Levothyroxine therapy and impaired clearance are the strongest contributors to small intestinal bacterial overgrowth: Results of a retrospective cohort study

Table 1 Basic characteristics

	SIBO		Non-SIBO		χ2 or Student’s t-test
	n = 175	%	n = 1634	%	P value
Age (yr)	48.7 ± 17.9	-	49.3 ± 18.0	-	0.70
Sex (female)	107	61.1	924	56.5	0.139
Pathological LHBT	102	58.3	212	13.0	< 0.0011
Pathological GHBT	146	83.4	9	0.6	< 0.0011
Diarrhoea	72	41.1	648	39.7	0.380
Constipation	4	2.3	38	2.3	0.616
Weight Loss	39	22.3	313	19.2	0.185
Malabsorption	9	5.1	53	3.2	0.138
Iron Deficiency Anaemia	2	1.1	38	2.3	0.240
Vitamin B12 Anaemia	1	0.6	4	0.2	0.399
Number of drugs used	1.61	-	1.32	-	0.0051
Supplementation of folic acid	3	1.7	22	1.3	0.442
Supplementation of iron	17	9.7	18	1.1	0.0221
Supplementation of vitamin B12	6	3.4	18	1.1	0.0231
Abdominal ultrasound	152	86.9	1508	92.3	0.0221
EGD	120	68.6	1187	72.6	0.146
Colonoscopy	100	57.1	1069	65.4	0.0191
Enteroclysis	45	25.7	357	21.8	0.143
Video capsule endoscopy	7	4.0	19	1.2	0.0091
Enteroscopy	1	0.6	4	0.2	0.399

¹Statistically significant with P value < 0.05 in χ² or Student’s t-test. As expected, the SIBO group showed a pathological hydrogen breath test. Symptoms did not differ significantly. Patients with SIBO took more drugs and were more likely to supplement vitamin B12 or iron. During the hospital stay, patients with SIBO underwent small bowel diagnostic procedures more often, while patients without SIBO were more likely to undergo other diagnostic procedures. SIBO: Small intestinal bacterial overgrowth; LHBT: Lactulose Hydrogen Breath Test; GHBT: Glucose Hydrogen Breath Test; EGD: Esophagogastroduodenoscopy.

Table 2 Hypo-/achlorhydria

	SIBO		Non-SIBO		χ2 test	OR	RR
	n = 175	%	n = 1634	%	P value
Gastrectomy	4	2.3	11	0.7	0.0491	3.451	0.295
Atrophic gastritis	2	1.1	5	0.3	0.141	-	-
PPI therapy	70	40.0	519	31.8	0.0341	1.432	0.794
Ulcer indicated PPI therapy	5	2.9	47	2.9	0.611	-	-
Gastritis indicated PPI therapy	20	11.4	195	11.9	0.481	-	-
GERD indicated PPI therapy	20	11.4	179	11.0	0.464	-	-
Indicated PPI therapy	42	24.0	395	24.2	0.522	-	-
Not indicated PPI therapy	58	33.1	370	22.6	0.0021	1.728	0.693

¹Statistically significant with P < 0.05 in χ² test. Patients with SIBO had a history of gastrectomy more often and were more likely to take PPI. In subgroup analysis, those patients who received PPI due to peptic ulcer disease, gastritis or GERD had the same risk of developing SIBO, while those patients who did not exhibit such indications had a 1.7-fold increased risk of showing SIBO. SIBO: Small intestinal bacterial overgrowth; PPI: Proton pump inhibitor; GERD: Gastroesophageal reflux disease.

