Modulation Of Microbiome Research Articles

Emerging Therapeutics Targeting Cellular Stress Pathways to Mitigate End-Organ Damage in Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency and impaired glucose regulation. While daily insulin therapy is life-saving, many patients struggle to achieve optimal glycemic control, leading to microvascular complications affecting various organs, including the kidneys and the liver. This review aims to summarize the current state of knowledge regarding the pathogenesis of hepatic and renal complications in T1D, highlight recent advances in potential therapeutic targets, and provide evidence-based recommendations for mitigating end-organ damage. Chronic hyperglycemia drives diabetic complications through several interrelated mechanisms, including increased polyol pathway flux, advanced glycation end-product (AGE) formation, protein kinase C activation, and mitochondrial reactive oxygen species overproduction. In the liver, these processes contribute to non-alcoholic fatty liver disease, with up to 50% of T1D patients developing hepatic steatosis. Diabetic nephropathy, affecting 25%–40% of long-term T1D patients, is characterized by glomerular basement membrane thickening, mesangial expansion, and tubulointerstitial fibrosis. Recent innovations in T1D management include genomics and precision medicine approaches, gut microbiome modulation, nanomedicine, and artificial intelligence-driven glucose monitoring systems. Emerging immunotherapies aim to fundamentally modify the autoimmune response in T1D. Mitigating T1D complications requires intensive glycemic control, targeted pharmacotherapy, and lifestyle modifications. Emerging therapies and precision medicine approaches offer promising avenues. Ongoing research into molecular mechanisms remains crucial for developing novel interventions and improving long-term outcomes in T1D patients.

Comprehensive insights into berberine's hypoglycemic mechanisms: A focus on ileocecal microbiome in db/db mice

The efficacy of berberine in managing diabetes through modulation of gut microbiome has been established through fecal sample analyses. However, relying solely on fecal materials constrains our comprehension of berberine's effects on diverse gastrointestinal locations. This study specifically explores the ileocecal region, a segment characterized by higher microbial diversity than fecal samples. Berberine exhibits a robust hypoglycemic impact by significantly reducing glucose levels in blood and urine. Beyond glycemic control, berberine ameliorates various diabetes-related symptoms in serum, including increased insulin and leptin, but decreased NEFA and MDA. Notably, berberine demonstrates liver-protective functions by alleviating oxidative stress and enhancing hepatic glycogen abundance. These outcomes prompted a high-throughput sequencing analysis of the ileocecal microbiome, revealing an augmentation of beneficial bacterial genera (four genera in the Lachnospiraceae family, Erysipelatoclostridium, and Escherichia-Shigella), along with a reduction in harmful bacterial genera (Romboutsia). Additionally, we predicted the impact of the ileocecal microbiome on clinically relevant factors associated with diabetes. These findings elucidate the multi-pathway mechanisms of berberine in treating T2D, underscoring its potential as a natural anti-diabetic agent or functional food, particularly through the modulation of the gut microbiota.

Modulation of Gut Microbiome and Autism Symptoms of ASD Children Supplemented with Biological Response Modifier: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study.

The etiology and mechanisms of autism and autism spectrum disorder (ASD) are not yet fully understood. There is currently no treatment for ASD for providing significant improvement in core symptoms. Recent studies suggest, however, that ASD is associated with gut dysbiosis, indicating that modulation of gut microbiota in children with ASD may thus reduce the manifestation of ASD symptoms. The aim of this pilot study (prospective randomized, double-blinded, placebo-controlled) was to evaluate efficacy of the biological response modifier Juvenil in modulating the microbiome of children with ASD and, in particular, whether Juvenil is able to alleviate the symptoms of ASD. In total, 20 children with ASD and 12 neurotypical children were included in our study. Supplementation of ASD children lasted for three months. To confirm Juvenil's impact on the gut microbiome, stool samples were collected from all children and the microbiome's composition was analyzed. This pilot study demonstrated that the gut microbiome of ASD children differed significantly from that of healthy controls and was converted by Juvenil supplementation toward a more neurotypical microbiome that positively modulated children's autism symptoms.

