Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal ...studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background and Aims
It remains unclear to what extent and which components of advanced liver disease improve after bariatric surgery. We herein describe the histological outcome in patients with ...advanced NASH and its relationship with weight loss and metabolic improvement.
Approach and Results
One hundred ninety‐six patients with advanced NASH underwent bariatric surgery, 66 of whom agreed to a follow‐up liver biopsy at 6 ± 3 years (36 with advanced fibrosis AF and 30 with high activity HA grade without AF). Liver biopsies LBs were centrally read and histological response was defined as the disappearance of AF or HA. Bariatric surgery induced major histological improvement: 29% of patients had normal histology at follow‐up biopsy; 74% had NASH resolution without fibrosis progression; and 70% had ≥1 stage fibrosis regression. However, AF persisted in 47% of patients despite NASH resolution and some degree of fibrosis reversal, only evidenced by the EPoS seven‐tier staging classification. These patients had lower weight loss and reduced hypertension or diabetes remission rates. Older age and sleeve gastrectomy were the only independent predictors for persistent AF after adjustment for duration of follow‐up. All HA patients had major histological improvement: 50% normal histology, 80% NASH resolution, and 86% a ≥1 grade steatosis reduction. Patients with normal liver at follow‐up had the largest weight loss and metabolic improvement. Independent predictors of normal liver were amount of weight loss, high histological activity, and the absence of AF before surgery.
Conclusions
Although bariatric surgery successfully reverses active steatohepatitis, AF can persist for many years and is associated with lesser weight loss and metabolic improvement. Weight loss alone may not be sufficient to reverse AF.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cardiometabolic diseases (CMDs) have been associated with changes in the composition of the gut microbiota, with links between the host environment and microbiota identified in preclinical models. ...High-throughput sequencing technology has facilitated in-depth studies of the gut microbiota, bacterial-derived metabolites, and their association with CMDs. Such strategies have shown that patients with CMDs frequently exhibit enrichment or depletion of certain bacterial groups in their resident microbiota compared to healthy individuals. Furthermore, the ability to transfer resident gut microbiota from mice or humans into germ-free mouse models, or between human patients, has enabled researchers to characterize the causative role of the gut microbiota in CMDs. These approaches have helped identify that dietary intake of choline, which is metabolized by the gut microbiota, is associated with cardiovascular outcomes in mice and humans. Trimethylamine N-oxide (TMAO) - a metabolite derived from the gut microbiota - is also associated with poor cardiovascular outcomes in patients with cardiovascular disease and is elevated in patients with chronic kidney disease (CKD). TMAO might represent a biomarker that links the environment and microbiota with CKD. This Review summarizes data suggesting a link between the gut microbiota and derived metabolites with food intake patterns, metabolic alterations, and chronic CMDs.
Purpose of Review
The aim of this review is to summarize the current data available on the metabolic effects of fecal microbiota transplantation (FMT) including obesity and glucose metabolism in ...humans.
Recent Findings
Gut microbiota dysbiosis is a frequent characteristic observed in obesity and related metabolic diseases. Pieces of evidence mostly generated in mouse models suggest that rescuing this dysbiosis associates with improved metabolism. In humans, dietary or bariatric surgery interventions are often accompanied by complete or partial restoration of this dysbiosis together with weight reduction and metabolic amelioration. FMT is an interesting option to modify gut microbiota and has been associated with improved clinical outcomes, albeit only used in routine care for
Clostridium difficile
infection. However, there are only limited data on using FMT in the metabolic context.
Summary
FMT from lean donors significantly improves insulin sensitivity in obese subjects with metabolic syndrome. However, there is a wide range of clinical responses. Interestingly in subjects with high microbial gene richness at baseline and when FMT donors that are metabolically compromised are used, no metabolic improvement is seen. Moreover, more studies evaluating the effect of FMT in patients with overt type 2 diabetes are warranted. Furthermore, interventions (in the receiver prior to FMT) aiming to enhance FMT response also need evaluation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim/hypothesis
Altered adipose tissue secretory profile contributes to insulin resistance and type 2 diabetes in obesity. Preclinical studies have identified senescent cells as a cellular source of ...proinflammatory factors in adipose tissue of obese mice. In humans, potential links with obesity comorbidities are poorly defined. Here, we investigated adipose tissue senescent status and relationships with metabolic complications in human obesity.
Methods
The study includes a prospective cohort of 227 individuals with severe obesity. A photometric method was used to quantify senescence-associated β-galactosidase (SA-β-gal) activity in paired subcutaneous and omental adipose tissue biopsies obtained during gastric surgery. Gene and secretory profiling was performed in adipose tissue biopsies and in human primary pre-adipocytes in the presence or absence of senolytic drugs targeting senescent cells. Participants were phenotyped for anthropometric and bioclinical variables, metabolic complications and gastric surgery-induced improvement to address relationships with adipose tissue SA-β-gal.
