play within the intestinal epithelium and how these responses are shaped by the microbiota.

High prevalent human papillomavirus infections of the oral cavity of asymptomatic HIV-positive men.

BACKGROUND: Incidence of anal and oral infections with Human Papillomavirus (HPV) is increasing, particularly among Human Immunodeficiency Virus-positive (HIV+) men. HPV type 16 has exhibited the highest incidence and only limited data is available on other prevalent types, variants of HPV16, as well as associated factors. We were interested in identifying prevalent HPV types, variants of type 16, as well as factors associated with HPV16 infections in the oral cavity of HIV+ men who have sex with men (MSM). METHODS: A cross-sectional study of oral cavity samples from HIV+ MSM, that in a previous study were identified as positive for HPV16 in the anal canal. Cells from the oral cavity (102 samples, paired with 102 from the anal canal of same patient) were used to extract DNA and detect HPV infections using INNO-LiPA HPV Genotyping Extra II, and PCR. From these, 80 samples (paired, 40 anal and 40 oral) were used to identify variants of type 16 by sequencing. Statistical differences were estimated by the X2 test, and p values equal to or less than 0.05 were considered significant. SPSS ver. Twenty-four statistical software (IBM Corp) was used. RESULTS: We found a high prevalence of High-Risk HPV (HR-HPV) and Low-Risk HPV (LR-HPV). Patients were positive in the oral cavity for HR types; 16, 39 and 18 (80.4, 61.8 and 52.9% respectively) and LR types 11 and 6 (53.9 and 34.3% respectively). Surprisingly, only European variants of type 16 were found in the oral cavity, although American Asian (22.5%) and African (2.5%) variants were identified in the anal canal. The analysis showed that CD4 counts could be the most important risk factor associated with HR-HPV infections in the oral cavity, anal canal or both anatomical regions. The risk of infection of the oral cavity with type 18 increased in men diagnosed with HIV for more than 6 years. CONCLUSIONS: Prevalence of both HR and LR HPV's in the oral cavity of Mexican HIV+ MSM is very high. The fact that only European variants of HPV16 were found in the oral cavity suggest a possible tropism not previously described.

Rotavirus Reprograms Multiple Interferon Receptors and Restricts Their Intestinal Antiviral and Inflammatory Functions.

Rotaviruses (RV) cause acute severe diarrhea in the absence of substantial intestinal inflammation. They are also highly infectious in their homologous host species. The replication capacity of RV in the small bowel is substantially due to its ability to inhibit different types of interferons (IFNs). Here, we found that during RV infection in vitro, both virus-infected and uninfected bystander cells resist STAT1 phosphorylation and interferon regulatory factor 7 (IRF7) induction in response to exogenous interferon (IFN). Functionally, cellular transcription in response to stimulation with IFN, but not intracellular double-stranded RNA (dsRNA), was inhibited by RV. Further, IFNAR1 stimulation during RV infection significantly repressed a set of virus-induced transcripts. Regulation of IFN signaling in vivo was studied in suckling mice using the highly infectious murine EW RV strain. Kinetic studies indicated that sustained EW RV replication and IFN induction in the small intestine are accompanied by significant decreases in IFN-stimulated transcripts. Lipopolysaccharide (LPS)-mediated intestinal damage, driven by STAT1-induced inflammation, was also prevented in EW RV-infected mice. Remarkably, by ectopically stimulating either IFNAR1 or IFNGR1 in EW RV-infected mice, we could eliminate several intestinal antiviral and inflammatory transcriptional responses to RV. In contrast to infection with homologous RV, infection with a STAT1-sensitive heterologous RV strain induced IFN-stimulated transcripts, inflammatory cytokines, and intestinal expression of STAT1-pY701. Finally, RV strain-specific STAT1 regulation also likely determines the intestinal activation of multiple caspases. The simian RRV strain, but not murine EW RV, uniquely triggers the cleavage of both extrinsic and intrinsic caspases (caspases 8, 9, and 3) in a STAT1-mediated manner. Collectively, our findings reveal efficient reprograming of multiple IFN receptors toward a negative-feedback mode of signaling, accompanied by suppression of IFN-mediated antiviral, apoptotic, and inflammatory functions, during natural RV intestinal infection.IMPORTANCE Rotavirus is a highly infectious pathogen that causes severe diarrhea. Replication of RV in the small intestine is restricted to homologous host species, and host range restriction is substantially determined by the interferon response. In this study, we demonstrate that during infection, RV bystander cells resist exogenous IFN-mediated STAT1 signaling and transcription. In a suckling mouse model, ectopically stimulating different intestinal interferon receptors during RV infection eliminates several innate and inflammatory antiviral responses. Different intestinal inflammatory cytokines were also suppressed by homologous RV, as was intestinal damage in response to endotoxin. The ability of RV to suppress IFN-mediated receptors likely impacts intestinal cell homeostasis, as the cleavage of multiple intestinal caspases during RV infection is mediated by the IFN-STAT1 signaling pathway. Together, our results provide a mechanism underlying both the remarkable interferon resistance of homologous RV and its ability to prevent substantial inflammatory damage to the small bowel.

