Introduction

There is a widespread agreement that age is a significant predictor of impaired response to nutritional support. For the same amount of protein and energy provided, the increase in weight and fat-free mass is significantly lower in older persons. This is generally attributed to anabolic resistance, and impaired absorption is usually considered non-existent/irrelevant. Nevertheless, in older rats gradual changes of the intestinal mucosa were observed, including reductions in villus height/width and density, which reduce absorption. Despite this, the aging influence on human intestinal mucosa is a matter of debate, and the lack of knowledge is partially explained by the exclusion criteria of older patients from most research protocols.

Aims & Methods

We aimed to evaluate potential histological and ultrastructural changes associated with aging that may reflect reduced absorption in older people.
The present single-center study is observational and prospective. Younger (18-45 years) and older (≥70 years) adults referred for upper endoscopy for reasons unrelated with intestinal alterations were included and underwent duodenal biopsies. Those biopsies were analyzed for histological, histomorphometric and ultrastructural changes. Histologic analysis was performed using optical microscopy with hematoxylin–eosin staining observed by two pathologists, including one expert gastrointestinal pathologist. All samples were analyzed for the presence of mucosal atrophy according to the adapted Marsh–Oberhuber classification and histomorphometric evaluation of duodenal villi length in micrometers, with at least two villi being measured through the use of an automatic scale. For transmission electron microscopy, duodenal fragments were fixed in 3% glutaraldehyde in cacodylate buffer (0.1 M, pH 7.4) overnight at 4 °C. The fixed fragments were rinsed and post-fixed in 1.0% osmium tetroxide for 1 h in the same buffer and dehydrated in graded ethanol passages. The fragments were embedded in a mixture of Epon and Araldite after two 15-min passages in propylene oxide. Thin sections, cut on a ultramicrotome with a diamond knife, were stained on the grid with uranyl acetate and lead citrate and examined with a electron microscope.

Results

A total of 84 patients were included (38 men/46 women), 33 with 18-45 years and 50 with ≥70 years. There were no duodenal endoscopic or microscopic changes apart from mucosal atrophy that was evident in one older adult. The median villi length was 0.35 mm (0.23-0.43 mm) in older persons, lower than in younger adults (0.65 mm; 0.37-0.79 mm) (p<0.01). On ultrastructural evaluation, the enterocytes of older group showed several changes suggesting compromise of the normal cell physiology. These changes were not observed in younger adults, who displayed normal cell architecture with regular microvilli structure and normal organelles.

Conclusion

Aging is associated with histological, histomorphometric and ultrastructural changes in the intestinal mucosa that can be linked with reduced absorptive capacity. Besides anabolic resistance, this could be a reason for the reduced response to nutritional support found in older citizens.

References

1. Soenen S, Rayner CK, Jones KL, et al. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):12-8.
2. Patel BA, Patel N, Fidalgo S, et al. Impaired colonic motility and reduction in tachykinin signalling in the aged mouse. Exp Gerontol 2014; 53:24 – 30.
3. Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age 2014; 36:9603.
4. Ren WY, Wu KF, Li X, et al. Age-related changes in small intestinal mucosa epithelium architecture and epithelial tight junction in rat models. Aging Clin Exp Res 2014; 26:183 – 191.
5. Thomson AB. Small intestinal disorders in the elderly. Best Pract Res Clin Gastroenterol. 2009;23(6):861-74.
6. Nalapareddy K, Zheng Y, Geiger H. Aging of intestinal stem cells. Stem Cell Reports. 2022 Apr 12;17(4):734-740.

Introduction

Prospective evidence of the long-term efficacy of endoscopic submucosal dissection (ESD) for T1 colorectal cancer (CRC) is insufficient.

Aims & Methods

We aimed to evaluate long-term ESD outcomes for T1 CRC, focusing on the risk stratification criteria and necessity of additional surgery.
This large-scale, multicenter, prospective cohort study was conducted by Hiroshima GI Endoscopy Research Group. All consecutive patients who underwent colorectal ESD between January 2014 and December 2018 were included, and those with pathologically confirmed T1 CRC were analyzed. Patients were classified into low-risk and high-risk groups based on histopathological risk factors for lymph node metastasis in JSCCR guidelines. High-risk patients were categorized into those who underwent additional surgery (surgery group) and those who were followed up without surgery (follow-up group).

Results

Among 2357 patients who underwent ESD for 2478 early colorectal neoplasms, 431 were diagnosed with T1 CRC. Ten recurrences (2.6%) and five T1 CRC-associated deaths (1.3%) occurred in the high-risk group, with none in the low-risk group. Five-year cumulative overall and local recurrence rates were significantly higher in the follow-up versus surgery group (7.7% and 1.9%; P=0.019 versus 6.4% and 0%; P<0.001), with no local recurrence in the surgery group. Five-year overall survival was significantly worse in the follow-up group (79.5% and 95.2%; P<0.001), while no significant difference was found in 5-y disease-specific survival (98.5% and 98.5%; P=0.447).

Conclusion

No recurrence or mortality occurred in the low-risk group, suggesting that intensive surveillance may be unnecessary for these patients after curative ESD. Additional surgery could prevent local recurrence for high-risk T1 CRC, supporting a risk-based treatment approach.

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to the metabolic syndrome of chronic liver disease and its pathogenesis involves a variety of cell types of metabolic disorders and inflammatory response, however, treatment is limited. Mas is a G protein-coupled receptor highly expressed by myeloid cells. It may play a key role in regulating myeloid-associated inflammation and metabolic homeostasis in the process of MASLD. However, its specific mechanism of action in MASLD remains unclear.

