Type 1 diabetes mellitus (T1DM) is a chronic autoimmune illness characterized by hyperglycemia caused by insulin deficiency due to the secondary loss of the pancreatic islet β­cells (1). T1DM, the most prevalent autoimmune disorder in children and teenagers, currently affects more than 500,000 children globally (2). Long-term hyperglycemia can destroy microvascular and macrovascular systems. Therefore, patients with T1DM may develop multiple organ or tissue diseases, such as cardiovascular disease, cerebrovascular disease, peripheral artery disease, sudden cardiac death, and cognitive dysfunction (2).

Infectious diseases are experienced several times in almost every human. Many people may experience sepsis, a high-mortality syndrome that develops with infection (3). Acute lower respiratory infection (ALRI) was the most common cause of death in children in 2019 and accounted for the deaths of 700,000 children (4). Urinary tract infection (UTI) is a common infectious disease in adults, with more than half of all women experiencing at least one UTI in their life; moreover, UTIs are associated with significantly increased mortality in elderly people (5). Infection of the genitourinary tract (GUTI) is the most common bacterial infection in pregnancy, and GUTIs may cause preterm birth (6). Infection of the skin and subcutaneous tissues (SSTI) is another common infectious disease that can progress to a life-threatening infection (7). A recent nationwide study in the United States found that intestinal infection (II) was one of the most common infectious diseases experienced by patients in hospital (8).

Infectious diseases cause a significant burden on families and society. Recently, there has been much debate regarding whether T1DM increases the risk of infections. Some studies have found that patients with diabetes mellitus may be more susceptible to infectious diseases (9–11). However, Liberatore et al. argued that there was no strong relationship between T1DM and the occurrence of infections (12), and other studies revealed that the relationship between T1DM and infections is bidirectional (13). Remarkably, these studies had small sample sizes and possible confounding variables. Some recent meta-analyses found a significant positive relationship between T1DM and different infectious diseases (14–16); however, most of the studies pooled in meta-analyses were case-control studies and case series, which cannot negate the possibility of reverse causality. Therefore, we cannot distinguish which is the cause and which is the effect in the relationship between T1DM and infectious diseases through meta-analyses. A recent review argued that patients with poorly controlled diabetes were immunocompromised and hence were at increased risk of experiencing infectious diseases and their complications (17).

Confirming a causal relationship between T1DM and infectious diseases is challenging due to the possibility of reverse causality and confounders (18). Therefore, randomized controlled trials (RCTs) are considered the gold standard for exploring exposure-outcome causality; however, conducting rigorous RCTs is challenging because of the restriction of the medical ethics committees and selection of participants, and the extrapolation of results is limited because of the strict requirements of population selection (19).

The Mendelian randomization (MR) method was used to infer causal associations between exposures and outcomes using single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) (20). Variants were randomly allocated from parents to offspring at conception. Therefore, the MR method was not susceptible to confounding or reverse causation, similar to the random assignment in RCTs (20). In this study, a two-sample MR was performed to investigate the causality of T1DM with high-frequency infections.

After the initial screening, 44 SNPs were obtained as IVs. Extensive information on 44 SNPs is presented in Supplementary Table 2 . Five SNPs (rs9273363, rs1131017, rs6679677, rs10830227, and rs2111485), which may be associated with confounders, were deleted using the PhenoScanner tool (http://www.phenoscanner.medschl.cam.ac.uk/), and no SNP traits were associated with sepsis, ALRIs, IIs, GUTIs in pregnancy, SSTIs, and UTIs ( Table 2 ). Finally, we obtained 39 SNPs as IVs of T1DM.

Based on the first MR study, we investigated the causality of T1DM in six high-frequency infections. There were two main results of the present MR study. First, the risk of IIs increased by 6.09% (OR=1.0609; 95% CI: 1.0281–1.0947, p=0.0002) in patients with T1DM even when a significant threshold was set at 0.008 (corrected by the Bonferroni method). The result was confirmed by sensitivity analyses. In the MVMR analyses, after adjusting for BMI and HbA1c, the causality of T1DM on IIs was still significant (MVMR-IVW, OR=1.0942; 95% CI, 1.0666–1.1224; p<0.0001); these results were consistent with those of the LASSO regression and MVMR-Robust. Second, T1DM may not be responsible for some infections, such as sepsis, ALRIs, GUTIs in pregnancy, SSTIs, and UTIs.