Gut microbiome composition and functionality impact the responsiveness to a dairy-based product containing galacto-oligosaccharides for improving sleep quality in adults.

Sleep quality and duration can be impacted by diet, and has been linked to gut microbiota composition and function as the result of communication via the microbiota-gut-brain axis. As one strategy to improve sleep quality could be through the modulation of the gut microbiome, we assessed the effects of a dairy-based product containing whey protein, galacto-oligosaccharides, tryptophan, vitamins and minerals after a 3 weeks intervention on gut microbiota composition and (gut-brain related) functions on basis of 67 healthy subjects with moderate sleep disturbances. Associations of the gut microbiota with sleep quality and with response/non-response to the treatment were revealed by shotgun metagenomics sequencing of faecal DNA samples, and subsequent analyses of microbiota taxonomy and generic functionality. A database of manually curated Gut-Brain Modules (GBMs) was applied to analyse specific microbial functions/pathways that have the potential to interact with the brain. A moderate discriminating effect of the DP treatment on gut microbiota composition was revealed which could be mainly attributed to a decrease in Pseudomonas resinovorans, Flintibacter sp. KGM00164, Intestinimonas butyriciproducens, and Flavonifractor plautii. As interindividual variance in microbiota composition could have given rise to a heterogenous responsiveness of the subjects in the intervention group, we zoomed in on the differences between responders and non-responders. A significant difference in baseline microbiota composition between responders and non-responders was apparent, showing lower Bifidobacterium longum and Bifidobacterium adolescentis, and higher Faecalibacterium prausnitzii relative abundances in responders. The findings provide leads with respect to the effectiveness and potential underlying mechanisms of mode of action in sleep improvement that could support future nutritional interventions to aid sleep improvement.

(129) WOMEN WHO REPORT PAIN WITH SEX HAVE VARYING MICROBIOME PROFILES BASED ON AGE

Abstract Introduction Even though the vaginal microbiome (VM) is a known contributor to vaginal epithelial health, the VM of women who report pain with sex has not been characterized. It is known that the VM shifts during menopause, therefore we segmented out analysis based on menopausal status. Objective An observational analysis comparing the vaginal microbiome composition and symptom profiles in individuals of both menopausal and reproductive age who experience moderate to severe pain with sex and those that do not report pain with sex. Methods This study involved the collection of self-reported health profiles and shotgun metagenomic analysis of vaginal samples from two distinct demographic groups: menopausal women and women of reproductive age (defined as non-pregnant, non-menopausal, and aged under 40 years). The focus was on identifying the microbial composition in individuals experiencing moderate to severe sexual intercourse pain and those without any reported pain, excluding samples from individuals with mild pain. An additional criterion for inclusion was a reported history of sexual activity within the preceding 30 days. The menopausal group comprised 157 individuals reporting pain and 367 individuals without pain. In the reproductive age cohort, there were 968 participants with pain and 968 age-matched controls without pain. Statistical analysis between the pain and control groups in both cohorts revealed no significant differences in body mass index (BMI, menopause p = 0.74, reproductive p = 0.19), reported hormone use (menopause p = 0.2, reproductive p = 0.24), or history of previous infections (menopause p = 0.29, reproductive p = 0.09). Results In both the menopausal and reproductive-aged cohorts, individuals experiencing pain during sexual intercourse exhibited a higher prevalence of symptomatic conditions, as illustrated in Figure 1 A & B. Reported symptoms included increased severity of burning, itchiness, vaginal and vulvar pain, erythema, dysuria, and vaginal dryness. A significant correlation was observed between these enhanced symptomatology and variations in vaginal microbiome compositions among the menopausal group, as depicted in Figure 2 A & B. Specifically, pain during sexual intercourse in menopausal women was linked to elevated vaginal microbiota (VM) diversity (p=0.047) and a reduction in lactobacilli levels (p=0.06). Conversely, in the reproductive-aged cohort, a higher VM diversity was noted in the control group (p=0.014), with no significant differences in Lactobacillus or Gardnerella concentrations between those experiencing pain and the control group. Conclusions Preliminary examination of the vaginal microbiome in women who self-report moderate to severe pain with sex reveals significant differences, particularly in menopausal women experiencing pain. These individuals exhibited a more diverse vaginal microbiome and lower levels of Lactobacillus. This study underscores the need for further research to explore the potential of targeted microbiome modifications as a therapeutic approach to alleviate pain symptoms in this demographic. Disclosure Yes, this is sponsored by industry/sponsor: Evvy. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Evvy.

