Summary of diseases or disorders with increased intestinal permeability and altered microbiota
| Condition | Small intestinal or colonic barrier function | Microbiota changes | Other effects | Effects of treatment | |
| IP probe molecules or epithelial damage | Serum biomarkers | ||||
| Ageing | No difference in LMR or most TJ protein expression, but increased claudin 2 expression and decreased transepithelial resistance in ileal biopsies ex vivo.83 | ↑ Zonulin84 |
↓ Firmicutes, Bifidobacteria, Faecalibacterium prausnitzii. ↑ Bacteroidetes, Clostridia and facultative anerobes.85 | ||
| Food allergy | ↑ LMR threefold versus health.86 ↑ LMR 38% in children with food allergy.87 | Postulated mast cell and IgE-mediated increase in inflammatory cytokines.88 | Increased LMR in children with food allergy despite dietary exclusion.87 | ||
| Eosinophilic oesophagitis | Increased small bowel IP based on lactulose absorption57 but not LMR in adults57 58 or in children89; ex vivo assessment of duodenal mucosal integrity was normal.58 | Oesophageal microbiome: increased haemophilus90 or Neisseria and Corynebacteriumin in active EoO.91 | Bacterial load and TLR1, TLR2, TLR4 and TLR9 were overexpressed and mucin genes underexpressed on biopsies with active EoO.92 | No effect of elemental diet on duodenal mucosa or LMR or TJ protein expression58; no effect of exclusion diets on oesophageal microbiome.91 | |
| Liver diseases | |||||
| NAFLD/NASH | ↑ LMR or 51Cr-EDTA in 39% of 139 patients with NAFLD (SRMA five studies).62 | ↑ LPS in 42% of NASH93; ↑ LPS in NAFLD associated with SIBO.94 | ↑ SIBO (37.5%) in patients with NAFLD, especially Gram negative bacteria and Escherichia coli
94; review documents show diverse microbiota changes (variable in different studies).95 | Increased endogenous ethanol production by gut bacteria in NAFLD.61 | |
| Cirrhosis | Significant microbiota change in liver cirrhosis.96 | Reduced cirrhosis severity with Lactobacillus and VSL#3 probiotics.64 | |||
| Sclerosing cholangitis | LRR normal (83% (19/22) with quiescent IBD).97 | Higher serum I-FABP associated with IgA antibodies against F-actin.98 | 1/22 had SIBO (Enterobacter)92; enhanced mucosal immune response to various microbial antigens associated with IgA antibodies against F-actin.97 | IgA antibodies against F-actin, independent predictor of poor disease outcome.98 | |
| TPN or enteral deprivation | ↑ FITC-Dextran I.P. ex vivo; ↓ ZO-1, E-cadherin and claudin-4 in unfed segments in paediatric patients99; ↓ ZO-1 and villus height in mice.100 | Wide variability in microbial diversity in patients with small bowel resections101; patients with short bowel on TPN have ‘lactobiota’ enriched in the Lactobacillus/Leuconostoc group, depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides).102 | In TPN liver disease, microbes or LPS reaching liver and activating Kupffer cells103; Lactobiota fermentation leads to increased risk of d-encephalopathy.102 | Successful use of faecal microbial transplant for the treatment of recurrent D-lactic acidosis.104 | |
| Neurological diseases | |||||
| Alzheimer | Differences in Bacteroides, Faecalibacterium, Anaerostipes, Prevotella, Escherichia and Lachnospira at genus level and decreased Firmicutes/Bacteroidetes (F/B) ratio at phylum level.105 | Only 2/6 trials of omega-3 FA showed any benefit on cognitive decline, typically in those with mild cognitive impairment.106 | |||
| Parkinson | Downregulation of occludin not ZO-1 in colonic mucosa; however, flux of sulfonic acid and horseradish peroxidase not abnormal with or without Lewy bodies107; LMR normal, but ↑ 24 hours urinary sucralose (marker of total intestinal permeability).108 | Lower plasma levels of LPS binding protein, an indirect measure of systemic endotoxin exposure.108 | Significantly more intense staining of E. coli in epithelium and lamina propria of sigmoid mucosa108; reduced butyrate-producing bacteria from the genera Blautia, Coprococcus and Roseburia; putative ‘proinflammatory’ Proteobacteria of the genus Ralstonia significantly more abundant in mucosa of patients with Parkinson’s disease.109 | Correlation of increased intestinal permeability in Parkinson’s disease with intestinal alpha-synuclein107; relative abundance of Enterobacteriaceae positively associated with severity of postural instability and gait difficulty.110 | |
| ALS | ↑ LPS in most severe amyotrophic lateral sclerosis.111 | Low diversity of the microbiome compared with healthy cohorts; low Ruminococcus spp. in 3/5 patients with low F/B ratio.112 | Decreased levels of butyrate-producing bacteria; decreased levels of micro-organisms of the genera Oscillibacter, Anaerostipes and Lachnospira
113; 3/5 patients had elevated inflammatory markers in stool.112 | ||
| Psychiatric diseases | Plasma levels of LPS, zonulin and FABP2 were each significantly elevated in depression/anxiety patients compared with non-depressed or anxious controls.114 | A review documents extensive literature on cross-sectional and longitudinal studies documenting association between stool microbiota and anxiety and depression.115 A review documents studies of the microbiome and microbial translocation in patients with schizophrenia and bipolar disorder.116 | Elevated serum IgM and IgA against LPS in depression117; psychological stress increases pro-inflammatory cytokines (extensive literature reviewed in ref. 118). | Probiotics reduce depression scores in six randomised, placebo-controlled trials (reviewed in ref. 119). | |
In each category, it is infrequent for the altered barrier dysfunction and microbiota to be documented in the same human study.
51Cr-EDTA , chromium-51 ethylenediamine tetraacetic acid; ALS, amyotrophic lateral sclerosis; EoO, eosinophilic oesophagitis; FA, fatty acids; FABP, fatty acid binding protein; FABP2, fatty acid-binding protein 2; FITC, fluorescein isothiocyanate; I-FABP, intestinal fatty acid binding protein; IgA, immunoglobulin A; IP, intestinal permeability; LMR, lactulose mannitol excretion ratio; LPS, lipopolysaccharide; LRR, lactulose rhamnose ratio; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; SIBO, small intestinal bacterial overgrowth; TJ, tight junction; TLR, Toll-like receptor; TPN, total parenteral nutrition; ZO, zonula occludens.