H Pylori infection increases diabetes risk

 A recent study reaffirmed a relationship between H Pylori infection in the development of Type II diabetes (see H pylori and development of diabetes BMCendo2024 in dropbox, or https://doi.org/10.1186/s12902-024-01694-2)

 

Details:

-- 4406 participants attending their annual health checkups at a single Chinese hospital were included in this study to assess the correlation between the incidence of Type II diabetes and H. pylori infection.

    -- 2053 participants were H. pylori positive as detected by breath test, 2353 were H. pylori negative

-- Mean age 48, 37% female

-- BMI 24, fasting blood glucose 95 mg/dL, total cholesterol 174/HDL 52/LDL 108 mg/dL

-- exclusion criteria included patients with severe hepatic, renal, cardiovascular or cerebrovascular diseases; those with malignant tumors or autoimmune diseases; and those with other endocrine disorders

 

-- main outcomes: assess the correlation between the incidence of Type II diabetes and H Pylori infection;  assess the potential mechanisms that might explain a relationship by evaluating differentially expressed genes common to both conditions

 

Results:

-- risk of diabetes, comparing H. pylori positive to H. pylori negative: 59% higher, HR 1.59 (1.17-2.15), p=0.003 in multivariate analysis, adjusting for age, gender, BMI, fasting blood glucose, and triglyceride/total cholesterol/HDL/and LDL

-- average diabetes-free survival time:

    -- H. pylori positive: 34.81 months (34.60-35.03)

    -- H. pylori negative: 35.42 months (35.28-35.56)

        -- a small but statistically significant difference

 

-- Another aspect of the study was to perform bioinformatic analysis to look for genetic overlap between H. pylori and type II diabetes:

    -- they identified common DEGs (differentially expressed genes) in diabetes and H. pylori infection in the GEO (Gene Expression Omnibus) database, in order to identify genes shared by both diseases and their functions.

        -- Diabetes: there were 648 DEGs identified, half were up-regulated and half down-regulated

        -- H. pylori: there were 234 DEGs identified, two thirds of which were up-regulated, one third down-regulated

              -- the overlap for both diseases included 21 common DEGs: "these common genes were primarily involved in chemotaxis, chemokine-mediated signaling pathway, neutrophil chemotaxis, inflammatory response, signal transduction, immune response, killing of cells of other organism, antimicrobial humoral immune response mediated by antimicrobial peptide, and negative regulation of cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. In cellular component, these common genes were mostly enriched in the extracellular region, extracellular space, tertiary granule lumen, specific granule lumen, cell surface, and external side of plasma membrane. In molecular function, these common genes were mainly involved in chemokine activity"

            -- "KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that these common DEGs were involved in viral protein interaction with cytokine and cytokine receptor, IL-17 signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, rheumatoid arthritis, TNF signaling pathway, and lipid and atherosclerosis signaling pathways. The protein-protein interaction network revealed extensive interactions among the proteins encoded by the 21 DEGs. These results suggested that inflammatory response and metabolism played a crucial role in the progression of T2DM and H. pylori infection." [see below for more interpretation of these genetic findings]

 

Commentary:

-- as mentioned in the multitude of prior H. pylori blogs, H. pylori is the most prevalent bacterial infection in the world, with estimates of 50% of the global population being affected (and, as we know, diabetes is rather prevalent...)

   -- the percentage of H. pylori infections does vary dramatically from one region of the world to another

   -- however, studies in the United States suggest that 30 to 40% of the US population may well be infected: https://gmodestmedblogs.blogspot.com/2023/06/h-pylori-common-in-us-veterans.html , a blog which refers to several studies in the US, the high rate of gastric cancer associated with H. pylori infection, eradication of zH. pylori infection even in those asymptomatic is associated with decreased gastric cancer risk, and the NIH now considers H. pylori to be a carcinogen

  -- several other medical conditions may well be related to H. pylori infection:

    -- immune thrombocytopenic purpura (ITP): many examples of an association with H. pylori in the literature, and with a suggestion to check for H. pylori in those with ITP in the hematologic literature over the past 10+ years (indeed, I had a case 35 years ago of a person who never traveled abroad, developed steroid-resistant ITP and was about to have a splenectomy, but who was tested  and found to be H. pylori positive, was treated, and the ITP vanished within one to two weeks.)

    -- dermatologic manifestations, including chronic pruritus. Again, I had a case of a patient with chronic pruritus for many years that resolved with H. pylori identification and treatment. for more info on the many different dermatologic associations with H pylori, see hpylori and skin disease amjclinderm2002 in the dropbox or Wedi B and Kapp A. Am J  Clin Dermatol 2002; 3(4);2373-282) and see hpylori chronic urticaria jallergclinimmunol2013 in dropbox, or hpylori urticaria page 1165 jamaderm1998 in dropbox, or Ozkaya-Bayazit. Arch Dermatol 1998; 134: 1165-6 for chronic urticaria resolving with treatment.

