Introduction

During the first 3 years of life, gut microbiota undergoes critical development and maturation, making it a vital stage for health.^{1, 2} Proper colonization relies on delivery mode, feeding mode, and environmental exposure.³ Maternal-infant transmission of microbiota occurs during delivery and breastfeeding.⁴ Interference with maternal gut microbiota during gestation/lactation can affect offspring's microbiota, persisting through 3 generations.
Polysorbate 80 (P80), a nonionic surfactant, disrupts intestinal barrier, causes dysbiosis/metabolic disorders. Maternal P80 intake during gestation/lactation may impact offspring. Study aims to investigate its influence on ontogeny and intestinal microbiota of 2nd and 3rd-generation offspring.

Aims & Methods

The study used six-week-old C57bl/6 mice, which were randomly assigned to two groups. One group was given sterile water throughout the study, while the other group was continuously provided with drinking water containing 1% P80. After co-housing with male mice from the same group for one week, successfully pregnant female mice were raised, and their offspring were delivered. The second generation of offspring were co-housed with their mothers and fed by maternal breast milk until weaning. Some of the second generation mice in both groups were sacrificed, and their body weight and liver weight were recorded. The remaining second generation mice were raised alone for five weeks using sterile water.
Afterward, each female mouse was co-housed with male mice from the same group for one week, respectively. Successfully pregnant female mice were raised, and their offspring were delivered. The third generation of offspring were co-housed with their mothers for three weeks before being sacrificed. The body weight and liver weight were recorded. Fecal samples and intestinal specimens were collected and stored for later assays. Ontogeny was estimated by comparing the body weight and liver mass and measuring the length of villi using HE stained specimens. The amount of goblet cells was counted using Periodic Acid-Schiff (PAS) dye. The expression of secretory IgA (sIgA) was evaluated using immunofluorescent staining. Real-time PCR (RT-PCR) was used to quantify the expression of components of tight junction and MUC2, as well as the expression of inflammatory cytokines. The fecal microbiota was analyzed using 16srDNA sequencing techniques.

Results

1. The second and third generations of mice exposed to P80 showed shorter intestinal villus, and the third generation had shorter jejunal villus. Additionally, the P80 group had shorter colonic glands in both generations.
2. The P80 group exhibited a different composition of gut microbiota compared to the control group in both the second and third generations. Notably, Mucispirillum was less abundant in both generations.
3. Both the second and third generations of mice in the P80 group had higher expression of IL-6 and IL-1β.
4. The P80 group had lower amounts of colonic goblet cells in both the second and third generations. Additionally, the P80 group had lower expression of ZO-1 and claudin-3, lower expression of MUC2, and a lower positive rate of sIgA dye in both generations.

Conclusion

This statement suggests that exposure to P80 during gestation and lactation could potentially cause negative effects on the offspring's gut health, including disruptions to intestinal barrier function, dysbiosis, and low-grade inflammation. These effects could, in turn, impact the ontogeny or developmental trajectory of the gut.

References

1. Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The intestinal microbiome in early life: health and disease. Front Immunol. 2014. 5: 427.
2. Tanaka M, Nakayama J. Development of the gut microbiota in infancy and its impact on health in later life. Allergol Int. 2017. 66(4): 515-522.
3. Tamburini S, Shen N, Wu HC, Clemente JC. The microbiome in early life: implications for health outcomes. Nat Med. 2016. 22(7): 713-22.
4. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med. 2015. 21(2): 109-17.