The findings of the present MR study did not support the findings of some observational studies that suggested that patients with T1DM had an increased risk of contracting some infections (41–43). A prospective cohort study reported that patients with T1DM were at a highly increased risk of lower respiratory tract, urinary tract, and skin infection (42). Another retrospective study that adjusted for age and sex also found that patients with T1DM were more susceptible to infection with the SARS-CoV-2 virus (43). Hence, our findings are consistent with those of many previous observational studies (12, 44, 45). One case-control study concluded that patients with T1DM were not susceptible to infections by comparing the plasma levels of immunoglobulins and complement proteins in patients with T1DM and controls (12). A survey with 10 years of follow-up stated that sexual activity rather than the T1DM was linked to an increased risk of UTIs in women (44). Czaja et al. believed that patients with T1DM may have an increased risk of asymptomatic bacteriuria (ASB). Nevertheless, due to impaired immunity caused by T1DM, ASB would not progress to a symptomatic infectious disease (44). Another prospective study showed that the risk of sepsis increased when T1DM was complicated with hind foot ulceration (45). Recently, a meta-analysis discovered that diabetes mellitus did not affect sepsis prognosis, although high blood glucose levels did (46).

T1DM and infections have been linked bidirectionally. As mentioned above, some studies argued that T1DM increased the occurrence of infections, whereas many other studies found that infections also have a marked influence on the onset of T1DM. For example, a study based on a population-based registry in Abruzzo (central Italy) found that multiple bacterial infections before diabetes mellitus could significantly delay the onset of T1DM (47). A review summarized that enterovirus infections, such as coxsackievirus B4, accelerated or promoted the initiation of T1DM (48). Another review also suggested that gut dysbiosis might be associated with the onset of T1DM, and different intestinal bacteria play different roles (49).

T1DM is a chronic disease, and patients with this disease may experience complications, long-term abnormal blood sugar levels, unhealthy diet habits, and different environments; hence, it is challenging for observational studies to adjust for all confounders (2). Therefore, residual confounding or reverse causation bias in observational research may explain our disagreement. The present study used an MR design to confirm the causality pathway from T1DM to six high-frequency infections. As no heterogeneity was observed in the MR analysis of T1DM on IIs, sepsis, ALRIs, GUTIs in pregnancy, and UTIs, we selected the IVW-fixed analysis results as our primary results. As significant heterogeneity was observed in the MR analysis of T1DM on SSTIs, we selected the IVW-random analysis result as the primary result. We also conducted different MR methods as complementary and sensitivity analyses to confirm our results. Moreover, to strictly meet the criteria of an “IVs not linked to confounding factors” and “IVs influence outcomes only through T1DM,” we deleted all SNPs potentially associated with confounders and outcomes according to the trait in PhenoScanner V2.

Approximately 451 million people have diabetes mellitus globally, approximately 5 million deaths were attributed to diabetes mellitus (DM) in 2017, and the number of people with DM may increase to 693 million by 2045 (50). Recently, Wang et al. conducted an MR to explore the causal relationship between T2DM and five high-frequency infectious diseases, including UTIs in pregnancy, ALRIs, sepsis, and SSTIs. They stated that no causal relationships existed (51). The present MR study complemented and extended the abovementioned study by Wang et al. In this study, we not only confirmed that T1DM has no causality with those five high-frequency infectious diseases but also found that T1DM increased the occurrence of IIs due to genetic liability.

Early in 2007, Oikarinen et al. examined enteroviruses in small intestinal tissue of T1DM and suggested that most had a persistent enterovirus infection of the intestinal mucosa (52). A later case-control study confirmed that enterovirus RNA was found more frequently in patients with T1DM than in controls, and the enterovirus was considered to be associated with IIs (53).

