Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance.

Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert; however, animal studies suggest that they may impact the microbiome and downstream glycemic responses. We causally assessed NNS impacts in humans and their microbiomes in a randomized-controlled trial encompassing 120 healthy adults, administered saccharin, sucralose, aspartame, and stevia sachets for 2 weeks in doses lower than the acceptable daily intake, compared with controls receiving sachet-contained vehicle glucose or no supplement. As groups, each administered NNS distinctly altered stool and oral microbiome and plasma metabolome, whereas saccharin and sucralose significantly impaired glycemic responses. Importantly, gnotobiotic mice conventionalized with microbiomes from multiple top and bottom responders of each of the four NNS-supplemented groups featured glycemic responses largely reflecting those noted in respective human donors, which were preempted by distinct microbial signals, as exemplified by sucralose. Collectively, human NNS consumption may induce person-specific, microbiome-dependent glycemic alterations, necessitating future assessment of clinical implications.

Diet Diurnally Regulates Small Intestinal Microbiome-Epithelial-Immune Homeostasis and Enteritis.

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.

Immune-Microbiota Interplay and Colonization Resistance in Infection.

Commensal microbial communities inhabit biological niches in the mammalian host, where they impact the host's physiology through induction of "colonization resistance" against infections by a multitude of molecular mechanisms. These colonization-regulating activities involve microbe-microbe and microbe-host interactions, which induce, through utilization of complex bacterial networks, competition over nutrients, inhibition by antimicrobial peptides, stimulation of the host immune system, and promotion of mucus and intestinal epithelial barrier integrity. Distinct virulent pathogens overcome this colonization resistance and host immunity as part of a hostile takeover of the host niche, leading to clinically overt infection. The following review provides a mechanistic overview of the role of commensal microbes in modulating colonization resistance and pathogenic infections and means by which infectious agents may overcome such inhibition. Last, we outline evidence, unknowns, and challenges in developing strategies to harness this knowledge to treat infections by microbiota transfer, phage therapy, or supplementation by rationally defined bacterial consortia.

Gut microbiota modulates weight gain in mice after discontinued smoke exposure.

Cigarette smoking constitutes a leading global cause of morbidity and preventable death1, and most active smokers report a desire or recent attempt to quit2. Smoking-cessation-induced weight gain (SCWG; 4.5 kg reported to be gained on average per 6-12 months, >10 kg year-1 in 13% of those who stopped smoking3) constitutes a major obstacle to smoking abstinence4, even under stable5,6 or restricted7 caloric intake. Here we use a mouse model to demonstrate that smoking and cessation induce a dysbiotic state that is driven by an intestinal influx of cigarette-smoke-related metabolites. Microbiome depletion induced by treatment with antibiotics prevents SCWG. Conversely, fecal microbiome transplantation from mice previously exposed to cigarette smoke into germ-free mice naive to smoke exposure induces excessive weight gain across diets and mouse strains. Metabolically, microbiome-induced SCWG involves a concerted host and microbiome shunting of dietary choline to dimethylglycine driving increased gut energy harvest, coupled with the depletion of a cross-regulated weight-lowering metabolite, N-acetylglycine, and possibly by the effects of other differentially abundant cigarette-smoke-related metabolites. Dimethylglycine and N-acetylglycine may also modulate weight and associated adipose-tissue immunity under non-smoking conditions. Preliminary observations in a small cross-sectional human cohort support these findings, which calls for larger human trials to establish the relevance of this mechanism in active smokers. Collectively, we uncover a microbiome-dependent orchestration of SCWG that may be exploitable to improve smoking-cessation success and to correct metabolic perturbations even in non-smoking settings.

Bacterial Skin Dysbiosis in Darier Disease.