Clinical Case Summary

Seronegative enteropathies pose a complex diagnostic challenge, as their histology mimics celiac disease (CeD) (1). We report a 51-year-old patient with hypertension and osteoporosis, referred for abdominal pain, weight loss, and constipation. Blood tests showed no anemia; anti-transglutaminase and anti-endomysium antibodies were negative, but HLA typing was compatible with CeD. Ileocolonoscopy excluded IBD and microscopic colitis, while OEGD revealed villous atrophy (MARSH 3c). Negative anti-enterocyte antibodies, and exclusion of drugs and infections, led to a diagnosis of seronegative CeD. A gluten-free diet was started, but after 1 year, symptoms improved only partially despite good adherence. OEGD showed persistent duodenal damage with increased intraepithelial lymphocytes (IELs), CD3+ and CD8+ T-cells with monoclonal TCR expression (fig. 1), consistent with RCeD type 1, despite no overt malabsorption. The patient began prednisone 50 mg/day, then switched to open-capsule budesonide, with some clinical benefit but persistent atrophy.
A year later, his daughter was diagnosed with CVID and a heterozygous STAT3 variant (c.1252T>C, p.Cys418Arg), somatically acquired in NK-cell leukemia. A luciferase assay confirmed its gain-of-function (GOF) effect (fig. 2). Family studies revealed the same germline variant in the patient. His diagnosis was revised to STAT3 GOF-associated enteropathy. Further investigations revealed hypogammaglobulinemia, splenomegaly, bronchiectasis, and emphysema. Treatment with Ruxolitinib (a JAK1/2 inhibitor) was started, resulting in clinical and histological remission (fig. 3).
STAT3 GOF enteropathy is a very rare condition (2,3) that should be considered in the differential diagnosis of seronegative villous atrophy. Anti-JAK therapy may be effective (4).

References

References of the images:
Figure 1: Histologic aspects at diagnosis
Figure 2: Luciferase assay of STAT3
Figure 3: Histologic aspects after 1 year of therapy

1. Schiepatti A, Sanders DS, Baiardi P, Caio G, Ciacci C, Kaukinen K, et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. Gut. 2022 Jun 8;71(11):2218–25.
2. Vogel TP, Leiding JW, Cooper MA, Forbes Satter LR. STAT3 gain-of-function syndrome. Vol. 10, Frontiers in Pediatrics. Frontiers Media SA; 2023.
3. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.
4. Kaneko S, Sakura F, Tanita K, Shimbo A, Nambu R, Yoshida M, et al. Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function. Immunotherapy Advances. 2023;3(1).

Introduction

T1 colorectal cancer can be managed either by surgery or interventional endoscopy. High-risk features after endoscopic resection (G3, submucosal invasion >1000 µm, lympho-vascular invasion, tumour budding+, or R1 resection) increase the risk of lymphnode metastasis (10-15%), often requiring additional surgery. However, the benefits of surgery versus endoscopic resection alone remain unclear, particularly in elderly or frail patients.

Aims & Methods

The aim of the study is to assess recurrence rate and overall survival in patients underwent surgery, endoscopy or both. Secondary endpoints is to evaluate incidence of adverse events and length of hospital stay
All consecutive patients diagnosed with T1 colorectal cancer from 2018 to 2024 in our institution were enrolled in this retrospective study. We divided this cohort in 3 groups: endoscopic resection plus surgery (ER-S), upfront surgery (SR), or endoscopic resection alone (ER). Demographics data, mortality, cancer recurrence rate, disease free survival and AEs were recorded.

Results

One-hundred and thirty-three patients were enrolled in the study: 34 (72 years±10) in the SR group, 65 (65 years±11) in the ER-S group and 34 (77 years±11) in ER, respectively.
Lesions were similar (p-value 0.30) for dimension: 31±15 mm (ER) vs 23±12 mm (ER-S) vs 30±13 mm (ER) such as follow-up (23 vs 24 vs 21 months) for the three groups (p-value 0.428). Hospital stay after the procedure was significantly lower in the ER group (1 day median) vs SR (median 9 days;p-value 0.0001) and ER-S group (7 days median;p-value 0.003). Cumulative 30 days adverse events were higher in the SR group (62%; p-value 0.0001) and in the ER-S group (22%; p-value 0.001) compared to ER alone (12%). During the study period, no endoscopic/radiological recurrence occurred in the SR group whereas 1 patient in the ER-S group and 2 in the ER group showed recurrence non suitable for further treatments.
Five patients in SR group died after a median of 18 months (1 for early surgical complication); 2 died in the ER-S group after a median of 34 months and 3 died in the ER group after a median of 24 months (1 for rectal cancer progression) (p-value 0.365).
Overall survival was comparable among the three groups with no significant difference (p-value 0.718) with a median of 40 months (SR), 28 (ER-S) and 26 (ER) months.