Unraveling colorectal cancer prevention: The vitamin D - gut flora - immune system nexus.

Colorectal cancer (CRC) is one of the most common cancers diagnosed in the world. Although environmental and genetic factors play a major role in the pathogenesis of CRC, extensive research has suggested that vitamin D may play a pivotal role in the development of CRC. Vitamin D, primarily obtained through sunlight exposure, dietary sources, and supplements, has long been recognized for its essential functions in maintaining health, including immune regulation. This article delves into the intricate relationship between vitamin D, the immune system, gut flora, and the prevention of CRC. It presents a synthesis of epidemiological data, experimental studies, and clinical trials, highlighting the mechanisms by which vitamin D influences immune cell function, cytokine production, and inflammation. By enhancing the immune system's surveillance and anti-tumor activity, vitamin D may offer a promising avenue for CRC prevention. Furthermore, this comprehensive review delves into the prospective clinical applications of vitamin D supplementation and delineates the forthcoming avenues of research in this dynamic domain. Additionally, the paper tentatively outlines a spectrum of prophylactic impacts of vitamin D on CRC, emphasizing its significant potential in reducing CRC risk through shedding light on its mechanisms, encompassing antineoplastic mechanisms, influences on the immune system, and modulation of the gut microbiome.

Therapeutic microbiome modulation: new frontiers in HIV treatment.

Dysbiosis may be a key driver of systemic inflammation, which increases the risk of non-AIDS events in people living with HIV (PLWH). Modulation of the microbiome to reverse this dysbiosis may be a novel approach to decrease inflammation and therefore morbidity and mortality in PLWH. Fecal microbiota transplantation (FMT), probiotics, prebiotics, synbiotics, postbiotics, and dietary modifications have the potential to modulate the microbiome. These interventions have been well tolerated in clinical trials to date. However, these interventions have not resulted in consistent or lasting changes to the microbiome or consistent changes in biomarkers of intestinal permeability, microbial translocation, inflammation, immune activation, or CD4 + T cell counts. Sustained engraftment may require prebiotics and/or dietary modifications added to either probiotics or FMT. Adequately powered randomized controlled trials are needed to elucidate whether microbiome modulation can be achieved and impact systemic inflammation in PLWH.

Unravelling the Microbiome's Role in Healing Diabetic Wounds.

The process of wound healing is intricate and requires close coordination; any disruption to this process can have catastrophic results. It is hypothesized that chronic wounds that do not heal or that cease healing entirely can be caused by a combination of host factors and bacteria that are present in a wound bed or wound bed environment. There is currently a lack of understanding regarding the role that the cutaneous microbiome plays in the healing process of wounds, despite the fact that methods that do not rely on culture have revealed the role that the gut microbiome plays in human health and illness. In order to keep the host immune system in check, protect the epithelial barrier function, and ward off harmful microbes, skin commensals play a crucial role. This review compiles the research on the effects of microbiome modifications on wound healing and tissue regeneration from both clinical and pre-clinical investigations on a variety of chronic skin wounds. It is now clear that human skin commensals, symbionts, and pathogens all play a part in the inflammatory response, which in turn suggests a number of ways to treat wounds that are infected and not healing. To fully understand the function of the human skin microbiome in both short-term and long-term wound healing, additional study is required to reconcile the conflicting and contentious results of previous investigations.

Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury.