Results
SA-β-gal activity was sevenfold higher in subcutaneous than in omental adipose tissue and not associated with BMI or chronological age. Several factors, including insulin-like growth factor binding protein 3 (IGFBP3), plasminogen activator inhibitor 1 (PAI1), C–C motif chemokine ligand 2 (CCL2) and IL-6, were upregulated in subcutaneous adipose tissue in relation with SA-β-gal (
p
for linear trend across tertiles <0.05) and in pre-adipocytes cultured with inflammatory macrophage conditioned media. Senolytic treatment reduced SA-β-gal staining and normalised these alterations. In the whole population, subcutaneous adipose tissue SA-β-gal activity was positively associated with serum leptin, markers of insulin resistance and increased trunk fat mass. Metabolic complications, including type 2 diabetes and dyslipidaemia, were more prevalent in patients with high levels of SA-β-gal, but improved with bariatric surgery whatever the initial adipose tissue senescent status.
Conclusions/interpretation
This study highlights a phenotype of senescence in adipose tissue of severely obese individuals, which characterises prominently subcutaneous fat depots. Subcutaneous adipose tissue senescence is significantly linked to altered glucose metabolism and body fat distribution. Elimination of senescent cells through senolytic treatment could alleviate metabolic complications in severely obese people.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although food marketing is often accused of increasing population obesity, the relationship between individual responsiveness to marketing and obesity has yet to be established: Are people with ...obesity more responsive to food marketing and, if so, is it a stable trait or can it be reversed by bariatric surgery? We studied the responses to three common marketing tactics that frame foods and portions as healthier than they really are in three groups of women: (a) a group of patients with obesity before, 3 months, and 12 months after bariatric surgery, (b) a control group of lean women, and (c) another control group of women with obesity but not seeking any treatment for their obesity. People with obesity were initially more responsive to food marketing, but bariatric surgery reduced their responsiveness down to the level of lean people. In addition to documenting another potential psychological consequence of bariatric surgery, our study suggests that the higher responsiveness of people with obesity is not a stable individual predisposition and supports the notion of a reciprocal relationship between obesity and sensitivity to environmental influences.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The gut microbiota is recognized to have an important role in energy storage and the subsequent development of obesity. To date, bariatric surgery (indicated for severe obesity) represents the only ...treatment that enables substantial and sustained weight loss. Bariatric surgery is also a good model to study not only the pathophysiology of obesity and its related diseases but also the mechanisms involved in their improvement after weight reduction. Scarce data from humans and animal models have demonstrated that gut microbiota composition is modified after Roux-en-Y gastric bypass (RYGB), suggesting that weight reduction could affect gut microbiota composition. However, weight loss might not be the only factor responsible for those modifications. Indeed, bariatric surgery not only improves hormonal and inflammatory status, but also induces numerous changes in the digestive tract that might account for the observed modifications of microbiota ecology. In future bariatric surgery studies in humans or mice, these major surgery-induced modifications will need to be taken into account when analyzing the link between gut microbiota composition, obesity, its complications and their improvement after bariatric surgery. This Review outlines the potential mechanisms by which the major changes in the digestive tract after bariatric surgery can affect the gut microbiota.
Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric ...surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes.
Sixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included.
Low gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including
,
and
) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients.
We identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome-host interactions in severe obesity.
NCT01454232.
Objective
Obesity is a major risk factor for severe forms of coronavirus disease (COVID‐19), but little is known about the post–bariatric surgery (BS) setting. The prevalence of likely COVID‐19 and ...its risk factors in patients followed up after BS was assessed.
Methods
A total of 738 patients who underwent BS and were followed up at a university medical center were surveyed. A retrospective comparison of characteristics at baseline, 1 year after BS, and at the time of lockdown was performed between patients with COVID‐19–likely events (CL) based on a combination of reported symptoms and those for whom COVID‐19 was unlikely.
Results
CL occurred in 62 (8.4%) patients, among whom 4 (6.4%) had a severe form requiring hospitalization and 1 (1.6%) died. The CL group had a higher proportion of persistent type 2 diabetes (T2D) at last follow‐up (36.2% vs. 20.3%, P = 0.01). BMI at the time of lockdown was lower in the CL group (30.2 ± 5.1 vs. 32.8 ± 6.5 kg/m2; P < 0.01) with higher percent weight loss since BS in the CL group. Severe forms of COVID‐19 requiring hospitalization were associated with persistent T2D at the last follow‐up visit.
Conclusions
In BS patients, CL were associated with persistent T2D and lower BMI.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Bariatric surgery induces weight loss and major improvement in insulin-resistance through many mechanisms some of which are weight independent. It is now well acknowledged that gut microbiota is ...involved in the development of obesity and its related metabolic diseases, at least in mice. However, its causal role in human obesity progression remains to be demonstrated. Few studies now pointed at changes in microbiota composition after bariatric surgery, suggesting links between gut microbiota switch and metabolic improvement observed after surgery. As such new potential mechanisms of actions have been proposed. The aim of this review is to describe microbiota modifications observed after bariatric surgery and its potential relationships with improved insulin resistance. We here list some hypotheses, which will need further demonstration.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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