Conclusion

Endoscopic resection alone appears to be a reasonable option for high-risk T1 CRC patients, especially those with increased surgical risk due to low rate of recurrence, low adverse events and a comparable overall survival in short-mid term.

References

1. Quénéhervé, L.; Pioche, M.; Jacques, J. Curative Criteria for Endoscopic Treatment of Colorectal Cancer. Best Pract. Res. Clin. Gastroenterol. 2024, 101883, doi:10.1016/j.bpg.2024.101883.
2. Chen, Y.; Jing, W.; Chen, M.; Wang, Z.; Wu, J.; Yang, J.; Yang, L.; Deng, K. Long-Term Outcomes of Local Resection versus Surgical Resection for High-Risk T1 Colorectal Cancer: A Systematic Review and Meta-Analysis. Gastrointest. Endosc. 2023, 97, 1016-1030.e14, doi:10.1016/j.gie.2023.02.027.
3. Spadaccini M, Bourke MJ, Maselli R, et al. Clinical outcome of non-curative endoscopic submucosal dissection for early colorectal cancer. Gut. Published online January 20, 2022. doi:10.1136/gutjnl-2020-323897
4. Corre, F.; Albouys, J.; Tran, V.-T.; Lepilliez, V.; Ratone, J.-P.; Coron, E.; Lambin, T.; Rahmi, G.; Karsenti, D.; Canard, J.-M.; et al. Impact of Surgery after Endoscopically Resected High-Risk T1 Colorectal Cancer: Results of an Emulated Target Trial. Gastrointest. Endosc. 2023, S0016-5107(23)02933-4, doi:10.1016/j.gie.2023.09.027.
5. UICC. TNM. Classification of malignant tumours. eighth ed. Wiley; 2016. p. 272

Disclosure

Giuseppe Grande is consultant for Olympus, Boston Scientific, ERBE, Fujifilm

Introduction

Decompensated alcohol-related cirrhosis (ArC) is a major cause of liver-related morbidity and mortality. There is a significant proportion of patients with ArC who achieve recompensation, defined as the absence of ascites or encephalopathy and no active treatment for either. Thus, recompensation is a relevant event in clinical practice. However, the factors and metabolic pathways involved in the resolution of clinical decompensation are poorly understood.

Aims & Methods

We aimed to assess the metabolomic profile associated with recompensated ArC. Patients with ArC were recruited from a prospective cohort followed between 2016 and 2020 in a referral hepatology unit (n=63). According to the evolution event at the end of follow-up, they were classified into 4 groups: group 0 patients compensated at baseline and during follow-up; group 1 patients who achieved recompensation; group 2 patients decompensated throughout the study period; group 3 patients who died in the 3 first months since inclusion. Demographic, clinical, and analytic parameters were retrieved from chart review together with evolution events. Plasma samples were analyzed at baseline to identify a metabolic signature using high-performance liquid chromatography-tandem mass spectroscopy. A principal component analysis of the implicated pathways was done using the Metaboanalyst platform.