Virome-host interactions in intestinal health and disease.

The enteric virome consists largely of bacteriophages and prophages related to commensal bacteria. Bacteriophages indirectly affect the host immune system by targeting their associated bacteria; however, studies suggest that bacteriophages also have distinct pathways that enable them to interact directly with the host. Eukaryotic viruses are less abundant than bacteriophages but are more efficient in the stimulation of host immune responses. Acute, permanent, and latent viral infections are detected by different types of pattern recognition receptors and induce host immune responses, including the antiviral type I interferon response. Understanding the complex interplay between commensal microorganisms and the host immune system is a prerequisite to elucidating their role in intestinal diseases.

Associations between soil-transmitted helminthiasis and viral, bacterial, and protozoal enteroinfections: a cross-sectional study in rural Laos.

BACKGROUND: Humans are susceptible to over 1400 pathogens. Co-infection by multiple pathogens is common, and can result in a range of neutral, facilitative, or antagonistic interactions within the host. Soil-transmitted helminths (STH) are powerful immunomodulators, but evidence of the effect of STH infection on the direction and magnitude of concurrent enteric microparasite infections is mixed. METHODS: We collected fecal samples from 891 randomly selected children and adults in rural Laos. Samples were analyzed for 5 STH species, 6 viruses, 9 bacteria, and 5 protozoa using a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. We utilized logistic regression, controlling for demographics and household water, sanitation, and hygiene access, to examine the effect of STH infection on concurrent viral, bacterial, and protozoal infection. RESULTS: We found that STH infection was associated with lower odds of concurrent viral infection [odds ratio (OR): 0.48, 95% confidence interval (CI): 0.28-0.83], but higher odds of concurrent bacterial infections (OR: 1.81, 95% CI: 1.06-3.07) and concurrent protozoal infections (OR: 1.50, 95% CI: 0.95-2.37). Trends were consistent across STH species. CONCLUSIONS: The impact of STH on odds of concurrent microparasite co-infection may differ by microparasite taxa, whereby STH infection was negatively associated with viral infections but positively associated with bacterial and protozoal infections. Results suggest that efforts to reduce STH through preventive chemotherapy could have a spillover effect on microparasite infections, though the extent of this impact requires additional study. The associations between STH and concurrent microparasite infection may reflect a reverse effect due to the cross-sectional study design. Additional research is needed to elucidate the exact mechanism of the immunomodulatory effects of STH on concurrent enteric microparasite infection.

Norovirus strain types found within the second infectious intestinal diseases (IID2) study an analysis of norovirus circulating in the community.

BACKGROUND: Norovirus is the commonest cause of infectious intestinal disease (IID) worldwide. In the UK community incidence of norovirus has been estimated at 59/1000 population, equating to four million cases a year. Whilst norovirus infects people of all ages, a substantial burden occurs in infants and young children. The population of viruses found in sporadic cases among infants has been observed to be more diverse than that associated with outbreaks. In this study, we analysed norovirus-positive specimens collected during the second study of infectious intestinal diseases (IID2 Study) a national community cohort study conducted between April 2008 and August 2009 We examined the data for differences in circulating norovirus strains between two arms of a community cohort, and differences between genotypes and disease outcomes such as illness duration and symptom profiles. METHODS: Analysis was conducted to assess genetic diversity of noroviruses in the community. We also assessed differences in the cycle threshold (Ct) value, as a proxy for viral load, between norovirus genogroups and genotypes, and differences in reported symptoms or length of illness in relation to genogroup and genotype. RESULTS: There were 477 samples where norovirus was detected. Whilst 85% of people recovered within two days for vomiting; diarrhoea symptoms were reported to day 4 for 83% of the cases, and 10% of people reported symptoms of diarrhoea lasting between five and six days. Both diarrhoea and vomiting symptoms lasted longer in children aged < 5 years compared to adults. There was a significantly higher proportion of GII.4 in samples obtained from the GP arm of the study (chi-square = 17.8, p < 0.001) compared to samples received via post in the self-reporting arm. In the latter group, the prevalence of GII.6 was significantly higher (chi-square = 7.5, p < 0.001). CONCLUSIONS: We found that there is a difference in disease severity by age group. Children aged < 5 years had longer duration of illness, with 10% still having diarrhoea at seven days, and vomiting of between four and five days. The duration of illness reported is higher overall than one might expect for cases in the community in otherwise healthy individuals which has implications for infection control. No differences were observed in relation to duration of vomiting and or diarrhoea by genotype.

Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC+ CD4+ cell levels: a surrogate marker candidate of HIV-induced intestinal damage.

INTRODUCTION: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection. METHODS: Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naïve or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21. RESULTS: We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in CD4+ than CD4- leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. CONCLUSION: These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage.