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Published in final edited form as: Diabetes Obes Metab. 2022 Nov 2;25(2):325–330. doi: 10.1111/dom.14899

Is intestinal permeability increased in obesity? A review including the effects of dietary, pharmacological and surgical interventions on permeability and the microbiome

Michael Camilleri 1
PMCID: PMC10112051  NIHMSID: NIHMS1889954  PMID: 36263962

1 |. INTRODUCTION

Obesity is among the diseases that have been associated with increased intestinal permeability or ‘leaky gut’,1 and this defect may facilitate dietary and microbial antigen influx leading to chronic inflammation, tissue damage and allergy. Such a defect is considered a factor predisposing to the inflammatory state associated with obesity, or to observations such as increased glucose in the wall of the intestine shown by combined positron emission tomography and magnetic resonance imaging in patients with type 2 diabetes treated with metformin,2 consistent with the report of a reduced rate of small intestinal glucose absorption in type 2 diabetes.3 Alterations in mucosal permeability may also impact the absorption of intraluminal molecules, which are dependent on diffusion for their concentration-dependent uptake. An example is the absorption of propionate by colonic mucosa that improves beta-cell function in humans.4 Altered barrier function has also been reported to be a factor impacting the effect of the microbiota in type 2 diabetes.5,6

The objective of this review is to appraise the evidence supporting the hypothesis that the intestinal barrier is deficient in human obesity. The review is based on a PubMed search using the terms overweight, obesity, weight loss, barrier, permeability, intestine, treatment, zonulin, endotoxin, lipopolysaccharide (LPS), LPS-binding globulin and combinations of these terms. The review includes observations of intestinal permeability in overweight or obesity at baseline, as well as after dietary, pharmacological and surgical interventions.

The objective was not to appraise the evidence of altered microbiota in obesity that has been appraised elsewhere. Pivotal observations included the original observation (subsequently confirmed in other studies) of the altered composition in the microbiota of obese humans with a marked decrease in bacterial diversity, and similar characteristics to obese mice, with a higher proportion of Firmicutes and comparatively less Bacteroidetes.7 Studies conducted in lean and obese twins showed that obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathway.8

Another analysis showed only small, but statistically significant, differences in phylum-level taxonomic composition between lean and obese individuals in several cohorts, with no association between body mass index (BMI) and taxonomic composition of stool microbiomes in the larger Human Microbiome Project and MetaHIT datasets.9 More recently, there have been recommendations on directions to advance the obesity-microbiome field, with particular emphasis on the development of microbiome-targeted therapies for obesity prevention and treatment.10 In the current review, effects of weight loss interventions on the intestinal permeability included effects on the microbiome, and the latter effects are also included.

2 |. MEASUREMENTS OF INTESTINAL PERMEABILITY

A critical factor in appraising the published evidence from human studies is the accuracy, specificity and sensitivity of the methods used to appraise the intestinal barrier function. The diverse methods have been appraised elsewhere.11 For the objective of this analysis, we focused on the publications that appraised barrier functions in participants in vivo, based on serum and stool measurements proposed as biomarkers of barrier function, and urinary excretion of orally administered probes (Figure 1). The evidence is summarized for each of these measurements and is appraised relative to the published validity of the biomarkers.

FIGURE 1.

FIGURE 1

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Methods of measurement of intestinal permeability.51Cr-EDTA, chromium-51 labeled ethylenediamine tetraacetic acid; I-FABP, intestinal fatty acid binding protein; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide

3 |. SERUM AND FAECAL ZONULIN IN OBESITY

Zonulin is human protein analogue to the Vibrio cholerae-derived zonula occludens toxin, which induces tight junction disassembly and subsequently increases intestinal permeability in non-human primate intestinal epithelia. It was shown to be a modulator of intestinal permeability, and its expression was upregulated in the small intestinal enterocytes of patients with celiac disease12 and other diseases such as ankylosing spondylitis.13 Indeed, in ankylosing spondylitis, which may be associated with overt or subclinical bowel inflammation, there was a strong correlation of serum zonulin with intestinal permeability measured by the lactulose-to-mannitol ratio (LMR) (r2 = 0.7236, P = .0177) and other serological markers associated with increased intestinal permeability, such as serum LPS, lipopolysaccharide binding protein and intestinal fatty acid binding protein. The latter is a marker of epithelial damage.13 Serum zonulin measurements are also associated with obesity-associated insulin resistance, BMI, waist-to-hip ratio, and serum fasting insulin, fasting triglycerides, uric acid and interleukin-614; and in a separate study with 50 obese and 30 normal-weight participants, the zonulin levels were higher in the obese group and were associated with higher serum levels of inflammatory markers such as tumour necrosis factor-alpha15; however, total bacterial as well as Bacteroides and Firmicutes counts and the ratio of Bacteroides to Firmicutes spp. were similar in both study groups.