Results

63 patients with ArC were included: 18 in group 0, 15 in group 1, 15 in group 2 and 15 in group 3. All four groups were similar in terms of age and sex. Baseline MELD score was 8, 17, 16 and 27, respectively. In relation to abstinence during follow-up, 61% of patients in group 1, 47% in group 2 and 20% in group 3 achieved alcohol abstinence (p=0.04).
Median follow-up time was similar when comparing group 1 and 2 (3.5 years and 3.3 years), which were the groups of interest (recompensated vs. decompensated). Each group displayed a distinct metabolic signature. By comparing groups 1 and 2, differences among 32 metabolites were detected: 20 lipids were at a higher concentration in recompensated individuals, which included polyunsaturated fatty acids (docosahenoic and docosapanthenoic acid 2 times greater (p<0.05)) and acylchcoline metabolism compounds; 7 amino acids, as phenyl-lactate (three times less in the recompensated group (p=0.04)) and 5 vitamins.
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Conclusion

Patients who achieved recompensation at the end of follow-up exhibited a distinct metabolomic profile, regarding the metabolism of polyunsaturated fatty acids, acylcarnitines and amino acids. It is likely that these metabolic pathways may play a role in resolution of decompensations in patients with ArC.

Introduction

Sexually transmitted infections (STIs) are increasingly recognized as causes of proctitis, particularly among men who have sex with men (MSM). These infections frequently mimic inflammatory bowel diseases (IBD) in clinical, endoscopic, and histological presentations, leading to potential misdiagnosis and inappropriate treatments. Accurate recognition requires detailed sexual history and targeted diagnostic tests.

Aims & Methods

Patients were identified from IBD outpatient visits (2021–2023) and retrospectively selected for suspected infectious proctitis mimicking IBD. Diagnosis was confirmed via clinical evaluation, targeted tests (rectal swabs, PCR, serology), and histology. Follow-up continued for six months post-treatment.

Results

1. A 42-year-old MSM with secondary syphilis treated with benzathine penicillin presented with bloody diarrhea, tenesmus, anorectal pain, and 10-kg weight loss. Mild anemia (Hb 12 g/dL) and elevated CRP were noted. Rectosigmoidoscopy (RSCS) revealed fibrinous ulcers causing luminal narrowing. Rectal swabs confirmed Chlamydia trachomatis. Treatment with doxycycline led to clinical and endoscopic resolution at six months.
2. A 33-year-old MSM with unprotected intercourse reported mucorrhea and tenesmus for one month. Calprotectin levels were elevated (861 µg/g). Colonoscopy revealed mild proctitis with mucosal hyperemia, and histology showed mild-to-moderate inflammation with crypt abscesses. Swabs confirmed Neisseria gonorrhoeae. Ceftriaxone resolved symptoms and normalized calprotectin (40 µg/g).
3. A 34-year-old male with primary sclerosing cholangitis (PSC) presented with two weeks of tenesmus, anal bleeding, and pruritus. Colonoscopy appeared macroscopically normal, but histology revealed human papillomavirus (HPV) infection. Anal canal condylomas were identified and successfully treated with cryotherapy, resulting in significant relief.

Conclusion

The rising prevalence of STI-related proctitis highlights the need for awareness among clinicians, as these infections often mimic IBD. Misdiagnosis can lead to inappropriate treatments, including steroids or biologics, causing adverse effects and delays in proper management. Detailed sexual history and targeted diagnostics, such as PCR and rectal swabs, are critical for accurate identification and effective treatment. These cases emphasize the critical role of integrating sexual history into clinical evaluation for proctitis. Awareness and timely recognition of STI-related proctitis are crucial to avoid misdiagnosis as IBD, ensure effective and targeted treatment, improve patient outcomes, and prevent inappropriate and prolonged follow-up.

References

-Infectious Proctitis: When to Suspect It Is Not InflammatoryBowel DiseaseFrank Hoentjen • David T. Rubin (Dig Dis Sci (2012) 57:269–273) -Proctitis: a glance beyond inflammatory bowel diseasesStefano Rizza et all Minerva Gastroenterol Dietol. 2020 Sep;66(3):252-266
-Proctitis in Men Who Have Sex with Men. Julia M. Steed et all