Table 3 Impaired clearance

	SIBO		Non-SIBO		χ2 test	OR	RR
	n = 175	%	n = 1634	%	P value
Any abdominal surgery	51	29.1	487	29.8	0.466	-	-
Obstetric surgery	2	1.1	45	2.8	0.135	-	-
Abdominal w/o obstetric surgery	49	28.0	444	27.2	0.438	-	-
Gastrectomy	4	2.3	11	0.7	0.0491	3.451	0.295
BII-resection	5	2.9	31	1.9	0.265	-	-
Existence of blind loops	8	4.6	41	2.5	0.0942	1.861	0.549
Any resecting gastric surgery	12	6.9	45	2.8	0.0071	2.600	0.402
Resection of Ileocecum	7	4.0	41	2.5	0.176	-	-
Appendectomy	7	4.0	134	8.2	0.0271	0.466	2.050
Functional appendectomy	14	8.0	175	10.7	0.163	-	-
Cholecystectomy	8	4.6	127	7.8	0.0782	0.568	1.700
Resection of small intestine	11	6.3	80	4.9	0.260	-	-
Any colonic resection	19	10.9	97	5.9	0.0131	1.930	0.547
Sigmoid resection	3	1.7	13	0.8	0.196	-	-
Vagotomy	2	1.1	6	0.4	0.177	-	-
Fistula	2	1.1	16	1.0	0.532	-	-
Stenosis	10	5.7	29	1.8	0.0031	3.354	0.311
Impaired motility	17	9.7	9	0.6	< 0.0011	5.157	0.202
Gastroparesis	5	2.9	24	1.5	0.0301	3.403	0.300
Neuropathy	9	5.1	39	2.4	0.0371	2.217	0.464
Opioid use	10	5.7	55	3.4	0.0902	1.740	0.589

¹Statistical significant with P value P < 0.05;

²Statistical tendency with P value 0.05 < P < 0.1 χ² test each. Overall abdominal surgery was not associated with an increased risk of developing SIBO. Resecting gastric surgery in general and gastrectomy was associated with the development of SIBO. Patients with SIBO were less likely to have a history of appendectomy and - as a tendency - cholecystectomy. Ileocecal resection had no impact on the development of SIBO. As a further anatomical alteration, stenoses were more frequent in SIBO patients. Impaired motility, as shown by gastroparesis, led to SIBO; patients with neuropathy or opioid medication are patients at risk. SIBO: Small intestinal bacterial overgrowth.

Table 4 Immunological factors

	SIBO		Non-SIBO		χ2 test	OR	RR
	n = 175	%	n = 1634	%	P value
IgA-deficiency	0 of 6	0.0	13 of 75	17.3	0.337	-	-
IgG-deficiency	3 of 5	60.0	15 of 52	28.8	0.175	-	-
IgM-deficiency	0 of 5	0.0	15 of 54	21.7	0.311	-	-
5-Aminosalicylates	24	13.7	183	11.2	0.191	-	-
Steroid use	36	20.6	222	13.6	0.0101	1.647	0.660
Immunosuppressant use	8	4.6	31	1.9	0.0291	2.477	0.415
Azathioprin use	7	4.0	31	1.9	0.0672	2.155	0.474
Metotrexate use	3	1.7	0	0.0	0.0011	n/a	n/a
Any drug-induced immunosuppression	39	22.3	230	14.1	0.0041	1.751	0.632
Steroid plus immunosuppressant	7	4.0	23	1.4	0.0211	2.918	0.352

¹Statistical significant with P value P < 0.05;

²Statistical tendency with P value 0.05 < P < 0.1 χ² test each. Deficiencies of immunoglobulins were not associated with a higher prevalence of SIBO. On the other hand, pharmacologically induced immunosuppression with steroids alone, with an immunosuppressant alone or with both in combination lead to a higher risk of developing of SIBO. SIBO: Small intestinal bacterial overgrowth.

Table 5 Miscellaneous variables

	SIBO		Non-SIBO		χ2 test	OR	RR
	n = 175	%	n = 1634	%	P value
Thyroid gland surgery	7	4.0	33	2.0	0.0852	2.021	0.505
Hypothyroidism	17	9.7	66	4.0	0.0021	2.556	0.416
Hyperthyroidism	1	0.6	24	1.5	0.287	-	-
Levothyroxine use	30	17.1	106	6.5	< 0.0011	2.982	0.378
Adipositas	31	17.7	307	18.8	0.410	-	-
Diabetes mellitus	25	14.3	132	8.1	0.0061	1.896	0.565
Steatosis hepatis	22	12.6	158	9.7	0.139	-	-
Hepatitis	7	4.0	61	3.7	0.492	-	-
Liver cirrhosis	2	1.1	35	2.1	0.289	-	-
Renal insufficiency	2	1.1	16	1.0	0.532	-	-
Colonic diverticulosis	6	3.4	37	2.3	0.229	-	-
Sigmoid diverticulosis	8	4.6	151	9.2	0.0201	0.470	2.021
Crohn’s disease	19	10.9	134	8.2	0.146	1.363	0.755
Ulcerative colitis	2	1.1	52	3.2	0.0922	0.352	2.785
Alcoholism	3	1.7	36	2.2	0.468	-	-
Smokers	10	5.7	52	3.2	0.0702	1.844	0.557
NSAID use	29	16.6	284	17.4	0.442	-	-
Laxative use	3	1.7	58	3.5	0.142	-	-
Antidiarrhoics use	9	5.1	118	7.2	0.195	-	-
Spasmolytics use	9	5.1	257	15.7	< 0.0011	0.290	3.058
Antiemetics use	22	12.6	144	8.8	0.0712	1.488	0.701
Irritable bowel syndrome	8	4.6	322	19.7	< 0.0011	0.195	4.311

¹Statistical significant with P-value P < 0.05;

²Statistical tendency with P-value 0.05 < P < 0.1 χ² test each. Patients with hypothyroidism and substitution of levothyroxine show a higher risk of SIBO. In the case of thyroidectomy, statistical significance was not achieved. The presence of diverticulosis of the sigmoid, but not of the entire colon was associated with a decreased risk of SIBO. Patients with Crohn’s disease did not exhibit a higher prevalence of SIBO, and ulcerative colitis tended to be protective, but did not reach statistical significance. Patents without SIBO were more likely to use spasmolytics and to suffer from irritable bowel syndrome. SIBO: Small intestinal bacterial overgrowth; NSAID: Non-steroidal anti-inflammatory drugs.

Table 6 Multivariate analysis

Equation variables	Regression coefficient B	Wald	Significance	Exp (B)	95%CI for Exp (B)
					Lower limit	Upper limit
PPI therapy	0.241	2.015	0.156	1.273	0.912	1.776
Gastrectomy	0.600	0.676	0.411	1.821	0.436	7.604
Any resecting gastric surgery	0.875	4.369	0.037	2.399	1.056	5.450
Stenoses	1.033	7.011	0.008	2.809	1.308	6.033
Gastroparesis	1.016	3.244	0.072	2.762	0.914	8.345
Any colon resection	0.479	3.012	0.083	1.614	0.940	2.772
Any medical immunosuppression	0.428	4.380	0.036	1.534	1.028	2.291
Levothyroxine therapy	1.070	20.980	0.000	2.916	1.845	4.609
Diabetes mellitus	-0.453	3.223	0.073	0.636	0.388	1.042
Sigmoid diverticulosis	0.832	4.835	0.028	2.298	1.095	4.823

Binary logistic regression analysis for risk factors for SIBO. All parameters found to be significant in previous analyses were used for analysis with binary logistic regression. A history of gastric surgery, stenoses, medical immunosuppression, levothyroxine therapy and sigmoid diverticulosis showed statistical significance as contributors to SIBO. SIBO: Small intestinal bacterial overgrowth; Exp: Exponent.

Table 7 Binary logistic regression for categorised variables

Equation variables	Regression coefficient B	Wald	Significance	Exp (B)	95%CI for Exp (B)
					Lower limit	Upper limit
Impaired acid barrier	0.277	2.780	0.095	1.319	0.953	1.827
Impaired clearance	0.772	14.463	0.0001	2.164	1.454	3.221
Impaired immune response	0.453	5.161	0.0231	1.572	1.064	2.324
Hypothyroidism	1.083	22.514	0.0001	2.953	1.888	4.620

¹Statistically significant with P value < 0.05 in binary logistic regression. Regression analysis for categorised variables: CI: Confidence Interval. Exp (B): Exponent B. A simplified model, which included a leading factor of each pathophysiological pathway, revealed that, in ascending order, impaired immune response, impaired intestinal clearance and hypothyroidism are the key pathways for the development of small intestinal bacterial overgrowth.