Aasbrenn et al.16 measured serum zonulin using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Immundiagnostik AG, Germany; assay sensitivity < 0.01 ng/ml, normal values < 38 ng/ml) in 143 individuals (77% women) with a mean age of 43.0 (SD 8.7) years and BMI of 42.1 (SD 3.8) kg/m2. At inclusion into the study, patients with class II (BMI > 35 and < 40 kg/m2) or class lIII (> 40 kg/m2) obesity had a mean serum zonulin of 62 (95% CI: 57–66) ng/ml, which was significantly higher than controls. After conservative weight loss interventions (group counselling and personalized lifestyle interventions as well as reduced daily energy intake and recommendation of food items with a high micronutrient content) followed by bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy), there were significant reductions in serum zonulin compared with baseline during both interventions: 43 (SD 7) ng/ml after the conservative weight loss intervention, and 29 (18) ng/ml after bariatric surgery (normal < 38 ng/ml).

Another study17 measured faecal zonulin using the same ELISA method and used the published cut-off value of more than 61 ng/ml to identify increased intestinal permeability. The study included 72 participants with a mean BMI of 34.0 ± 6.9 (SD) kg/m2 (range 25.0–56.4); 31.5% were obese and 68.5% overweight. The faecal concentration of zonulin in all subjects was 67.9 ± 53.82 (SD) ng/ml. In a single, blinded 12-week trial with 36 patients randomized to a synbiotic group and 20 to a placebo group, there was a significant reduction in faecal zonulin in the synbiotic group but not in the placebo group, with reductions in mean faecal zonulin of 17.4 (P = .024) and 6.4 (P = .54) ng/ml, respectively. In addition, synbiotic treatment was associated with an increase in the diversity of intestinal bacteria (increase in the Shannon–Weaver index and the Simpson index), and statistically significant correlation between serum zonulin and Bifidobacterium spp.

These two studies appear to support the conclusion that obesity is associated with increased intestinal permeability. However, accumulated evidence has raised questions regarding the validity of the ELISA assay for zonulin. Thus, the widely used commercial ELISA does not detect the precursor of haptoglobin-2 (pre-haptoglobulin-2), but it recognizes properdin, which is a potential second member of the zonulin family but with unproven significance from the perspective of documenting altered intestinal barrier function.18 This does not diminish the potential of the zonulin family of proteins as biomarkers of epithelial and endothelial permeability,19 but it indicates the need to cautiously interpret reports based on that ELISA, or the need to corroborate with other measurements. Thus, for example, serum zonulin measured by the commercial kit failed to correlate with physiological measures of altered gut permeability by the LMR in first-degree relatives of patients with Crohn disease.20

4 |. SERUM ENDOTOXIN OR LPS

Serum endotoxin or LPS (a component of the outer cell wall of gram negative bacteria that assists in stabilizing the bacterial cell wall, and is a potent activator of the immune system) is usually measured using the Limulus amebocyte lysate assay (LAL test) by the chromogenic kinetic method of Bio-Whittaker Co. Its sensitivity is 0.005–50 endotoxin units (EU)/ml. The mean plasma level of endotoxin in 116 healthy blood donors was 0.128 EU/ml.21 An alternative assay is available from Cambrex Limulus Amebocyte Lysate kit (Lonza Inc., Walkersville, MD). This assay has a sensitivity range of 0.1 to 1.0 EU/ml and a normal value range from 0.15 to 0.35 EU/ml.22 Expressing endotoxin concentrations in EU addresses the issue of different potencies of different endotoxins. In general, 1 EU equals approximately 0.1 to 0.2 ng EU/ml. In 15 adults with type 2 diabetes, the LPS level was increased preoperatively (0.567 ± 0.033 EU/ml compared with the normal range of 0.15 to 0.35 EU/ml) and there was a reduction in plasma LPS as well as inflammatory mediators (such as C-reactive protein) following RYGB.22

