The gut wall's potential as a partner for precision oncology in immune checkpoint treatment

The gut wall is the largest immune organ and forms a barrier through which gut microbiota interact with the immune system in the rest of the body. Gut microbiota composition plays a role in the strength and timing of the anticancer immune response on immune checkpoint inhibitors (ICI). Surprisingly, the effects of gut wall characteristics, such as physical barrier integrity, permeability, and activity and composition of the intestinal immune system, on response to ICI has received little attention. Here, we provide an overview of markers to characterize the gut wall and interventions that can modulate these gut wall characteristics. Finally, we present a future perspective on how these gut wall markers and interventions might be utilized and studied to improve ICI treatment strategies

Enteral enriched nutrition to prevent cognitive dysfunction after surgery:A study in rats

BACKGROUND: Inflammation plays an important role in postoperative cognitive dysfunction (POCD), particularly in elderly patients. Enteral enriched nutrition was shown to inhibit the response on inflammatory stimuli. Aim of the present study was to explore the therapeutic potential of enteral enriched nutrition in our rat model for POCD. The anticipated mechanism of action was examined in young rats, while responses in the target group of elderly patients were evaluated in old rats. METHODS: Male 3 and 23 months old Wistar rats received a bolus of enteral fat/protein-enriched nutrition 2 ​h and 30 ​min before surgery. The inflammatory response was evaluated by systemic inflammation markers and brain microglia activity. Additionally, in old rats, the role of the gut-brain axis was studied by microbiome analyses of faecal samples. Days 9–14 after surgery, rats were subjected to cognitive testing. Day 16, rats were sacrificed and brains were collected for immunohistochemistry. RESULTS: In young rats, enriched nutrition improved long-term spatial learning and memory in the Morris Water Maze, reduced plasma IL1-β and VEGF levels, but left microglia activity and neurogenesis unaffected. In contrast, in old rats, enriched nutrition improved short-term memory in the novel object- and novel location recognition tests, but impaired development of long-term memory in the Morris Water Maze. Systemic inflammation was not affected, but microglia activity seemed even increased. Gut integrity and microbiome were not affected. CONCLUSION: Enteral enriched nutrition before surgery in young rats indeed reduced systemic inflammation and improved cognitive performance after surgery, whereas old rats showed a mixed favorable/unfavorable cognitive response, without effect on systemic inflammation. Anti-inflammatory effects of enriched nutrition were not reflected in decreased microglia activity. Neither was an important role for the gut-brain axis observed. Since the relatively straight forward effects of enriched nutrition in young rats could not be shown in old rats, as indicated by a mixed beneficial/detrimental cognitive outcome in the latter, caution is advised by translating effects seen in younger patients to older ones

Taste, smell and mouthfeel disturbances in patients with gastrointestinal stromal tumors treated with tyrosine-kinase inhibitors

CONTEXT: Taste, smell, and mouthfeel disturbances are underrated and underreported, but important side effects of anti-cancer medication. These symptoms are associated with a lower quality of life (QoL). The prevalence and the impact of taste, smell, and mouthfeel disturbances on daily life in patients with a gastrointestinal stromal tumor (GIST) are largely unknown. OBJECTIVES: This exploratory study assessed the prevalence and type of taste, smell, and mouthfeel disturbances and their impact on daily life and QoL in patients with a GIST treated with a tyrosine-kinase inhibitor (TKI). METHODS: Patients currently treated with TKIs for GIST completed a standardized questionnaire. The questionnaire addressed changes in taste, smell, and mouthfeel and, if changes occurred, impact on daily life and QoL. Statistics are descriptive. RESULTS: A total of 65 GIST patients on TKI treatment completed the questionnaire. Of these patients, 79%, 12%, and 9% currently used imatinib, sunitinib, and regorafenib respectively. Taste, smell, and mouthfeel disturbances were reported by 25 (38%), 15 (23%), and 36 (55%) patients respectively. Salty and sweet tastes were mostly affected, respectively in 14 and 13 patients. A dry mouth was experienced by 29 (45%) patients. Taste disturbances were more often reported to have impact on daily life and QoL (80% and 60%) than smell (47% and 31%) and mouthfeel disturbances (47% and 30%). CONCLUSION: Taste, smell, and mouthfeel disturbances are frequent side effects of TKIs in GIST patients. Daily life and QoL are affected in a considerable number of those patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NL7827 (2019-06-25)