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome

AimsPrecocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut–brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional). Materials and methodsIn the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk. Key findingsGlycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39–0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic–pituitary–gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations. SignificanceOur findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.

Legume-supplemented feed for children hospitalised with severe malnutrition: a phase II trial.

Children hospitalised with severe malnutrition have high mortality and readmission rates post-discharge. Current milk-based formulations target restoring ponderal growth but not the modification of gut barrier integrity or microbiome which increases the risk of gram-negative sepsis and poor outcomes. We propose that legume-based feeds rich in fermentable carbohydrates will promote better gut health and improve overall outcomes. We conducted an open-label phase II trial at Mbale and Soroti Regional Referral Hospitals, Uganda, involving 160 children aged 6 months to 5 years with severe malnutrition (mid-upper arm circumference (MUAC) < 11·5 cm and/or nutritional oedema). Children were randomised to a lactose-free, chickpea-enriched legume paste feed (LF) (n 80) v. WHO standard F75/F100 feeds (n 80). Co-primary outcomes were change in MUAC and mortality to day 90. Secondary outcomes included weight gain (> 5 g/kg/d), de novo development of diarrhoea, time to diarrhoea and oedema resolution. Day 90 MUAC increase was marginally lower in LF v. WHO arm (1·1 cm (interquartile range (IQR) 1·1) v. 1·4 cm (IQR 1·40), P = 0·09); day 90 mortality was similar (11/80 (13·8 %) v. 12/80 (15 %), respectively, OR 0·91 (95 % CI 0·40, 2·07), P = 0·83). There were no differences in any of the other secondary outcomes. Owing to initial poor palatability of the LF, ten children switched to WHO feeds. Per-protocol analysis indicated a trend to lower day 90 mortality and readmission rates in the LF (6/60 (10 %) and 2/60(3 %)) v. WHO feeds (12/71(17·5 %) and 4/71(6 %)). Further refinement of LF and clinical trials are warranted, given the poor outcomes in children with severe malnutrition.

Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).

TPS9607 Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .

Analyzing the gut microbiome in adolescent and young adult patients with melanoma receiving immune checkpoint blockade.

9563 Background: Melanoma is the third most common cancer in adolescent and young adults (AYA), a unique cohort defined as patients between 15-39 years of age per the National Cancer Institute. Immune checkpoint inhibitors (ICI) have changed the landscape for advanced melanoma treatment, and the gut microbiota has been shown to remodel the tumor microenvironment to improve ICI efficacy. There is a paucity of research in this cohort, however studies show that AYA patients, in general, have historically not seen the same survival gains as other age groups. Furthermore, literature shows that survival was much worse for AYA's with stage IV melanoma than observed among older adults. Methods: The AYA cohort in this retrospective review is from the 2021 Science publication entitled "Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response". This cohort was matched on a 2:1 basis with older non-AYA patients 50-70 years of age. We controlled for sex, BMI, race, treatment naivety, stage of disease, as well as smoking, drug, and alcohol status. Results: Our AYA cohort of 23 patients is comprised of 15 females, 22 Caucasians, 20 with primary cutaneous melanoma, 12 with stage III at the start of treatment and 11 with stage IV, 17 were BRAF positive, 8 received combined immunotherapy, 20 were treatment naïve, and 11 were responders. We found no difference in alpha or beta diversity in AYA and older non-AYA patients, however alpha diversity increased with age. This is consistent with literature regarding aging gut microbiomes. Furthermore, we noted the most common microbes found between these groups varied considerably. Using differential analyses, we found, for example, a higher abundance of Ruminococcaceae, at the family level, in older non-AYA patients and a higher abundance of Bacteroides stercoris in AYA patients. Literature shows the relative abundance of Ruminococcaceae increased with age and was significantly higher in older patients. Furthermore, Bacteroides stercoris correlates positively with fiber, grain, and vegetable intake. Additionally, Blautia massiliensia, Blautia obeum, and Dorea longicatena were found to be significantly more prevalent (p=0.010, p=0.34, and p=0.035, respectively)) in older non-AYA patients. These species are all known to be obesity biomarkers. Conclusions: We found that the gut microbiota of AYA and older non-AYA melanoma patients differ. Older non-AYA patients have bacterial species associated with negative biomarkers which may be due to an aging gut microbiome. Establishing microbial features in the AYA population can help with microbiome modulation as a therapeutic strategy. Enriching modalities include fecal microbiota transplantation, probiotics, and improving diet as well as fiber intake. Further research should explore if the gut microbiome influences worse outcomes in AYA's with late stage melanoma.