A high-fat diet is associated with endotoxemia, which originates from the gut. When healthy participants were fed a Western-style diet for 1 month, there was a 71% increase in plasma endotoxin, whereas a prudent-style diet reduced levels by 31%.23 Similarly, dietary fat overload in morbidly obese individuals is associated with elevated plasma endotoxin, which correlates with increased postprandial triglyceride levels24 and elevated LPS in metabolically unhealthy children with increased visceral fat accumulation, and higher monosaccharide intake.25

Obese subjects also had elevated LPS levels measured by the same LAL assay, with results expressed in pg/ml26; obesity (n = 49) median 85 (IQR: 70, 110) compared with controls (n = 17) median 62 (IQR: 55, 72) pg/ml. Plasma levels of LPS and LPS-binding protein are also shown to be reduced by 20% ± 5% 1 year after RYGB or duodenal switch surgery,26 as well as after biliopancreatic diversion or sleeve gastrectomy.27 LPS levels were closely correlated with HbA1c and intra-abdominal fat volumes, and abdominal fat volumes, but only moderately correlated with subcutaneous fat volumes.26

In summary, measurements support the concept that serum endotoxin or LPS levels are increased in obesity, but high-fat content of the diet at baseline or reduced fat intake or absorption following bariatric surgery may be significant confounders that may impact the assessment of intestinal permeability by serum LPS.

5 |. SERUM LIPOPOLYSACCHARIDE-BINDING PROTEIN

The ELISA assay for lipopolysaccharide-binding protein ([LBP] detection limit of ~100 pg/ml) detects a high level of LBP in obesity, with mean baseline levels reported as ~130 μg/ml in one study,28 and higher levels in obese participants (49.9 ± 15.7 μg/ml) than in normal-weight participants (25.2 ± 7.5 μg/ml; P < .001).29 The levels were not significantly decreased following laparoscopic banding,28 but they were decreased after four different bariatric surgeries, that is, mini-gastric bypass, RYGB, sleeve gastrectomy and adjustable gastric banding.29 The latter study showed that, after multivariate analyses, preoperative serum LBP and the change of serum LBP with surgery were independently associated only with highly sensitive C-reactive protein (hs-CRP) (P < .001) and the change of hs-CRP (P = .012), respectively.29 A controlled study of a probiotic supplement did not reveal a significant alteration in LBP after controlling for changes in weight and energy intake from baseline.30

Similarly, the baseline serum LBP levels of obese (30.9 ± 7.4 μg/ml) and overweight (29.6 ± 6.3 μg/ml) subjects were significantly higher than those of normal controls (23.1 ± 5.6 μg/ml; P < .001). The change of LBP in response to a 1-year, non-surgical weight management programme was significantly related to the changes of hs-CRP, leukocyte count and non-alcoholic fatty liver disease fibrosis score before weight management by multivariate linear regression analysis in the obese group.31

These observations suggested that serum LBP is most consistent with an acute phase reactant role rather than impacting outcomes related to obesity or as a marker of increased intestinal permeability.29

6 |. URINARY EXCRETION OF ORALLY ADMINISTERED PROBES

Several studies using lactulose as disaccharide and mannitol or rhamnose as monosaccharide showed no increase in small bowel or colonic permeability in overweight or obesity relative to normal control data.32–35 There was no change in LMR in response to obesity treatment with Endobarrier, whereas there was an improvement in insulin sensitivity and a significant reduction in body weight and fat mass.32 In a prior study from our laboratory, we failed to see significant effects in intestinal permeability measurements using 13C-mannitol and lactulose when comparing healthy volunteers with BMI below or above 25 kg/m2.33 In patients with class III obesity, small intestinal and colonic permeability (urinary recovery of lactulose/L-rhamnose and sucralose/erythritol, respectively) were not significantly different from controls; however, gastroduodenal permeability (urinary sucrose recovery) was significantly increased in obese compared with lean controls, and this normalized following sleeve gastrectomy.34 In a study of 15 non-obese (BMI < 28 kg/m2), 11 obesity class I, seven obesity class II and 13 obesity class III, Kellerer et al. also identified no differences in permeability based on BMI class and, paradoxically, the highest serum LBP and zonulin were observed in class I obesity.35 In the same study, reductions in serum LBP and urinary mannitol and lactulose excretion (but not LMR) were observed following sleeve gastrectomy.35 Microbiota alpha-diversity (richness and the Shannon effective number of species) were lower in patients with obesity compared with non-obese subjects; specifically, obese patients had a higher abundance of Bacteroidetes and a lower abundance of Firmicutes.35 Alpha diversity increased after surgery and the microbiota composition of the obese patients postsurgery became similar to that of the non-obese group.

