Johne's disease in sheep can cause subtle pathological changes in tissues and equally subtle signs of disease.

In early phases of M. paratuberculosis infection, no lesions may be detectable and the sheep appears healthy. In more advanced stages of Johne's disease lesions can be found, primarily in the gastrointestinal tract. The small intestine may be thickened and corrugated and the neighboring lymph nodes are enlarged. Infected sheep may lose weight at this point. Some cases of infection never develop visible lesions. Diarrhea is not a common clinical sign of Johne's disease in sheep.

There is a range of pathology that can be seen in infected sheep. Grossly (when the gastrointestinal tract is examined at necropsy), there can be a complete lack of lesions - the intestine may appear entirely normal. In cases at the other extreme, it appears thickened and corrugated and the neighboring lymph nodes are enlarged and edematous. This thickening and enlargement is due to the influx of inflammatory cells to the infected region. These animals are often emaciated with a total absence of abdominal fat stores. There are cases with lesions that fall between these two extremes.

When the tissues are examined microscopically, again the animal may present one of a number of pathologic pictures for both clinically and sub-clinically affected sheep. The tissues may appear normal in virtually every site. In another case florid signs of infection such as numerous macrophages and giant cells packed with acid-fast rods may be present. Other cases may fall between these two extremes. The likely sites of infection are the terminal ileum and mesenteric lymph nodes although neighboring portions of the gastrointestinal tract (colon, jejunum) are frequently affected as well.