The potential mechanism between T1DM and IIs may be explained by the following three pathways. First, many studies have reported dysbiosis of the intestinal microbiomes in patients with T1DM, which would promote inflammation in the gut (49, 54). Second, a review article suggested that a genetically deficient macrophage migration inhibitory factor, one of the mechanisms for the occurrence of T1DM, would induce the Th1 inflammatory cytokines and reduce regulatory T cells (Treg), thereby finally causing colitis (55). Third, celiac disease primarily affects the small intestine, causes weight loss, anemia, and intestinal mucosal damage, and has been found to be associated with T1DM (56, 57). Both celiac disease and T1DM are linked to high-risk human lymphocyte antigens (HLAs) (58). HLAs present antigens to antigen-responsive T cells, resulting in the destruction of the intestinal enterocyte (58).

Based on our positive findings, we provide some prevention strategies for infections in T1DM. First, hand hygiene: good hand hygiene is the most important step in preventing infections. Second, food hygiene: individuals with T1DM should ensure that their food is clean and thoroughly cooked. Third, immunization: individuals with T1DM should receive all recommended vaccinations, especially some vaccines to prevent intestinal infections, such as the rotavirus vaccine, enterohemorrhagic E. coli vaccine, and salmonella vaccine (59). Fourth, blood sugar control: individuals with T1DM should aim to maintain good glycemic control to reduce the risk of infections. Fifth, probiotics are live microorganisms that can help to promote a healthy gut microbiome and prevent intestinal infections. T1DM can take probiotic supplements. Sixth, follow a strict gluten-free diet when T1DM is complicated with celiac disease (60).

The MR study design, which reduces confounders and reverse causality which may influence the findings of epidemiological studies, is a key strength of this work. Additionally, we systematically explored the causalities between T1DM and six common infections. For all the selected IVs, F-statistics were more than 10. Furthermore, no pleiotropy was detected, confirming our results’ accuracy. After a causal association between T1DM and IIs was detected, we performed three different MVMR analyses (MVMR-IVW, LASSO, and MVMR-Robust) to assess the validity of the results by adjusting for BMI and HbA1c. LASSO and MVMR-Robust provided a reliable estimation even with high pleiotropy, and no heterogeneity was observed; the results obtained using the three methods were consistent, demonstrating their credibility. The datasets of exposure and outcomes were mainly composed of European populations; consequently, these findings were less likely to be influenced by population stratification, although it limits the applicability to other ethnic groups. Moreover, we presented a checklist based on the previous work by Woolf et al. (61) to improve our reporting quality, and most of the list items were attained. Since we could not obtain detailed information from the original research, it was challenging to evaluate the quality of the data sources ( Supplementary Table 9 ). We only chose recent datasets provided by widely recognized consortiums to address this limitation. Furthermore, we cannot exclude the possibility that other potential confounders may have influenced our results. We excluded all SNPs associated with more than ten potential confounders possibly associated with the outcomes and performed three MVMR methods adjusting for BMI and HbA1c. However, we cannot rule out all the direct pathways between T1DM and IIs, as pleiotropy could not be controlled entirely. Since some previous studies showed some infectious diseases might cause T1DM, a bidirectional MR analysis should be performed to explore the association of infectious diseases with T1DM. However, none of the six infectious diseases GWAS datasets could supply sufficient SNPs (clumped at p< 5 × 10⁻⁸, kb=10,000, and r²<0.001) to perform MR and sensitivity analyses. Therefore, this was one limitation we could not improve and should be performed in future studies.

In conclusion, our study found no convincing evidence of a causal link between T1DM and sepsis, ALRIs, GUTIs in pregnancy, SSTIs, or UTIs in the European population. However, there was a genetic liability in T1DM for increased risk of contracting IIs. Larger epidemiological studies or metagenomic studies are needed to better understand the observed association between susceptibility of certain infectious diseases in patients with T1DM.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The datasets [T1DM, sepsis, ALRIs, GUTI susceptibility in pregnancy, SSTIs, UTIs, IIs] for this study can be found in the GWAS summary data [https://gwas.mrcieu.ac.uk/].

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

TX, HW, and X-HC contributed to the conception and design of the study. H-QL and QN organized the database. X-HC and QN performed the statistical analyses. X-HC and H-QL wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.