Another study also showed no difference among normal weight, overweight or obese in small intestinal permeability (LMR), but it showed higher colonic permeability based on sucralose excretion.36 Similarly, a pilot study showed no difference in lactulose, mannitol or Sucralose excretion among 13 obese and 11 controls.37 The study showed faecal microbiota was altered in the obese group, with predominance of bacterial populations having a lower microbial genomic guanine plus cytosine (G + C) content and decreased concentrations of high G + C microbial populations.37

In a study comparing 20 lean and 20 obese women, there was increased urinary excretion of lactulose during 5 hours after ingestion, although the LMR was not significantly different in the two groups.38

One study assessed permeability based on chromium-51 labelled ethylenediamine tetraacetic acid (51Cr-EDTA) excretion during 24 hours after 51CrEDTA administration; normal subjects excrete 1%−3%. Of the 20 obese patients, 70% had intestinal permeability alteration at baseline, with a mean percentage retention and excretion of 51Cr-EDTA of 5.4% ± 4.7%. There were no significant changes in intestinal permeability measured by 51Cr-EDTA excretion at the end of 16 weeks with Mediterranean or low-fat diets.39

7 |. COMPREHENSIVE STUDIES USING MULTIPLE PERMEABILITY MARKERS AT BASELINE AND IN RESPONSE TO TREATMENT

In a comprehensive study, Seethaler et al.40 evaluated 31 normal-weight healthy, 20 overweight and 27 obese individuals using measurements of lactulose and mannitol excretion and excreted ratio, as well as six potential surrogate biomarkers (faecal albumin, calprotectin, zonulin, plasma intestinal fatty acid binding protein [I-FABP], LBP and zonulin). The data, which constitute the most comprehensive appraisal of the methods available in a single cohort and analysis, are reproduced in Table 1. The authors concluded that intestinal permeability may be associated with body weight (based on excretion of lactulose, mannitol and LMR). Faecal calprotectin and zonulin, as well as plasma I-FABP and plasma LBP, but not plasma zonulin, increased in parallel with BMI (Table 1).

TABLE 1.

Characteristics of the cohorts included in a comprehensive study reported in the literature. Reproduced from Seethaler et al.40 Am J Physiol Gastrointest Liver Physiol. 2021;321:G11-G17

Healthy cohort Obesity cohort
Normal weight Overweight Obese
Number 31 20 27a
Female/male, n 22/9 14/6 14/13
Age, y 31.0 (28–36) 41.5 (29–54.8) 45.0 (38–49)
BMI, kg/m2 21.7 (20–24) 28.9 (25–32) 42.2 (41–47)
CRP, mg/l 0.7 (0.3–0.9) 2.1 (1.0–4.2) 7.6 (5.5–11)
Lactulose/mannitol test
 Lactulose, % excreted 0.04 (0.01–0.05) 0.04 (0.02–0.07) 1.1 (0.5–1.1)
 Mannitol, % excreted 6.2 (4.4–8.6) 6.7 (4.6–10) 21.7 (20–26)
 LMR 0.006 (0.004–0.007) 0.008 (0.005–0.010) 0.045 (0.028–0.053)
 Increased IP, %b 3% 15% 93%
IP biomarkers
 Faecal albumin, ng/mg 3.0 (0.9–6.4) 1.9 (1.1–4.7) 0.6 (0.3–1.1)
 Faecal calprotectin, ng/mg 17 (9–37) 25.2 (15–44) 36.1 (25–79)
 Faecal zonulin, ng/mg 109 (84–155) 130 (94–206) 171 (87–360)
 Plasma I-FABP, pg/ml 477 (368–804) 502 (267–829) 840 (495–1072)
 Plasma LBP, μg/ml 6.5 (5.6–7.5) 8.0 (6.5–10) 13.7 (8.5–17.1)
 Plasma zonulin, ng/ml 42.5 (38–51) 38.5 (30–48) 52.0 (35–75)
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Abbreviations: BMI, body mass index; CRP, C-reactive protein; I-FABP, intestinal fatty acid binding protein; IP, intestinal permeability; LBP, lipopolysaccharide binding protein; LMR, lactulose-to-mannitol ratio.