Aims & Methods

This study aims to explore the regulatory mechanism of MAS in myeloid cells in the occurrence and development of MASLD. In this study, liver tissues of patients with MASLD and animal models of MASLD induced by high-fat diet (HFD) were analyzed. In this study, myeloid-specific Mas1 knockout (Lysm^creMas1^f/f) mice were constructed. Single-cell RNA sequencing and multi-omics analysis were used to explore the role and mechanism of myeloid Mas in HFD-induced MASLD mice.

Results

The study found that the expression of MAS protein on myeloid cells in the livers of MASLD patients and MASLD animal models was significantly increased. Mononuclear phagocyte system（MPs）undergo metabolic disorders in the MASLD model, with elevated glycolysis levels, increased lactic acid production, and at the same time, the expression of cellular senescence markers (such as p16 and p21) is upregulated, and the secretion of inflammatory factors is increased. Single-cell multi-omics analysis revealed that myeloid MAS1 knockout activated the FN1⁺CCR2⁺monocytes first. Pseudo-temporal analysis showed that the FN1⁺CCR2⁺ monocytes had spatiotemporal metabolic responses with the macrophages, significantly involving the activation of glycolysis and inflammatory senescence by myeloid MAS. Non-target metabolomics of MASLD patients also revealed elevated glycolytic metabolism and increased lactic acid secretion. Mass spectrometry revealed that Mas specifically bound to the key glycolytic protein pyruvate kinase M2 (PKM2) and activated the lactylation of transcription factor Spi1-K208 site mediated by PKM2. The lactylation of Spi1-K208 promoted the transcription of senescence-associated secretory phenotype (SASP) -related proteins. Myeloid Mas1 knockout inhibited the nuclear translocation of PKM2 and blocked the lactylation of Spi1, inhibiting the transcriptional initiation of SASP. Screening of over 100,000 small molecule compounds through a virtual drug library revealed that Theaflavin 3,3'-digallate (TFDG) might reduce the protein expression of Mas and PKM2, and block the binding of the MAS-PKM2 complex. We synthesized macrophage membrane to encapsulat PLGA nanoparticles loaded with TFDG (MM@NP-TFDG) and found that MM@NP-TFDG effectively reduced the expression level of Mas-PKM2 complex protein expression in the MASLD mouse model, inhibited the glycolytic - inflammatory senescence axis of FN1⁺CCR2⁺ monocytes and macrophages, and alleviated liver inflammation and tissue damage. While the lipid deposition in the liver is reduced and the fatty acid oxidation is enhanced.

Conclusion

This study reveals that myeloid MAS1 protein participates in the occurrence and development of MASLD by regulating PKM2-mediated Spi1 lactylation and reprogramming the metabolic-inflammatory senescence axis of MPs during the process of MASLD. This discovery provides new potential targets for the treatment of MASLD patients and is expected to offer new clinical treatment strategies for MASLD patients.

Disclosure

The authors declare no conflict of interest.

Introduction

Colorectal cancer is one of the most prevalent cancers with an estimated 1.8 million newly developed cases and 0.9 million cancer-related deaths in 2020.Resection of adenomatous polyps decreases the incidence and mortality of colorectal cancer. Narrow-band imaging (NBI) and linked color imaging (LCI) are the most predominantly conducted image-enhanced endoscopy using short-wavelength light but their usefulness in screening and surveillance colonoscopy remains controversial.

Aims & Methods

Our aim in this study was to investigate the superiority of LCI over NBI for ADR.
This is an open-label, two-arm, parallel, 1:1, multicenter, randomized, controlled, right-sided colonoscopy study and included patients who underwent colonoscopy at six endoscopy centers in Japan from November 2020 through November 2023. The patients were randomly assigned to undergo a proximal-sided colonoscopy (cecum and ascending colon) with LCI or 2G-NBI followed by WLI. The primary outcome included the ADR and secondary outcomes involved polyp detection rate (PDR), polyp miss rate, and adenoma miss rate. This study was registered on November 4, 2020, in the Japan Registry of Clinical Trials (jRCT1012200007).

Results

During the study period, 1,655 patients were randomly assigned to the LCI group (828 patients, primary LCI followed by secondary WLI) and the 2G-NBI group (827 patients, primary 2G-NBI followed by secondary WLI), and 776 patients in the LCI group and 752 patients in the 2G-NBI groups were finally analyzed. The ADRs were 26.7% and 23.4% and the PDRs were 32.6% and 28.9% in primary LCI and 2G-NBI, respectively, with no statistically significant differences in ADR and PDR between groups (P = 0.14 and P = 0.12). However, multivariate regression analysis revealed primary LCI observation as an independent predictor for reducing PDR in the secondary WLI (Odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.53−0.97, P = 0.029). Moreover, polyp analysis demonstrated that miss rates of adenomas and polyps were significantly lower in the LCI group than in the NBI group (OR: 0.54, 95% CI: 0.39−0.76 in adenoma; OR: 0.59, 95% CI: 0.44−0.78 in polyp).

Conclusion

LCI is not superior to 2G-NBI in ADR and PDR in a clinical right-sided colonoscopy setting. However, LCI significantly reduced miss rates of adenomas and polyps.

Disclosure

Naohisa Yoshida has received lecture and/or consulting fees from Fujifilm and Olympus; Shoko Ono has received lecture and/or consulting fees from Fujifilm and Olympus; Momoko Tsuda has received lecture and/or consulting fees from Fujifilm; Nobuaki Yagi have received lecture and/or consulting fees from Fujifilm and Olympus; Mototsugu Kato has received lecture and/or consulting fees from Fujifilm. The remaining authors disclose no conflicts.