Table 3.

Summary of diseases or disorders with increased intestinal permeability and altered microbiota. In each category, it is infrequent for the altered barrier dysfunction and microbiota to be documented in the same human study.

Condition	Small Intestinal or Colonic Barrier Function		Microbiota Changes	Other Effects	Effects of Treatment
	IP probe molecules or epithelial damage	Serum biomarkers
Aging	No difference in LMR or most TJ protein expression, but increased claudin 2 expression and decreased transepithelial resistance in ileal biopsies ex-vivo[83]	↑ zonulin[84]	↓ Firmicutes, Bifidobacteria, Faecalibacterium prausnitzii ↑ Bacteroidetes, Clostridia and facultative anerobes[85]
Food allergy	↑ LMR 3 fold vs 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 esophagitis	Increased small bowel IP based on lactulose absorption[89] but not LMR in adults[89, 90] or in children;[91] ex-vivo assessment of duodenal mucosal integrity was normal[90]		Esophageal microbiome: increased hemophilus[92] or Neisseria and Corynebacteriumin in active EoE[93]	Bacterial load and TLR1, TLR2, TLR4, and TLR9 were overexpressed and mucin genes under-expressed on biopsies with active EoE[94]	No effect of elemental diet on duodenal mucosa or LMR or tight junction protein expression;[90] No effect of exclusion diets on esophageal microbiome[93]
Liver Diseases
NAFLD/ NASH	↑ LMR or 51Cr-EDTA in 39% of 139 pts with NAFLD (SRMA 5 studies)[62]	↑ LPS in 42% of NASH;[95] ↑ LPS in NAFLD associated with SIBO[96]	↑ SIBO (37.5%) in pts with NAFLD, especiallygram –ve bacteria and E.coli;[96] Review documents show diverse microbiota changes (variable in different studies)[97]	Increased endogenous ethanol production by gut bacteria in NAFLD[61]
Cirrhosis			Significant microbiota change in liver cirrhosis[98]		Reduced cirrhosis severity with Lactobacillus and VSL#3 probiotics[64]
Sclerosing cholangitis	LRR normal [83% (19/22) with quiescent IBD][99]	Higher serum I-FABP associated with IgA antibodies against F-actin[100]	1/22 had SIBO (Enterobacter);[94] Enhanced mucosal immune response to various microbial antigens associated with IgA antibodies against F-actin[99]	IgA antibodies against F-actin, independent predictor of poor disease outcome [100]
TPN or enteral deprivation	↑ FITC-Dextran I.P ex-vivo and ↓ ZO-1, E-cadherin, and claudin-4 in unfed segments in pediatric patients;[101] ↓ ZO-1 and villus height in mice[102]		Wide variability in microbial diversity in patients with small bowel resections;[103] Patients with short bowel on TPN have “lactobiota” enriched in the Lactobacillus/Leuconostoc group, depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides)[104]	In TPN-liver disease, microbes or LPS reaching liver and activating Kupffer cells;[105] Lactobiota fermentation leads to increased risk of d-encephalopathy[104]	Successful use of fecal microbial transplant for the treatment of recurrent D-lactic acidosis[106]
Neurological Diseases
Alzheimer			Differences in Bacteroides, Faecalibacterium, Anaerostipes, Prevotella, Escherichia, and Lachnospira at genus level and decreased Firmicutes/ Bacteroidetes ratio at phylum level[107]		Only 2/6 trials of omega-3 FA showed any benefit on cognitive decline, typically in those with mild cognitive impairment[108]
Parkinson	Down-regulation of occludin not ZO-1 in colonic mucosa; however, flux of sulfonic acid and horseradish peroxidase not abnormal with or without Lewy bodies;[109] LMR normal, but ↑ 24h urinary sucralose (marker of total intestinal permeability)[110]	Lower plasma levels of LPS binding protein, an indirect measure of systemic endotoxin exposure[110]	Significantly more intense staining of E. coli in epithelium and lamina propria of sigmoid mucosa;[110] Reduced butyrate-producing bacteria from the genera Blautia, Coprococcus and Roseburia; putative “proinflammatory” Proteobacteria of the genus Ralstonia significantly more abundant in mucosa of Parkinson’s patients[111]	Correlation of increased intestinal permeability in Parkinson disease with intestinal alpha–synuclein;[109] Relative abundance of Enterobacteriaceae positively associated with severity of postural instability and gait difficulty[112]
ALS	↑ LPS in most severe amyotrophic lateral sclerosis[113]		Low diversity of the microbiome compared to healthy cohorts; low Ruminococcus spp. in 3/5 patients with low Firmicutes/Bacteroidetes (F/B) ratio[114]	Decreased levels of butyrate-producing bacteria; decreased levels of micro-organisms of the genera Oscillibacter, Anaerostipes, and Lachnospira;[115] 3/5 patients had elevated inflammatory markers in stool[114]
Psychiatric diseases	Plasma levels of LPS, zonulin and FABP2 were each significantly elevated in depression/anxiety patients compared to non-depressed or anxious controls.[116]		A review documents extensive literature on cross-sectional and longitudinal studies documenting association between stool microbiota and anxiety and depression.[117] A review documents studies of the microbiome and microbial translocation in patients with schizophrenia and bipolar disorder.[118]	Elevated serum IgM and IgA against LPS in depression;[119] Psychological stress increases pro-inflammatory cytokines (extensive literature reviewed in ref. 120).	Probiotics reduce depression scores in 6 randomized, placebo-controlled trials (reviewed in ref. 121).

EoE=eosinophilic esophagitis; FABP= fatty-acid binding protein; FITC=fluorescein isothiocyanate; IBD=inflammatory bowel disease; 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