a

For plasma samples n = 20.

b

Percentage of individuals with LMR exceeding normal range, defined as means ± SD of the normal-weight subgroup in the healthy cohort.

The LMR correlated with plasma LBP levels in all cohorts consistently (independent of age, BMI and sex), and LMR correlated with faecal zonulin in overweight and obese, independent of BMI, but not age and sex. The authors proposed faecal zonulin as a potential biomarker of intestinal permeability in overweight and obese individuals.

Finally, Koutoukidis et al.41 examined the published literature based on a systematic review and meta-analysis to assess the association of weight loss (after diverse treatments, that is, three energy-restricted diets, one pharmacotherapy, nine bariatric surgery [which included one study with four separate types of bariatric procedures29], and one diet and surgery) with intestinal permeability changes. Given that the permeability measurements varied in the 17 studies included in the analysis, the effects on permeability were appraised using standardized mean difference (SMD). The article suggests that, based on imprecise evidence but with a fairly consistent direction of effect, weight loss was associated with a statistically significant increase in α-diversity (SMD: 0.4 [95% CI: 0.2, 0.6], P < .0001, I2 = 70%, n = 30 studies) and a statistically significant reduction in intestinal permeability (SMD: −0.7 [95% CI: −0.9, −0.4], P < .0001, n = 17 studies).41 There was significant overall heterogeneity among the studies (I2 = 83%); however, the meta-regression analysis showed that, for every kg of weight loss, there was a0.017 (95% CI: −0.034, −0.001, P = .038) reduction in the SMD of intestinal permeability. There was also funnel plot asymmetry in the funnel plot of intestinal permeability, suggesting publication bias. Nevertheless, restricting the permeability analyses to 11 studies that were judged overall at lower risk of bias still revealed a significant reduction in intestinal permeability with weight loss (SMD: −0.6 [95% CI: −0.9, −0.4]), although significant heterogeneity was still present (I2 = 83%).41

In conclusion, a thorough review of the published literature identifies weak evidence of increased intestinal or colonic permeability in obesity and some responsiveness to therapy, particularly with bariatric surgery. However, the diversity, incomplete validation and specificity or significance of the diverse test methods used do not currently support the hypothesis of impaired barrier function in obesity, whether barrier function was measured by serum, or faecal biomarkers, or by urine excretion of orally administered probes. There is also significant confounding by differences in dietary fat intake or fat absorption or inflammatory state as manifested by hs-CRP levels, particularly after bariatric surgery. Further research is required to address whether there is significant barrier dysfunction because of obesity per se. In addition, caution is required in the choice of method, given confounders caused by unconscious dietary intake of probe molecules (e.g. mannitol, sucralose and rhamnose)33 and the evidence that LBP correlates best with acute phase reactants rather than intestinal permeability.

ACKNOWLEDGEMENTS

The author thanks Mrs. Cindy Stanislav for secretarial assistance.

Funding information

National Institutes of Health, Grant/Award Number: R01-DK115950

FUNDING INFORMATION

Michael Camilleri received funding for research on intestinal functions in irritable bowel syndrome from National Institutes of Health (R01-DK115950).

Footnotes

CONFLICT OF INTEREST

Patent pending: application #US2019/0145953 “Methods and Materials for Assessing Intestinal Permeability”.

DATA AVAILABILITY STATEMENT

As this is a review of the literature, there are no new original data in this manuscript.

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Associated Data

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Data Availability Statement

As this is a review of the literature, there are no new original data in this manuscript.

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