Associations between specific dietary patterns, gut microbiome composition, and incident subthreshold depression in Chinese young adults

IntroductionThe interplay between influential factors and the incidence of subthreshold depression (SD) in young adults remains poorly understood. ObjectivesThis study sought to understand the dietary habits, gut microbiota composition, etc. among individuals with SD in young adults and to investigate their association with SD occurrence. MethodsEmploying a cross-sectional approach, 178 individuals with SD, aged 18–32 years, were matched with 114 healthy counterparts. SD status was evaluated using the Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Beck Depression Inventory 2nd version (BDI-II), the 17-item Hamilton Rating Scales of Depression (HAMD-17), and Pittsburgh Sleep Quality Index (PSQI). Metagenomic sequencing was utilized to identify fecal microbial profiles. Dietary patterns were discerned via factor analysis of a 25-item food frequency questionnaire (FFQ). Logistic regression analysis and mediation analysis were performed to explore the potential links between gut microbiota, dietary patterns, and incident SD. ResultsData on dietary habits were available for 292 participants (mean [SD] age, 22.1 [2.9] years; 216 [73.9 %] female). Logistic regression analysis revealed that dietary patterns Ⅰ (odds ratio [OR], 0.34; 95 % CI, 0.15–0.75) and IV (OR, 0.39; 95 % CI, 0.17–0.86 and OR, 0.39; 95 % CI, 0.18–0.84) were associated with reduced risk of SD. Distinct microbial profiles were observed in young adults with SD, marked by increased microbial diversity and taxonomic alterations. Moreover, mediation analysis suggested Veillonella atypica as a potential mediator linking SDS or BDI-II scores with a healthy dietary pattern rich in bean products, coarse grains, nuts, fruits, mushrooms, and potatoes (β = 0.25, 95 % CI: 0.02–0.78 and β = 0.18, 95 % CI: 0.01–0.54). ConclusionsOur findings highlight the complex interplay between dietary patterns, gut microbiota, and the risk of developing SD in young adults, underscoring the potential for dietary interventions and microbiome modulation in mental health promotion.

Plant-based milk alleviates antibiotics-induced intestinal barrier damage associated with modulation of gut microbiome and metabolome

Plant-based milk alleviates antibiotics-induced intestinal barrier damage associated with modulation of gut microbiome and metabolome

Phase I/II trial of healthy donor fecal microbiota transplant (hdFMT) in PD-1 relapsed/refractory (R/R) non-small cell lung cancer (NSCLC).

TPS8648 Background: A significant portion of patients (pts) with advanced NSCLC either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy administered alone or in combination with platinum chemotherapy. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1. In mice, gut microbiota modulate therapeutic activity of anti-PD-1 ICI, and administration of gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key bacterial species are associated with favorable response, although limited concordance among the identified species has been reported across studies. We and others have previously demonstrated that microbiome modulation reversed anti-PD-1 resistance in anti-PD-1 R/R melanoma, and augmented benefit of anti-PD-1 monotherapy in ICI-naïve melanoma. We hypothesize that intestinal dysbiosis mediates anti-PD-1 resistance in anti-PD-1 R/R NSCLC, and that hdFMT may resensitize NSCLC to PD-1 blockade. Methods: This is an investigator-initiated, phase II trial of hdFMT with pembrolizumab (P) in pts with R/R NSCLC progressed on prior anti-PD-1 based therapy alone or in combination with platinum chemotherapy. Pts must have measurable disease per RECIST v1.1, no untreated CNS metastases, and no contraindications to FMT administration. hdFMT is derived from non-obese, healthy, adults aged ≥18 to &lt;70, with no chronic diseases, and no recent antibiotic exposure. Donors are screened broadly for transmissible agents including SARS-CoV-2 using bookend screening. hdFMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts receive P 200mg every 3 weeks (Q3W). hdFMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo tumor biopsies at baseline and at W8, with optional post-progression biopsy. Primary endpoint: overall response rate (ORR) assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 5% will be tested versus a 1-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design (type I error 0.04, power 0.9, when true response rate is 0.25). PFS and OS will be estimated via Kaplan-Meier method. Enrollment has commenced. Clinical trial information: NCT05669846 .