    -- difficult-to-treat hypothyroidism, likely because of H. pylori-associated gastritis and decreased levothyroxine absorption(see h pylori hypothyroid inadeq resp Helicobacter2011 in dropbox, or Bugdaci MS et al. Helicobacter 2011; 16: 124-130). this study also found that TSH decreased after H Pylori eradication, and provides the warning that patients with H pylori on levothyroxine who have appropriate TSH levels may in fact become hyperthyroid if they have H pylori and it is treated

 

-- And, related to this current article, several studies (but not all) have found H. pylori infection to be associated with type II diabetes:

    -- H pylori significantly affects glucose metabolism and immune function in patients with type II diabetes, with altered glucose metabolism, impaired immune responses, and increased susceptibility to infection

    -- H. pylori is also associated with chronic inflammation and insulin resistance in other studies, likely related to the development of type II diabetes

    -- in addition, H. pylori infection may lead to more GI adverse effects from metformin (and we should check for H Pylori infection in patients intolerant of metformin)

    -- for more information on H pylori from the many prior blogs, please go to https://gmodestmedblogs.blogspot.com/ and search for “H pylori”

 

so, this current paper adds to the medical literature both by finding a significant relationship between H. pylori infection and type II diabetes, and by also providing a genetic analysis that provides biological plausibility by confirming that both illnesses are associated with several inflammation-related intermediaries (cytokines etc), with potential genetic effects of H. pylori leading to type II diabetes as well as type II diabetes leading to more H. pylori infection:

    -- H. pylori leads to the secretion of several interleukins (including IL-1, IL-6, IL-8, IL-17, IL-18, IL21, and IL22), TGF-b, TNF-a, and IFN-g) leading to an inflammatory state (and there seems to be a connection between inflammation and the development  of diabetes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523054/); H. pylori causes DNA damage, and there are studies suggesting this plays a role in type II diabetes; H. pylori infection is associated with gastric neuroendocrine cells secreting gastrin, leptin, and somatostatin which affect the host’s metabolic state; and H. pylori can cause abnormalities in glucose metabolism and insulin tolerance through signaling pathways (e.g. NF-kB, c-Jun/miR-203/SOCS3) also leading to a higher likelihood of diabetes

    -- type II diabetes seems to increase susceptibility to H. pylori infection: it causes gastrointestinal motility disorders, it decreases gastric acid secretion, and micro-angiography that might facilitate H. pylori colonization; it impairs immune cell function due to abnormal glucose metabolism, potentially facilitating H. pylori infection; and it alters chemical production in the gastric mucosa, and promoting bacterial colonization

        -- from their article, the overlap for both diseases included 21 common DEGs: in these 21 DEGs, “the main pathways involved are viral protein interaction with cytokine and cytokine receptor, IL-17 signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, rheumatoid arthritis, TNF signaling pathway, lipid and atherosclerosis signaling pathway” and “elevated levels of IL-17 have been implicated in the chronic inflammation observed in both H. pylori infection and type II diabetes. Additionally, the TNF signaling pathway is another critical pathway where TNF-a, a pro-inflammatory cytokine induced by H. pylori infection, is known to interfere with insulin signaling, potentially leading to insulin resistance and type II diabetes 

 

Limitations:

-- this was a study of 4000 participants from a particular area in China going to a single hospital for their annual checkups, limiting generalizability of results to more diverse communities throughout the world. And there may well have been a selection bias as to which individuals participated in having an annual checkup as well as then volunteering to be involved in the study

-- there is limited granular information about the patients involved in the study, including no information on family histories, personal medical histories, diet and exercise, smoking and alcohol history, medications taken.... And there is no information about other pro-inflammatory states that might have played a part in the H. pylori/diabetes interface, including many rheumatologic diseases, hyperuricemia, depression, stress, microplastic and pollution exposures, etc., etc.

 

So, this study adds to the panoply of reasons that we should be testing for and treating H. pylori infections on a routine basis:

-- there are a huge array of conditions associated with H. pylori infection, some clearly related to the infected stomach (peptic ulcer disease, gastritis, GERD in some cases) as well as some gastric cancers (adenocarcinomas as well as MALT lymphomas) and changes in medication absorption (eg thyroid hormone replacement) and exacerbation of medication intolerance (eg metformin)

    -- many of these occur at a higher incidence in those with asymptomatic H. pylori infections as well

    -- and treatment of both asymptomatic and symptomatic H. pylori infections decreases the incidence of gastric cancers, even in the elderly who have likely had H. pylori infection for a very long time

-- also, as noted above, there seem to be several conditions beyond the stomach associated with H. pylori infection including ITP, chronic urticaria, several other dermatologic manifestations, diabetes, and even the suggestion in the literature that early-onset cancers, which are becoming more common recently, may also be in part related to H. pylori infection (the VacA variant of H pylori, for example, is associated with colon cancer)

-- though H. pylori prevalence does vary from country to country, it is clear from several studies that the rate of the US is not insignificant, in the 30 to 40% range, and studies in the US have found that treating even asymptomatic infections does decrease the risk of gastric cancer

-- so, to me, the bottom line is that there is increasing evidence we should be diagnosing H. pylori routinely, usually a one-time test, in pretty much all patients, typically through either the stool antigen test or breath test, and treating it if present. I also believe we should be doing repeat test-of-cures to assure eradication of the bug, since none of the treatment regimens are 100% effective

 

geoff

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