| The Role of Fecal Microbiota Transplantation in the Treatment of Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease


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The Role of Fecal Microbiota Transplantation in the Treatment of Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease


Benjamin H. Mullish, MB, BChir, MRCP, PhD


Over the course of the past decade, there has been a growing literature base of observational studies demonstrating an association between the interrelated metabolic conditions of obesity, metabolic syndrome, and NAFLD and alterations in the composition and functionality of the gut microbiota. Animal models and emerging human studies have begun to explore this association mechanistically. The success of FMT in treating rCDI has been a launch pad for interest in its potential application in metabolic conditions where perturbation of the gut microbiota may contribute to the pathology observed and where current medical therapy may be limited. In this section, we will summarize the current knowledge within this area.


Overview of the Role of the Gut Microbiota in Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease


Multiple cross-sectional studies have demonstrated that individuals with obesity have alterations in their gut microbiota,1 and individuals with a gut microbiota of low bacterial richness have more marked insulin resistance and dyslipidemia compared with those with a higher bacterial richness.2 In addition, women with normal, impaired, or diabetic glucose control were able to be identified based upon the composition and functionality of their stool microbiome profile.3


A range of animal models, including humanized mouse models, have demonstrated that vulnerability to obesity and metabolic syndrome may be transferred with transfer of the gut microbiota, giving further circumstantial evidence for the contribution of the gut microbiota to these conditions. This includes studies in which stool from human twins discordant for obesity has been transferred into the gut of germ-free mice (ie, mice lacking a microbiota), with mice receiving stool from the obese twin gaining much more weight than those treated with stool from the nonobese twin.4 Furthermore, there is evidence from animal models that the metabolic improvements observed post-bariatric surgery may be causally related to surgery-related changes in the gut microbiota.5 One prominent theory is that the obese gut microbiota has an increased capacity to harvest energy from the host’s diet, with the major consequence being fat deposition and its associated sequelae.6


Using a combination of samples collected from patients with morbid obesity and mouse models, it has recently been demonstrated that the microbial metabolite phenylacetic acid may be contributory to the development of hepatic steatosis, and, by extension, to the development and progression of NAFLD.7


One possible mechanistic explanation for the association between alterations in the gut microbiota and vulnerability to and development of these conditions includes alterations in the level of production of gut bacterial fermentation products, such as short-chain fatty acids (SCFAs). SCFAs appear to mediate the release of the gut peptide glucagon-like peptide-1 (GLP-1), which has actions including the promotion of satiety and slowing of gastric emptying, among others. The gut microbiota also influences the composition of the gut bile acid pool, which in turn may directly impact upon host lipid metabolism and weight.8,9


Clinical Trials of Fecal Microbiota Transplantation for Treating Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease


A high-profile case report from 2015 described rapid, marked weight gain in a woman who was treated for rCDI with FMT obtained from her healthy but overweight daughter,10 raising interest in the possible direct transferability of obesity as a gut microbiota trait in humans. However, larger studies have failed to replicate this observation, and it is now widely accepted that stool donor body mass index (BMI) does not appear to affect recipient weight after FMT for rCDI.11


In 2 randomized studies reported from the same academic group, collectively including 56 white, male, obese, treatment-naïve patients with metabolic syndrome, a significant improvement was demonstrated in peripheral (but not hepatic) insulin sensitivity following 1 to 2 upper GI infusions of lean donor FMT.12,13 This improvement was observed at 6 weeks post-FMT but was no longer present at later time points. However, no improvement in insulin sensitivity occurred in patients treated with autologous FMT (ie, patients transplanted with their own collected feces).12,13 Importantly, these findings were observed without the use of maintenance FMT, raising the possibility that with an increased dosing schedule, improvements in insulin sensitivity may have been sustained. Of note, lean donor FMT was not associated with changes in weight or other relevant metabolic parameters. The effect of FMT upon the levels of fecal SCFAs was variable between patients, but relatively modest overall.


Allegretti et al14 conducted a randomized clinical trial where 22 patients with obesity (BMI ≥ 35 kg/m2) but without other metabolic diseases (ie, no NAFLD, diabetes mellitus, or other features of metabolic syndrome) were randomized to receive either FMT or placebo (Figure 10.6-1).14 FMT was administered as capsules derived from a single lean donor (BMI 17.5 kg/m2) divided over 3 doses (30 capsules at induction and 12 capsules at week 4 and week 8). Although FMT appeared overall safe and well-tolerated, no significant changes in GLP-1, the primary endpoint, or in BMI were seen across 12 weeks of follow-up. It was further observed that patients who received FMT, but not those who received placebo, demonstrated particular changes in the microbiome and bile acid profiles of the gut to resemble that of donors. In another randomized placebo-controlled trial, 24 obese adults with mild-to-moderate insulin resistance were randomized to receive 6 weekly treatments with capsules of either a metabolically healthy lean donor FMT or placebo and were followed for up to 12 weeks.15 Although there were numerically greater improvements in insulin sensitivity in the FMT group compared with the placebo arm, this did not reach statistical significance.15



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Figure 10.6-1. Fecal microbiota transplantation by oral capsules for the treatment of obesity.14

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May 23, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on | The Role of Fecal Microbiota Transplantation in the Treatment of Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease
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