INTRODUCTION: Darier disease is a rare inherited disease with dominant skin manifestations including keratotic papules and plaques on sebaceous and flexural areas. Secondary infection of skin lesions is common, and Staphylococcus aureus commonly colonizes these lesions. The aim of the study was to characterize the bacterial microbiome of cutaneous Darier lesions compared to normal-looking skin and disease severity. METHODS: All patients with a history of Darier followed up at Emek Medical Center were invited to participate in the study. Patients that did not use antibiotics in the past month and signed informed consent had four skin sites sampled with swabs: scalp, chest, axilla, and palm. All samples were analyzed for bacterial microbiome using 16S rDNA sequencing. RESULTS: Two hundred and eighty microbiome samples obtained from lesional and non-lesional skin of the scalp, chest, axilla, and palm of 42 Darier patients were included in the analysis. The most abundant bacterial genera across all skin sites were Propionibacterium, Corynebacterium, Paracoccus, Micrococcus, and Anaerococcus. Scalp and chest lesions featured a distinct microbiome configuration that was mainly driven by an overabundance of Staphylococci species. Patients with more severe disease exhibited microbiome alterations in the chest, axilla, and palm compared with patients with only mild disease, driven by Peptoniphilus and Moryella genera in scalp and palmar lesions, respectively. CONCLUSION: Staphylococci were significantly associated with Darier lesions and drove Darier-associated dysbiosis. Severity of the disease was associated with two other bacterial genera. Whether these associations also hold a causative role and may serve as a therapeutic target remains to be determined and requires further investigation.

Breakthroughs and Bottlenecks in Microbiome Research.

Over the past 15 years, the research community has witnessed unprecedented progress in microbiome research. We review this increasing knowledge and first attempts of its clinical application, and also limitations and challenges faced by the research community, in mechanistically understanding host-microbiome interactions and integrating these insights into clinical practice.

The Gut Microbiome and Individual-Specific Responses to Diet.

Nutritional content and timing are increasingly appreciated to constitute important human variables collectively impacting all aspects of human physiology and disease. However, person-specific mechanisms driving nutritional impacts on the human host remain incompletely understood, while current dietary recommendations remain empirical and nonpersonalized. Precision nutrition aims to harness individualized bodies of data, including the human gut microbiome, in predicting person-specific physiological responses (such as glycemic responses) to food. With these advances notwithstanding, many unknowns remain, including the long-term efficacy of such interventions in delaying or reversing human metabolic disease, mechanisms driving these dietary effects, and the extent of the contribution of the gut microbiome to these processes. We summarize these conceptual advances, while highlighting challenges and means of addressing them in the next decade of study of precision medicine, toward generation of insights that may help to evolve precision nutrition as an effective future tool in a variety of "multifactorial" human disorders.

Acute liver failure is regulated by MYC- and microbiome-dependent programs.

Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.

Fecal Microbial Transplantation and Its Potential Application in Cardiometabolic Syndrome.

Newly revealed links between inflammation, obesity, and cardiometabolic syndrome have created opportunities to try previously unexplored therapeutic modalities in these common and life-risking disorders. One potential modulator of these complex disorders is the gut microbiome, which was described in recent years to be altered in patients suffering from features of cardiometabolic syndrome and to transmit cardiometabolic phenotypes upon transfer into germ-free mice. As a result, there is great interest in developing new modalities targeting the altered commensal bacteria as a means of treatment for cardiometabolic syndrome. Fecal microbiota transplantation (FMT) is one such modality in which a disease-associated microbiome is replaced by a healthy microbiome configuration. So far clinical use of FMT has been overwhelmingly successful in recurrent Clostridium difficile infection and is being extensively studied in other microbiome-associated pathologies such as cardiometabolic syndrome. This review will focus on the rationale, promises and challenges in FMT utilization in human disease. In particular, it will overview the role of the gut microbiota in cardiometabolic syndrome and the rationale, experience, and prospects of utilizing FMT treatment as a potential preventive and curative treatment of metabolic human disease.

Vaginal microbiome transplantation in women with intractable bacterial vaginosis.

We report the results of a first exploratory study testing the use of vaginal microbiome transplantation (VMT) from healthy donors as a therapeutic alternative for patients suffering from symptomatic, intractable and recurrent bacterial vaginosis (ClinicalTrials.gov NCT02236429 ). In our case series, five patients were treated, and in four of them VMT was associated with full long-term remission until the end of follow-up at 5-21 months after VMT, defined as marked improvement of symptoms, Amsel criteria, microscopic vaginal fluid appearance and reconstitution of a Lactobacillus-dominated vaginal microbiome. One patient presented with incomplete remission in clinical and laboratory features. No adverse effects were observed in any of the five women. Notably, remission in three patients necessitated repeated VMT, including a donor change in one patient, to elicit a long-standing clinical response. The therapeutic efficacy of VMT in women with intractable and recurrent bacterial vaginosis should be further determined in randomized, placebo-controlled clinical trials.