Bacteriophages Therapy: Exploring Their Promising Role in Microbiome Modulation and Combatting Antibiotic Resistance

Bacteriophages, or phages, are viruses that infect bacteria, exhibiting specificity towards particular bacterial strains. Despite being overshadowed by traditional antibiotics in the West, interest in phage therapy has resurged due to the escalating antimicrobial resistance crisis. Understanding phage biology, selection, production, and pharmacology is crucial for their clinical application. Phages interact intricately with the human microbiome, influencing bacterial populations and potentially offering therapeutic avenues for microbiome-related diseases. Moreover, phages present a promising alternative to combat antibiotic resistance, leveraging their specificity and evolutionary adaptability. Regulatory approval and standardization challenges persist, yet ongoing research underscores the potential of phage therapy in clinical medicine.

Microbiome Modulation in Acne Patients and Clinical Correlations.

The imbalance of skin microbiota in acne can induce changes leading to induction or to aggravation of chronic inflammatory lesions; complex mechanisms are involved. Cutibacterium acnes (C. acnes) ribotypes RT4 and RT5 express more biofilm and are associated with inflammatory acne lesions. C. acnes RT6 is a non-acne ribotype, beneficial for the skin. In an open clinical trial, acne adults were included and assessed clinically at baseline and at month 2 using the Investigator Global Assessment of Acne (IGA) score. A topical emulsion was applied twice daily for 2 months (M2) in each included patient. In the same series of acne patients, skin swab samples were collected from acne patients at baseline and M2 from lesional and non-lesional skin; skin swabs were collected for the metagenomic long-read analysis of microbiota. Acne patients with a gravity score IGA of >1<3 were included in this pilot study. An emulsion of O/W formulated with vegetal extract of Umbelliferae associated with a polysaccharide at 1% was applied twice daily for 2 months. At baseline and M2 clinical assessments were made; skin swab samples were also taken for microbiota analysis from lesional and non-lesional skin in each included patient. Extractions of genomic DNA (gDNA) from swab samples from baseline and from M2 were made, followed by full-length (V1-V9) amplification of the 16S rDNA and sequencing of amplicon libraries for strain-level bacterial community profiling. In a series of 32 adult acne patients, the mean initial IGA scale was 3.1; at M2 the IGA scale was 1.5 (p < 0.001). The mean decrease in acne lesions was by 63%. Microbiome metagenomic long-read analysis in these series was mainly dominated by C. acnes followed by Staphylococcus epidermidis (S. epidermidis). The density of C. acnes ribotypes RT6 (non-acne strain) was increased at M2 compared to baseline and the density of ribotypes C. acnes RT1 to RT5 was decreased at M2, compared to baseline (p < 0.0001). S. epidermidis ribotypes (1 to 36) were non significantly increased at M2, compared to baseline (p < 0.1). In a series of 32 acne patients that applied an emulsion based on vegetal extract of Umbelliferae and a polysaccharide at 1% twice daily, a significant clinical improvement in IGA scale for acne lesions was seen at M2, compared to baseline (p < 0.0001). The clinical improvement was correlated with an improvement in skin microbiome at M2 compared to baseline, indicated by the increase in the relative abundance of non-acne strain of C. acnes ribotype 6 and of the decrease in the relative abundance of acne strains ribotypes C. acnes RT1 to RT5.