Rapid development of intestinal cell damage following severe trauma: a prospective observational cohort study

Introduction Loss of intestinal integrity has been implicated as an important contributor to the development of excessive inflammation following severe trauma. Thus far, clinical data concerning the occurrence and significance of intestinal damage after trauma remain scarce. This study investigates whether early intestinal epithelial cell damage occurs in trauma patients and, if present, whether such cell injury is related to shock, injury severity and the subsequent inflammatory response. Methods Prospective observational cohort study in 96 adult trauma patients. Upon arrival at the emergency room (ER) plasma levels of intestinal fatty acid binding protein (i-FABP), a specific marker for damage of differentiated enterocytes, were measured. Factors that potentially influence the development of intestinal cell damage after trauma were determined, including the presence of shock and the extent of abdominal trauma and general injury severity. Furthermore, early plasma levels of i-FABP were related to inflammatory markers interleukin-6 (IL-6), procalcitonin (PCT) and C-reactive protein (CRP). Results Upon arrival at the ER, plasma i-FABP levels were increased compared with healthy volunteers, especially in the presence of shock (P < 0.01). The elevation of i-FABP was related to the extent of abdominal trauma as well as general injury severity (P < 0.05). Circulatory i-FABP concentrations at ER correlated positively with IL-6 and PCT levels at the first day (r2 = 0.19; P < 0.01 and r2 = 0.36; P < 0.001 respectively) and CRP concentrations at the second day after trauma (r2 = 0.25; P < 0.01). Conclusions This study reveals early presence of intestinal epithelial cell damage in trauma patients. The extent of intestinal damage is associated with the presence of shock and injury severity. Early intestinal damage precedes and is related to the subsequent developing inflammatory response

Self-reported taste and smell alterations and the liking of oral nutritional supplements with sensory-adapted flavors in cancer patients receiving systemic antitumor treatment

Purpose Taste and smell alterations (TAs and SAs) are often reported by patients with cancer receiving systemic antitumor therapy and can negatively impact food intake and quality of life. This study aimed to examine the occurrence of TAs and SAs and investigate the impact of TAs on overall liking of oral nutritional supplements (ONS) with warming and cooling sensations. Methods Patients receiving systemic antitumor therapy completed a questionnaire on sensory alterations and evaluated overall liking of 5 prototype flavors of Nutridrink (R) Compact Protein (hot tropical ginger (HTG), hot mango (HM), cool red fruits (CRF), cool lemon (CL), and neutral (N)) on a 10-point scale via a sip test. Differences between patients with and without TAs were investigated using permutation analysis. Results Fifty patients with various cancer types and treatments were included. Thirty patients (60%) reported TAs and 13 (26%) experienced SAs. Three flavors were rated highly with a liking score > 6 (CRF 6.8 +/- 1.7; N 6.5 +/- 1.9; HTG 6.0 +/- 2.0). Larger variation in ONS liking scores was observed in patients with TAs with or without SAs (4.5-6.9 and 4.6-7.2, respectively) vs. patients without TAs (5.9-6.5). TAs were associated with increased liking of CRF (Delta = + 0.9) and N (Delta = + 1.0) flavors. Conclusions TAs and SAs are common in patients with cancer undergoing systemic antitumor therapy. Patients with TAs were more discriminant in liking of ONS flavors compared to patients without TAs, and sensory-adapted flavors appeared to be appreciated. The presence of TAs should be considered when developing or selecting ONS for patients with cancer

Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8+T cells and an infiltration pattern that resembles ulcerative colitis

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn’s disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00428-021-03170-x

The association between the inflammatory response to surgery and postoperative complications in older patients with cancer; a prospective prognostic factor study