Surgically induced weight loss results in a rapid and consistent improvement of female pelvic floor symptoms.

OBJECTIVE: The aim of this study was to evaluate the effect over time of bariatric surgery on female pelvic floor symptoms. METHODS: In total, 160 consecutive adult women were requested to complete four anonymous questionnaires [International Consultation on Incontinence Questionnaire (ICIQ), Bristol Female Lower Urinary Tract Symptoms (BFLUTS), Pelvic Floor Distress Inventory (PFDI-20) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12)] before bariatric surgery and at 3-6 months and 12-24 months postoperatively. Strict criteria were used to define clinically significant urinary incontinence (UI), pelvic organ prolapse (POP) and colorectal-anal (CRA) symptoms. Statistical analyses were performed using paired, two-sided, Student's t test for continuous data, and Fisher's exact test for categorical data. RESULTS: Altogether, 101 women (67%, mean age 41.6 ± 11.8 years, mean preoperative body mass index 41.6 ± 4.6 kg/m²) completed all questionnaires. In women who had preoperative UI (42.6%), mean ICIQ score decreased from 9.5 ± 4.0 at baseline to 3.0 ± 3.6 (p < .001) and 2.9 ± 3.9 (p < .001) at 3-6 and 12-24 months postoperatively, respectively. In women who had preoperative POP symptoms (17.8%), mean PFDI-20/POP score decreased from 23.8 ± 10.9 at baseline to 12.7 ± 12.9 (p = .010) and 13.7 ± 17.1 (p = .025) at 3-6 and 12-24 months postoperatively. In women who had preoperative CRA symptoms (35.6%), mean PFDI-20/CRA score decreased from 26.0 ± 14.9 at baseline to 15.4 ± 15.1 (p = .001) and 18.8 ± 15.4 (p = .045) at 3-6 and 12-24 months postoperatively. De novo postoperative POP and CRA symptoms were reported by up to 16% of patients. CONCLUSIONS: Surgically induced weight loss is associated with significant improvements in UI, POP and CRA symptoms. The maximal clinical effect was achieved within 3-6 months, and remained constant throughout the second postoperative year. Nevertheless, de novo POP and CRA symptoms are expected in up to 16% of patients.

Effects of Bariatric Surgery on Female Pelvic Floor Disorders.

OBJECTIVE: To assess the effect of weight loss on urinary incontinence (UI), pelvic organ prolapse, colorectal-anal complaints, and sexual dysfunction among obese women undergoing bariatric surgery. MATERIALS AND METHODS: One hundred sixty consecutive women who underwent bariatric surgery were prospectively enrolled. Four validated questionnaires (International Consultation on Incontinence Questionnaire-UI [ICIQ-UI], Bristol Female Lower Urinary Tract Symptoms-SF [BFLUTS-SF], Pelvic Floor Distress Inventory-20 [PFDI-20], and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 [PISQ-12]) were used to evaluate pelvic floor disorders and sexual dysfunction before and 3-6 months after surgery. RESULTS: One hundred fifty participants (mean age: 43 ± 12.8 years; mean preoperative body mass index: 42 ± 4.6 kg/m2) completed all pre- and postoperative questionnaires. Preoperatively, 56 (37.3%) women had UI, 44 (29.3%) women had pelvic organ prolapse symptoms, and 66 (44%) women had colorectal-anal symptoms. Overall, surgically induced weight loss was associated with statistically significant improvement in UI (mean ICIQ score: 9.3 ± 3.9 vs 3.3 ± 3.8, P <.001), pelvic organ prolapse symptoms (mean PFDI score: 19 ± 13.2 vs 11 ± 12.8, P <.001), and colorectal-anal symptoms (mean PFDI score: 21 ± 15.9 vs 14 ± 14.9, P = .004). Moreover, half of preoperatively incontinent women and more than one quarter of women who had either pelvic organ prolapse or colorectal-anal symptoms reported complete resolution of their symptoms. Statistically significant improvement in sexual function was suggested by both BFLUTS-SF (0.3 ± 0.8 vs 0.1 ± 0.6; P = .011) and PISQ-12 (37.9 ± 6.1 vs 39.5 ± 5; P = .003) questionnaires. CONCLUSION: Surgically induced weight loss was associated with a significant improvement in pelvic floor disorders, including UI, pelvic organ prolapse, and colorectal-anal symptoms, as well as improved sexual performance.