#2683 Targeted antibiotic modulation of the gut microbiome ameliorates hypertensive kidney damage

Abstract Background and Aims High blood pressure is associated with measurable inflammation, which precedes and promotes damage to the heart and kidneys. Microbiome-derived metabolites, particularly indole metabolites, modulate inflammation and host physiology, partially through aryl hydrocarbon receptor (AhR) signaling. To better understand the potential of a microbiome-targeting therapeutic approach to achieve organ protection in hypertension, we used narrow-spectrum antibiotics without enteral absorption to specifically deplete gram-negative or -positive bacteria in double transgenic rats (dTGR). Method Four-week-old dTGR (transgenic for human renin and angiotensinogen) were treated with oral Vancomycin (Vanco), Polymyxin B (Poly) or Vehicle (Veh) for 3 weeks. Seven-week-old SD rats were included as healthy controls. Microbiome, clinical and immune phenotype were analyzed by shotgun metagenomic sequencing, echocardiography, telemetric blood pressure (BP) measurement, clinical chemistry, bulk RNAseq and flow cytometry. Results Hypertensive kidney damage was ameliorated in Vanco treated dTGR, as assessed by renal Lcn2 expression, blood urea nitrogen and albuminuria. Vanco treated dTGR had significantly decreased cardiac hypertrophy. Poly treatment showed no effect. BP levels for both antibiotic treatments were not significantly different from Veh, despite a significantly improved endothelium-dependent and -independent vasorelaxation in isolated mesenteric arteries in both treated groups. Surprisingly, Vanco treatment led to a massive increase of gram-positive Lactobacilli and associated gene abundance for the production of indole lactic acid (ILA, via araT). We could previously show that ILA inhibits differentiation of pathological Th17 cells through AhR modulation. In line, Vanco treatment reduced the increased number of pathological Th17 in the kidney and intestine of dTGR. Poly treatment did not alter the inflammatory signature. Conclusion Modulation of the intestinal microbiome by narrow-spectrum antibiotics affects hypertensive organ damage. Our data underscores the importance of the gut microbiome in modulating hypertensive organ damage and helps to identify potential therapeutic strategies in the microbiome. Ongoing experiments investigate pro- and postbiotic therapeutic approaches and their AhR dependency.

Serum-Derived Bovine Immunoglobulin Promotes Barrier Integrity and Lowers Inflammation for 24 Human Adults Ex Vivo.

Serum-derived bovine immunoglobulin (SBI) prevents translocation and inflammation via direct binding of microbial components. Recently, SBI also displayed potential benefits through gut microbiome modulation. To confirm and expand upon these preliminary findings, SBI digestion and colonic fermentation were investigated using the clinically predictive ex vivo SIFR® technology (for 24 human adults) that was, for the first time, combined with host cells (epithelial/immune (Caco-2/THP-1) cells). SBI (human equivalent dose (HED) = 2 and 5 g/day) and the reference prebiotic inulin (IN; HED = 2 g/day) significantly promoted gut barrier integrity and did so more profoundly than a dietary protein (DP), especially upon LPS-induced inflammation. SBI also specifically lowered inflammatory markers (TNF-α and CXCL10). SBI and IN both enhanced SCFA (acetate/propionate/butyrate) via specific gut microbes, while SBI specifically stimulated valerate/bCFA and indole-3-propionic acid (health-promoting tryptophan metabolite). Finally, owing to the high-powered cohort (n = 24), treatment effects could be stratified based on initial microbiota composition: IN exclusively stimulated (acetate/non-gas producing) Bifidobacteriaceae for subjects classifying as Bacteroides/Firmicutes-enterotype donors, coinciding with high acetate/low gas production and thus likely better tolerability of IN. Altogether, this study strongly suggests gut microbiome modulation as a mechanism by which SBI promotes health. Moreover, the SIFR® technology was shown to be a powerful tool to stratify treatment responses and support future personalized nutrition approaches.