BACKGROUND: Accurate prognostic biomarkers would substantially improve surgical planning and decisions making yet no studies have been reported exploring the inflammatory response in surgically treated older patients with cancer. The aim of this study was to explore inflammatory biomarkers as potential prognostic factors for postoperative complications within 30 days in older patients with cancer. METHOD: Patients 65 years and older undergoing surgery for removal of a solid malignant tumour were included in an observational cohort study. All complications occurring up to 30 days postoperatively were documented prospectively. Inflammatory markers were measured in plasma samples pre- and postoperatively: C-reactive protein (CRP), Interleukin-1 beta (IL-1β), IL-6, IL-10, IL-12, and Tumour necrosis factor-alpha (TNF-α). Associations between inflammatory markers and postoperative complications were explored using logistic regression analysis. RESULTS: Between July 2010 and April 2014, plasma samples of 224 patients were collected. Median age was 72 (65-89) years and 116 (51.8%) patients were female. Approximately half of the patients developed postoperative complications (49.6%) of whom 62 patients (55.9%) developed >1 complication. An independent prognostic effect was observed for the inflammatory biomarkers IL-6 and IL-10 for the occurrence of postoperative complications. CONCLUSION: The perioperative inflammatory response is associated with complications, independently from patient and surgical factors which are also associated with outcome. Research is warranted towards further exploration of the perioperative inflammatory response with the aim to improve perioperative care and outcome, and might help to improve surgical planning and decision making for older patients with cancer

Compromised intestinal integrity in older adults during daily activities:a pilot study

Abstract Background Malnutrition is a common and significant problem in older adults. Insight into factors underlying malnutrition is needed to develop strategies that can improve the nutritional status. Compromised intestinal integrity caused by gut wall hypoperfusion due to atherosclerosis of the mesenteric arteries in the aging gastrointestinal tract may adversely affect nutrient uptake. The presence of compromised intestinal integrity in older adults is not known. The aim of this study is to provide a proof-of-concept that intestinal integrity is compromised in older adults during daily activities. Methods Adults aged ≥75 years living independently without previous gastrointestinal disease or abdominal surgery were asked to complete a standardized walking test and to consume a standardized meal directly afterwards to challenge the mesenteric blood flow. Intestinal fatty acid-binding protein (I-FABP) was measured as a plasma marker of intestinal integrity, in blood samples collected before (baseline) and after the walking test, directly after the meal, and every 15 min thereafter to 75 min postprandially. Results Thirty-four participants (median age 81 years; 56% female) were included. Of the participants, 18% were malnourished (PG-SGA score ≥ 4), and 32% were at risk of malnutrition (PG-SGA score, 2 or 3). An I-FABP increase of ≥50% from baseline was considered a meaningful loss of intestinal integrity and was observed in 12 participants (35%; 8 females; median age 80 years). No significant differences were observed in either baseline characteristics, walking test scores, or calorie/macronutrient intake between the groups with and without a ≥ 50% I-FABP peak. Conclusion This study is first to indicate that intestinal integrity is compromised during daily activities in a considerable part of older adults living independently

Patient attitudes towards faecal sampling for gut microbiome studies and clinical care reveal positive engagement and room for improvement

Faecal sample collection is crucial for gut microbiome research and its clinical applications. However, while patients and healthy volunteers are routinely asked to provide stool samples, their attitudes towards sampling remain largely unknown. Here, we investigate the attitudes of 780 Dutch patients, including participants in a large Inflammatory Bowel Disease (IBD) gut microbiome cohort and population controls, in order to identify barriers to sample collection and provide recommendations for gut microbiome researchers and clinicians. We sent questionnaires to 660 IBD patients and 112 patients with other disorders who had previously been approached to participate in gut microbiome studies. We also conducted 478 brief interviews with participants in our general population cohort who had collected stool samples. Statistical analysis of the data was performed using R. 97.4% of respondents reported that they had willingly participated in stool sample collection for gut microbiome research, and most respondents (82.9%) and interviewees (95.6%) indicated willingness to participate again, with their motivations for participating being mainly altruistic (57.0%). Responses indicated that storing stool samples in the home freezer for a prolonged time was the main barrier to participation (52.6%), but clear explanations of the sampling procedures and their purpose increased participant willingness to collect and freeze samples (P = 0.046, P = 0.003). To account for participant concerns, gut microbiome researchers establishing cohorts and clinicians trying new faecal tests should provide clear instructions, explain the rationale behind their protocol, consider providing a small freezer and inform patients about study outcomes. By assessing the attitudes, motives and barriers surrounding participation in faecal sample collection, we provide important information that will contribute to the success of gut microbiome research and its near-future clinical applications